Cancers

20 pages, 2716 KiB

Open AccessEditor’s ChoiceArticle

Machine Learning and Computed Tomography Radiomics to Predict Disease Progression to Upfront Pembrolizumab Monotherapy in Advanced Non-Small-Cell Lung Cancer: A Pilot Study

by Ian Janzen, Cheryl Ho, Barbara Melosky, Qian Ye, Jessica Li, Gang Wang, Stephen Lam, Calum MacAulay and Ren Yuan

Cancers 2025, 17(1), 58; https://doi.org/10.3390/cancers17010058 - 28 Dec 2024

Cited by 1 | Viewed by 1275

Abstract

Background/Objectives: Pembrolizumab monotherapy is approved in Canada for first-line treatment of advanced NSCLC with PD-L1 ≥ 50% and no EGFR/ALK aberrations. However, approximately 55% of these patients do not respond to pembrolizumab, underscoring the need for the early intervention of non-responders to optimize [...] Read more.

Background/Objectives: Pembrolizumab monotherapy is approved in Canada for first-line treatment of advanced NSCLC with PD-L1 ≥ 50% and no EGFR/ALK aberrations. However, approximately 55% of these patients do not respond to pembrolizumab, underscoring the need for the early intervention of non-responders to optimize treatment strategies. Distinguishing the 55% sub-cohort prior to treatment is a real-world dilemma. Methods: In this retrospective study, we analyzed two patient cohorts treated with pembrolizumab monotherapy (training set: n = 97; test set: n = 17). The treatment response was assessed using baseline and follow-up CT scans via RECIST 1.1 criteria. Results: A logistic regression model, incorporating pre-treatment CT radiomic features of lung tumors and clinical variables, achieved high predictive accuracy (AUC: 0.85 in training; 0.81 in testing, 95% CI: 0.63–0.99). Notably, radiomic features from the peritumoral region were found to be independent predictors, complementing the standard CT evaluations and other clinical characteristics. Conclusions: This pragmatic model offers a valuable tool to guide first-line treatment decisions in NSCLC patients with high PD-L1 expression and has the potential to advance personalized oncology and improve timely disease management. Full article

(This article belongs to the Special Issue Advances in Oncological Imaging)

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24 pages, 4058 KiB

Open AccessEditor’s ChoiceReview

Targeting of Non-Classical Human Leukocyte Antigens as Novel Therapeutic Strategies in Cancer

by Javier David Benitez Fuentes, Jorge Bartolome Arcilla, Kauzar Mohamed Mohamed, Alfonso Lopez de Sa, Alicia de Luna Aguilar, Kissy Guevara-Hoyer, Pablo Ballestin Martinez, Antonio David Lazaro Sanchez, Edgardo D. Carosella, Alberto Ocaña and Silvia Sánchez-Ramon

Cancers 2024, 16(24), 4266; https://doi.org/10.3390/cancers16244266 - 22 Dec 2024

Cited by 2 | Viewed by 1579

Abstract

Human leukocyte antigens (HLAs) are essential regulators of immune responses against cancer, with classical HLAs well-documented for their role in tumor recognition and immune surveillance. In recent years, non-classical HLAs—including HLA-E, HLA-F, HLA-G, and HLA-H—have emerged as critical players in the immune landscape [...] Read more.

Human leukocyte antigens (HLAs) are essential regulators of immune responses against cancer, with classical HLAs well-documented for their role in tumor recognition and immune surveillance. In recent years, non-classical HLAs—including HLA-E, HLA-F, HLA-G, and HLA-H—have emerged as critical players in the immune landscape of cancer due to their diverse and less conventional functions in immune modulation. These molecules exhibit unique mechanisms that enable tumors to escape immune detection, promote tumor progression, and contribute to therapeutic resistance. This review provides a comprehensive examination of the current understanding of non-classical HLAs in solid cancers, focusing on their specific roles in shaping the tumor microenvironment and influencing immune responses. By analyzing how HLA-E, HLA-F, HLA-G, and HLA-H modulate interactions with immune cells, such as T cells, natural killer cells, and antigen-presenting cells, we highlight key pathways through which these molecules contribute to immune evasion and metastasis. Additionally, we review promising therapeutic strategies aimed at targeting non-classical HLAs, including emerging immunotherapies that could potentially enhance cancer treatment outcomes by reversing immune suppression within tumors. Understanding the influence of these non-classical HLAs in solid cancers may offer new insights into cancer immunology and may lead to the development of innovative and more effective immunotherapeutic approaches. This review underscores the importance of non-classical HLAs as potential therapeutic targets, providing a necessary foundation for future studies in the evolving field of cancer immunotherapy. Full article

(This article belongs to the Special Issue Identification and Clinical Application of Immunological Receptors Targeting Mutated Antigens Expressed by Solid Tumors (2nd Edition))

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20 pages, 1081 KiB

Open AccessEditor’s ChoiceReview

Implication of the Extracellular Matrix in Metastatic Tumor Cell Dormancy

by Chloe Redoute-Timonnier and Patrick Auguste

Cancers 2024, 16(23), 4076; https://doi.org/10.3390/cancers16234076 - 5 Dec 2024

Cited by 1 | Viewed by 1132

Abstract

Metastasis is the main cause of cancer-related deaths. The formation and growth of metastasis is a multistep process. Tumor cells extravasating in the secondary organ are in contact with a new microenvironment and a new extracellular matrix (ECM), called the metastatic niche. Some [...] Read more.

Metastasis is the main cause of cancer-related deaths. The formation and growth of metastasis is a multistep process. Tumor cells extravasating in the secondary organ are in contact with a new microenvironment and a new extracellular matrix (ECM), called the metastatic niche. Some components of the ECM, such as periostin, can induce tumor cell growth in macrometastasis. In contrast, other components, such as Thrombospondin 1 (TSP-1), can maintain isolated cells in a dormant state. During dormancy, intracellular signaling activation, such as p38, maintains tumor cells arrested in the cell-cycle G0 phase for years. At any moment, stress can induce ECM modifications and binding to their specific receptors (mainly integrins) and reactivate dormant tumor cell growth in macrometastasis. In this review, we describe the tumor microenvironment of the different niches implicated in tumor cell dormancy. The role of ECM components and their associated receptors and intracellular signaling in the reactivation of dormant tumor cells in macrometastasis will be emphasized. We also present the different methodologies and experimental approaches used to study tumor cell dormancy. Finally, we discuss the current and future treatment strategies to avoid late metastasis relapse in patients. Full article

(This article belongs to the Special Issue Extracellular Matrix Proteins in Cancer)

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17 pages, 2527 KiB

Open AccessEditor’s ChoiceReview

Tracing Quiescent Cancer Cells In Vivo

by Moon Jong Kim

Cancers 2024, 16(22), 3822; https://doi.org/10.3390/cancers16223822 - 14 Nov 2024

Cited by 2 | Viewed by 1517

Abstract

QCCs have long gained significant interest as potential “seeds” for recurrent cancers. Clinical evidence suggests that a subset of cancer cells exits the cell cycle and enters a quiescent state following anti-cancer treatment. These microscopic-residual QCCs are extremely challenging to trace and detect [...] Read more.

QCCs have long gained significant interest as potential “seeds” for recurrent cancers. Clinical evidence suggests that a subset of cancer cells exits the cell cycle and enters a quiescent state following anti-cancer treatment. These microscopic-residual QCCs are extremely challenging to trace and detect within patients. Additionally, QCCs resist conventional anti-cancer therapies due to the lack of cell activity. Notably, upon the unknown environmental cues in unknown time points, sometimes decades later, QCCs can reactivate, triggering cancer relapse at primary or secondary sites. Currently, no targeted therapies or diagnostic tools exist for QCCs, and their molecular regulatory mechanisms remain largely unknown. The major challenge in understanding QCCs lies in the limited availability of human-relevant pre-clinical models that trace and collect QCCs in vivo. This review provides an overview of existing QCC tracing systems and analyzes their limitations. It also cautiously proposes potential improvements for tracing QCCs in vivo based on recent advancements in QCC studies and lineage-tracing techniques. Developing human-relevant and easily accessible in vivo tracing systems will be a crucial step in advancing QCC diagnostics and therapeutic strategies. Full article

(This article belongs to the Special Issue Cancer Cells Fostered Microenvironment in Metastasis)

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15 pages, 1325 KiB

Open AccessEditor’s ChoiceReview

Unlocking Intracellular Oncology Targets: The Unique Role of Antibody-Based T-Cell Receptor Mimic (TCRm) Therapeutics in T-Cell Engagers (TCEs) and Antibody-Drug Conjugates (ADCs)

by Jeffrey Molldrem and Dongxing Zha

Cancers 2024, 16(22), 3776; https://doi.org/10.3390/cancers16223776 - 8 Nov 2024

Cited by 1 | Viewed by 3235

Abstract

Effectively targeting intracellular tumor-associated proteins presents a formidable challenge in oncology, as they are traditionally considered inaccessible to conventional antibody-based therapies and CAR-T cell therapies. However, recent advancements in antibody engineering have revolutionized this field, offering promising new strategies to combat cancer. This [...] Read more.

Effectively targeting intracellular tumor-associated proteins presents a formidable challenge in oncology, as they are traditionally considered inaccessible to conventional antibody-based therapies and CAR-T cell therapies. However, recent advancements in antibody engineering have revolutionized this field, offering promising new strategies to combat cancer. This review focuses on the innovative use of T-cell receptor mimic (TCRm) antibodies within the therapeutic frameworks of T-cell engagers (TCE) and antibody-drug conjugates (ADCs). TCRm antibodies, designed to recognize peptide-MHC complexes rather than cell surface proteins, integrate the capacity of T-cells to reach intracellular targets with the unique strengths of antibodies. When incorporated into T-cell engaging therapeutics, TCRms redirect T cells to cancer cells, facilitating direct cytotoxicity. In ADCs, TCRm antibodies deliver cytotoxic agents with highly specific targeting to cancer cells, sparing healthy tissues. Together, these antibody-based strategies represent a significant leap forward in oncology, opening new avenues for the treatment of cancers previously deemed untreatable, with other potential applications in autoimmune diseases. This review discusses the mechanisms, clinical advancements, and future prospects of these cutting-edge therapies, highlighting their potential to transform the landscape of cancer treatment. Full article

(This article belongs to the Collection The Development of Anti-cancer Agents)

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17 pages, 9029 KiB

Open AccessEditor’s ChoiceArticle

Genome-Wide CRISPR Screen Identifies Genes Involved in Metastasis of Pancreatic Ductal Adenocarcinoma

by Risky Oktriani, Anna Chiara Pirona, Lili Kalmár, Ariani S. Rahadian, Beiping Miao, Andrea S. Bauer, Jörg D. Hoheisel, Michael Boettcher and Haoqi Du

Cancers 2024, 16(21), 3684; https://doi.org/10.3390/cancers16213684 - 31 Oct 2024

Cited by 1 | Viewed by 1582

Abstract

Background/Objectives: Early and aggressive metastasis is a major feature of pancreatic ductal adenocarcinoma. Understanding the processes underlying metastasis is crucial for making a difference to disease outcome. Towards these ends, we looked in a comprehensive manner for genes that are metastasis-specific. Methods [...] Read more.

Background/Objectives: Early and aggressive metastasis is a major feature of pancreatic ductal adenocarcinoma. Understanding the processes underlying metastasis is crucial for making a difference to disease outcome. Towards these ends, we looked in a comprehensive manner for genes that are metastasis-specific. Methods: A genome-wide CRISPR-Cas9 gene knockout screen with 259,900 single guide RNA constructs was performed on pancreatic cancer cell lines with very high or very low metastatic capacity, respectively. Functional aspects of some of the identified genes were analysed in vitro. The injection of tumour cells with or without a gene knockout into mice was used to confirm the effect on metastasis. Results: The knockout of 590 genes—and, with higher analysis stringency, 67 genes—affected the viability of metastatic cells substantially, while these genes were not vital to non-metastasizing cells. Further evaluations identified different molecular processes related to this observation. One of the genes was MYBL2, encoding for a well-known transcription factor involved in the regulation of cell survival, proliferation, and differentiation in cancer tissues. In our metastasis-focussed study, no novel functional activity was detected for MYBL2, however. Instead, a metastasis-specific transformation of its genetic interaction with FOXM1 was observed. The interaction was synergistic in cells of low metastatic capacity, while there was a strong switch to a buffering mode in metastatic cells. In vivo analyses confirmed the strong effect of MYBL2 on metastasis. Conclusions: The genes found to be critical for the viability of metastatic cells form a basis for further investigations of the processes responsible for triggering and driving metastasis. As shown for MYBL2, unexpected processes of regulating metastasis might also be involved. Full article

(This article belongs to the Section Cancer Metastasis)

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15 pages, 646 KiB

Open AccessEditor’s ChoiceReview

Copper and Colorectal Cancer

by Maciej Małyszko and Adam Przybyłkowski

Cancers 2024, 16(21), 3691; https://doi.org/10.3390/cancers16213691 - 31 Oct 2024

Cited by 1 | Viewed by 1888

Abstract

Minerals constitute only 5% of the typical human diet but are vital for health and functionality. Copper, a trace element, is absorbed by the human gut at 30–40% from diets typical of industrialized countries. The liver produces metallothioneins, which store copper. Copper is [...] Read more.

Minerals constitute only 5% of the typical human diet but are vital for health and functionality. Copper, a trace element, is absorbed by the human gut at 30–40% from diets typical of industrialized countries. The liver produces metallothioneins, which store copper. Copper is crucial for mitochondrial respiration, pigmentation, iron transport, antioxidant defense, hormone production, and extracellular matrix biosynthesis. Copper deficiency, often caused by mutations in the ATP7A gene, results in Menkes disease, an X-linked recessive disorder. On the contrary, Wilson disease is characterized by toxic copper accumulation. Cuproptosis, a unique form of cell death regulated by copper, is a subtype of necrosis induced by enhanced mitochondrial metabolism and intracellular copper accumulation. This process can reduce the malignant potential of tumor cells by inhibiting glucose metabolism. Therapeutically, copper and its complexes have shown efficacy in malignancy treatments. The disruption of copper homeostasis and excessive cuproplasia are significant in colorectal cancer development and metastasis. Therefore, manipulating copper status presents a potential therapeutic target for colorectal cancer, using copper chelators to inhibit copper formation or copper ion carriers to promote cuproptosis. This review highlights the role of copper in human physiology and pathology, emphasizing its impact on colorectal cancer and potential therapeutic strategies. Future AI-based approaches are anticipated to accelerate the development of new compounds targeting cuproptosis and copper disruption in colorectal cancer. Full article

(This article belongs to the Special Issue Advancing Horizons in Colorectal Surgery: Innovative Approaches and Outcomes)

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10 pages, 1838 KiB

Open AccessEditor’s ChoiceArticle

Examination of Sarcopenia with Obesity as a Prognostic Factor in Patients with Colorectal Cancer Using the Psoas Muscle Mass Index

by Kengo Haruna, Soichiro Minami, Norikatsu Miyoshi, Shiki Fujino, Rie Mizumoto, Yuki Toyoda, Rie Hayashi, Shinya Kato, Mitsunobu Takeda, Yuki Sekido, Tsuyoshi Hata, Atsushi Hamabe, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, Hirofumi Yamamoto, Yuichiro Doki and Hidetoshi Eguchi

Cancers 2024, 16(19), 3429; https://doi.org/10.3390/cancers16193429 - 9 Oct 2024

Cited by 1 | Viewed by 1517

Abstract

Background: Sarcopenia, the age-related loss of muscle mass, is a negative prognostic factor in gastrointestinal cancer. Sarcopenia combined with visceral obesity (sarcopenic obesity) is associated with poor outcomes. We explored the influence of obesity and other factors on the prognosis of patients [...] Read more.

Background: Sarcopenia, the age-related loss of muscle mass, is a negative prognostic factor in gastrointestinal cancer. Sarcopenia combined with visceral obesity (sarcopenic obesity) is associated with poor outcomes. We explored the influence of obesity and other factors on the prognosis of patients with colorectal cancer diagnosed with sarcopenia. Methods: We enrolled 211 patients with colorectal cancer diagnosed with preoperative sarcopenic obesity who underwent radical resection at Osaka University Hospital between January 2009 and January 2012. Muscle mass was assessed using the psoas muscle mass index. Obesity was evaluated by measuring the visceral fat area in the umbilical region. Patients were categorized into two groups: sarcopenia with obesity (SO) and sarcopenia without obesity (non-SO). Overall survival, cancer-specific survival, and cancer-related relapse-free survival (CRRFS) were compared between the two groups. Patient characteristics, including age, sex, body mass index, serum albumin, C-reactive protein, tumor markers, prognostic nutritional index (PNI), modified Glasgow prognostic score (mGPS), and geriatric nutritional risk index (GNRI), were also analyzed. Results: CRRFS was significantly shorter in the SO group than in the non-SO group (p = 0.028). PNI, mGPS, and GNRI were not identified as significant prognostic factors for CRRFS. Multivariate analysis highlighted sarcopenic obesity, elevated carcinoembryonic antigen levels, and unfavorable histological types as significant predictors of poor CRRFS outcomes. Conclusions: Sarcopenic obesity is an independent predictor of poor prognosis in patients with CRC. Thus, interventions aimed at increasing muscle mass and reducing visceral fat could potentially improve the prognosis of these patients. Full article

(This article belongs to the Special Issue Obesity and Cancers)

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43 pages, 1436 KiB

Open AccessEditor’s ChoiceReview

Orally Ingested Micro- and Nano-Plastics: A Hidden Driver of Inflammatory Bowel Disease and Colorectal Cancer

by Annalisa Bruno, Melania Dovizio, Cristina Milillo, Eleonora Aruffo, Mirko Pesce, Marco Gatta, Piero Chiacchiaretta, Piero Di Carlo and Patrizia Ballerini

Cancers 2024, 16(17), 3079; https://doi.org/10.3390/cancers16173079 - 4 Sep 2024

Cited by 5 | Viewed by 5315

Abstract

Micro- and nano-plastics (MNPLs) can move along the food chain to higher-level organisms including humans. Three significant routes for MNPLs have been reported: ingestion, inhalation, and dermal contact. Accumulating evidence supports the intestinal toxicity of ingested MNPLs and their role as drivers for [...] Read more.

Micro- and nano-plastics (MNPLs) can move along the food chain to higher-level organisms including humans. Three significant routes for MNPLs have been reported: ingestion, inhalation, and dermal contact. Accumulating evidence supports the intestinal toxicity of ingested MNPLs and their role as drivers for increased incidence of colorectal cancer (CRC) in high-risk populations such as inflammatory bowel disease (IBD) patients. However, the mechanisms are largely unknown. In this review, by using the leading scientific publication databases (Web of Science, Google Scholar, Scopus, PubMed, and ScienceDirect), we explored the possible effects and related mechanisms of MNPL exposure on the gut epithelium in healthy conditions and IBD patients. The summarized evidence supports the idea that oral MNPL exposure may contribute to intestinal epithelial damage, thus promoting and sustaining the chronic development of intestinal inflammation, mainly in high-risk populations such as IBD patients. Colonic mucus layer disruption may further facilitate MNPL passage into the bloodstream, thus contributing to the toxic effects of MNPLs on different organ systems and platelet activation, which may, in turn, contribute to the chronic development of inflammation and CRC development. Further exploration of this threat to human health is warranted to reduce potential adverse effects and CRC risk. Full article

(This article belongs to the Special Issue Signaling Mechanisms Underlying Gastrointestinal Tract Tumorigenesis)

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25 pages, 1386 KiB

Open AccessEditor’s ChoiceReview

Aberrant SWI/SNF Complex Members Are Predominant in Rare Ovarian Malignancies—Therapeutic Vulnerabilities in Treatment-Resistant Subtypes

by Yue Ma, Natisha R. Field, Tao Xie, Sarina Briscas, Emily G. Kokinogoulis, Tali S. Skipper, Amani Alghalayini, Farhana A. Sarker, Nham Tran, Nikola A. Bowden, Kristie-Ann Dickson and Deborah J. Marsh

Cancers 2024, 16(17), 3068; https://doi.org/10.3390/cancers16173068 - 3 Sep 2024

Cited by 1 | Viewed by 3033

Abstract

SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations [...] Read more.

SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations in ARID1A, encoding one of the mutually exclusive DNA-binding subunits of SWI/SNF, occur in 42–67% of ovarian clear cell carcinomas (OCCC). The concomitant somatic or germline mutation and epigenetic silencing of the mutually exclusive ATPase subunits SMARCA4 and SMARCA2, respectively, occurs in Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), with SMARCA4 mutation reported in 69–100% of SCCOHT cases and SMARCA2 silencing seen 86–100% of the time. Somatic ARID1A mutations also occur in endometrioid ovarian cancer (EnOC), as well as in the chronic benign condition endometriosis, possibly as precursors to the development of the endometriosis-associated cancers OCCC and EnOC. Mutation of the ARID1A paralogue ARID1B can also occur in both OCCC and SCCOHT. Mutations in other SWI/SNF complex members, including SMARCA2, SMARCB1 and SMARCC1, occur rarely in either OCCC or SCCOHT. Abrogated SWI/SNF raises opportunities for pharmacological inhibition, including the use of DNA damage repair inhibitors, kinase and epigenetic inhibitors, as well as immune checkpoint blockade. Full article

(This article belongs to the Special Issue Rare Gynecological Cancers)

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19 pages, 2049 KiB

Open AccessEditor’s ChoiceReview

TP53 Mutation-Mediated Immune Evasion in Cancer: Mechanisms and Therapeutic Implications

by Chuqi Wang, Jordan Yong Ming Tan, Nishtha Chitkara and Shruti Bhatt

Cancers 2024, 16(17), 3069; https://doi.org/10.3390/cancers16173069 - 3 Sep 2024

Cited by 14 | Viewed by 6771

Abstract

Mutation in p53 is the most frequent event in cancer development and a leading cause of cancer therapy resistance due to evasion of the apoptosis cascade. Beyond chemotherapies and radiation therapies, growing evidence indicates that p53-mutant tumors are resistant to a broad range [...] Read more.

Mutation in p53 is the most frequent event in cancer development and a leading cause of cancer therapy resistance due to evasion of the apoptosis cascade. Beyond chemotherapies and radiation therapies, growing evidence indicates that p53-mutant tumors are resistant to a broad range of immune-based therapies, such as immune checkpoint inhibitors, chimeric antigen receptor (CAR) T, and hematopoietic stem cell transplantation (HSCT). This highlights the role of p53 mutations in driving immune evasion of tumor cells. In this review, we first summarize recent studies revealing mechanisms by which p53-mutant tumors evade immune surveillance from T cells, natural killer (NK) cells, and macrophages. We then review how these mutant tumor cells reshape the tumor microenvironment (TME), modulating bystander cells such as macrophages, neutrophils, and regulatory T (Treg) cells to foster immunosuppression. Additionally, we review clinical observations indicative of immune evasion associated with p53 loss or mutations. Finally, we discuss therapeutic strategies to enhance immune response in p53 wild-type (WT) or mutant tumors. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment in Cancer: Promises and Challenges)

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24 pages, 1710 KiB

Open AccessEditor’s ChoiceReview

Recent Treatment Strategies and Molecular Pathways in Resistance Mechanisms of Antiangiogenic Therapies in Glioblastoma

by Md Ataur Rahman and Meser M. Ali

Cancers 2024, 16(17), 2975; https://doi.org/10.3390/cancers16172975 - 27 Aug 2024

Cited by 9 | Viewed by 3116

Abstract

Malignant gliomas present great difficulties in treatment, with little change over the past 30 years in the median survival time of 15 months. Current treatment options include surgery, radiotherapy (RT), and chemotherapy. New therapies aimed at suppressing the formation of new vasculature (antiangiogenic [...] Read more.

Malignant gliomas present great difficulties in treatment, with little change over the past 30 years in the median survival time of 15 months. Current treatment options include surgery, radiotherapy (RT), and chemotherapy. New therapies aimed at suppressing the formation of new vasculature (antiangiogenic treatments) or destroying formed tumor vasculature (vascular disrupting agents) show promise. This study summarizes the existing knowledge regarding the processes by which glioblastoma (GBM) tumors acquire resistance to antiangiogenic treatments. The discussion encompasses the activation of redundant proangiogenic pathways, heightened tumor cell invasion and metastasis, resistance induced by hypoxia, creation of vascular mimicry channels, and regulation of the tumor immune microenvironment. Subsequently, we explore potential strategies to overcome this resistance, such as combining antiangiogenic therapies with other treatment methods, personalizing treatments for each patient, focusing on new therapeutic targets, incorporating immunotherapy, and utilizing drug delivery systems based on nanoparticles. Additionally, we would like to discuss the limitations of existing methods and potential future directions to enhance the beneficial effects of antiangiogenic treatments for patients with GBM. Therefore, this review aims to enhance the research outcome for GBM and provide a more promising opportunity by thoroughly exploring the mechanisms of resistance and investigating novel therapeutic strategies. Full article

(This article belongs to the Special Issue Current Challenges and Opportunities in Treating Glioma)

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29 pages, 5058 KiB

Open AccessEditor’s ChoiceReview

Non-Small-Cell Lung Cancers (NSCLCs) Harboring RET Gene Fusion, from Their Discovery to the Advent of New Selective Potent RET Inhibitors: “Shadows and Fogs”

by Gianluca Spitaleri, Pamela Trillo Aliaga, Ilaria Attili, Ester Del Signore, Carla Corvaja, Gloria Pellizzari, Jalissa Katrini, Antonio Passaro and Filippo de Marinis

Cancers 2024, 16(16), 2877; https://doi.org/10.3390/cancers16162877 - 19 Aug 2024

Cited by 1 | Viewed by 2354

Abstract

RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1–2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading [...] Read more.

RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1–2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading to the brain. Chemotherapy and immunotherapy have a low impact on the prognosis of these patients. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy minimizing the known toxicities of the multitargeted agents. This review will describe the sensitivity of immune-checkpoint inhibitors (ICIs) in RET fusion + NSCLC patients, as well their experiences with the ‘old’ multi-targeted RET inhibitors. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with the new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events. Full article

(This article belongs to the Special Issue Lung Cancer—Molecular Insights and Targeted Therapies (Volume II))

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26 pages, 1512 KiB

Open AccessEditor’s ChoiceReview

Precision Targeting Strategies in Pancreatic Cancer: The Role of Tumor Microenvironment

by Nikolaos Vitorakis, Antonios N. Gargalionis, Kostas A. Papavassiliou, Christos Adamopoulos and Athanasios G. Papavassiliou

Cancers 2024, 16(16), 2876; https://doi.org/10.3390/cancers16162876 - 19 Aug 2024

Cited by 3 | Viewed by 2802

Abstract

Pancreatic cancer demonstrates an ever-increasing incidence over the last years and represents one of the top causes of cancer-associated mortality. Cells of the tumor microenvironment (TME) interact with cancer cells in pancreatic ductal adenocarcinoma (PDAC) tumors to preserve cancer cells’ metabolism, inhibit drug [...] Read more.

Pancreatic cancer demonstrates an ever-increasing incidence over the last years and represents one of the top causes of cancer-associated mortality. Cells of the tumor microenvironment (TME) interact with cancer cells in pancreatic ductal adenocarcinoma (PDAC) tumors to preserve cancer cells’ metabolism, inhibit drug delivery, enhance immune suppression mechanisms and finally develop resistance to chemotherapy and immunotherapy. New strategies target TME genetic alterations and specific pathways in cell populations of the TME. Complex molecular interactions develop between PDAC cells and TME cell populations including cancer-associated fibroblasts, myeloid-derived suppressor cells, pancreatic stellate cells, tumor-associated macrophages, tumor-associated neutrophils, and regulatory T cells. In the present review, we aim to fully explore the molecular landscape of the pancreatic cancer TME cell populations and discuss current TME targeting strategies to provide thoughts for further research and preclinical testing. Full article

(This article belongs to the Special Issue Clinical Applications of Molecular Subtyping of Pancreatic Cancer)

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36 pages, 955 KiB

Open AccessEditor’s ChoiceReview

The Genetic Analysis and Clinical Therapy in Lung Cancer: Current Advances and Future Directions

by Angela Rina, Debora Maffeo, Francesca Minnai, Martina Esposito, Maria Palmieri, Viola Bianca Serio, Diletta Rosati, Francesca Mari, Elisa Frullanti and Francesca Colombo

Cancers 2024, 16(16), 2882; https://doi.org/10.3390/cancers16162882 - 19 Aug 2024

Cited by 4 | Viewed by 6595

Abstract

Lung cancer, including both non-small cell lung cancer and small cell lung cancer, remains the leading cause of cancer-related mortality worldwide, representing 18% of the total cancer deaths in 2020. Many patients are identified already at an advanced stage with metastatic disease and [...] Read more.

Lung cancer, including both non-small cell lung cancer and small cell lung cancer, remains the leading cause of cancer-related mortality worldwide, representing 18% of the total cancer deaths in 2020. Many patients are identified already at an advanced stage with metastatic disease and have a worsening prognosis. Recent advances in the genetic understanding of lung cancer have opened new avenues for personalized treatments and targeted therapies. This review examines the latest discoveries in the genetics of lung cancer, discusses key biomarkers, and analyzes current clinical therapies based on this genetic information. It will conclude with a discussion of future prospects and potential research directions. Full article

(This article belongs to the Section Clinical Research of Cancer)

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20 pages, 642 KiB

Open AccessEditor’s ChoiceReview

Artificial Intelligence in Detection, Management, and Prognosis of Bone Metastasis: A Systematic Review

by Giuseppe Francesco Papalia, Paolo Brigato, Luisana Sisca, Girolamo Maltese, Eliodoro Faiella, Domiziana Santucci, Francesco Pantano, Bruno Vincenzi, Giuseppe Tonini, Rocco Papalia and Vincenzo Denaro

Cancers 2024, 16(15), 2700; https://doi.org/10.3390/cancers16152700 - 29 Jul 2024

Cited by 6 | Viewed by 3548

Abstract

Background: Metastasis commonly occur in the bone tissue. Artificial intelligence (AI) has become increasingly prevalent in the medical sector as support in decision-making, diagnosis, and treatment processes. The objective of this systematic review was to assess the reliability of AI systems in clinical, [...] Read more.

Background: Metastasis commonly occur in the bone tissue. Artificial intelligence (AI) has become increasingly prevalent in the medical sector as support in decision-making, diagnosis, and treatment processes. The objective of this systematic review was to assess the reliability of AI systems in clinical, radiological, and pathological aspects of bone metastases. Methods: We included studies that evaluated the use of AI applications in patients affected by bone metastases. Two reviewers performed a digital search on 31 December 2023 on PubMed, Scopus, and Cochrane library and extracted authors, AI method, interest area, main modalities used, and main objectives from the included studies. Results: We included 59 studies that analyzed the contribution of computational intelligence in diagnosing or forecasting outcomes in patients with bone metastasis. Six studies were specific for spine metastasis. The study involved nuclear medicine (44.1%), clinical research (28.8%), radiology (20.4%), or molecular biology (6.8%). When a primary tumor was reported, prostate cancer was the most common, followed by lung, breast, and kidney. Conclusions: Appropriately trained AI models may be very useful in merging information to achieve an overall improved diagnostic accuracy and treatment for metastasis in the bone. Nevertheless, there are still concerns with the use of AI systems in medical settings. Ethical considerations and legal issues must be addressed to facilitate the safe and regulated adoption of AI technologies. The limitations of the study comprise a stronger emphasis on early detection rather than tumor management and prognosis as well as a high heterogeneity for type of tumor, AI technology and radiological techniques, pathology, or laboratory samples involved. Full article

(This article belongs to the Special Issue Artificial Intelligence and MRI Characterization of Tumors: 2nd Edition)

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17 pages, 1234 KiB

Open AccessEditor’s ChoiceArticle

The Prognostic Impact of HER2-Low and Menopausal Status in Triple-Negative Breast Cancer

by Woong Ki Park, Seok Jin Nam, Seok Won Kim, Jeong Eon Lee, Jonghan Yu, Se Kyung Lee, Jai Min Ryu and Byung Joo Chae

Cancers 2024, 16(14), 2566; https://doi.org/10.3390/cancers16142566 - 17 Jul 2024

Cited by 2 | Viewed by 1720

Abstract

TNBC is noted for its aggressive behavior and poor prognosis. Recently developed HER2 target agents have shown potential benefit even in HER2-low expressing breast cancers. This study retrospectively analyzed 2542 non-metastatic TNBC patients from 2008 to 2020, revealing that 26.0% were HER2-low. Data [...] Read more.

TNBC is noted for its aggressive behavior and poor prognosis. Recently developed HER2 target agents have shown potential benefit even in HER2-low expressing breast cancers. This study retrospectively analyzed 2542 non-metastatic TNBC patients from 2008 to 2020, revealing that 26.0% were HER2-low. Data on demographics, tumor characteristics, pathologic complete response (pCR) rates and disease-free survival (DFS), distant metastasis-free survival (DMFS), overall survival (OS), and breast cancer-specific survival (BCSS) were analyzed. The HER2-low group, compared to the HER2-0 group, showed significantly better DFS, DMFS, OS, BCSS (p = 0.0072, p = 0.0096, p = 0.0180, and p = 0.0001, respectively) with older age and higher rates of postmenopausal status (p < 0.0001). No significant differences in pCR rates were observed. Multivariate analyses identified HER2 status as a significant prognostic factor for DFS (p = 0.048), DMFS (p = 0.018), OS (p = 0.049), and BCSS (p = 0.008). Subgroup analysis revealed that these effects varied with menopausal status, showing more pronounced benefits in postmenopausal women. Our findings suggest that HER2-low TNBC patients exhibit a distinct clinical profile and improved survival compared to HER2-0 TNBC patients, especially in postmenopausal patients. Further research on estrogen and HER2 interaction is needed. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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22 pages, 3817 KiB

Open AccessEditor’s ChoiceArticle

Enhancing Immunotherapy Response Prediction in Metastatic Lung Adenocarcinoma: Leveraging Shallow and Deep Learning with CT-Based Radiomics across Single and Multiple Tumor Sites

by Cécile Masson-Grehaigne, Mathilde Lafon, Jean Palussière, Laura Leroy, Benjamin Bonhomme, Eva Jambon, Antoine Italiano, Sophie Cousin and Amandine Crombé

Cancers 2024, 16(13), 2491; https://doi.org/10.3390/cancers16132491 - 8 Jul 2024

Cited by 2 | Viewed by 1687

Abstract

This study aimed to evaluate the potential of pre-treatment CT-based radiomics features (RFs) derived from single and multiple tumor sites, and state-of-the-art machine-learning survival algorithms, in predicting progression-free survival (PFS) for patients with metastatic lung adenocarcinoma (MLUAD) receiving first-line treatment including immune checkpoint [...] Read more.

This study aimed to evaluate the potential of pre-treatment CT-based radiomics features (RFs) derived from single and multiple tumor sites, and state-of-the-art machine-learning survival algorithms, in predicting progression-free survival (PFS) for patients with metastatic lung adenocarcinoma (MLUAD) receiving first-line treatment including immune checkpoint inhibitors (CPIs). To do so, all adults with newly diagnosed MLUAD, pre-treatment contrast-enhanced CT scan, and performance status ≤ 2 who were treated at our cancer center with first-line CPI between November 2016 and November 2022 were included. RFs were extracted from all measurable lesions with a volume ≥ 1 cm³ on the CT scan. To capture intra- and inter-tumor heterogeneity, RFs from the largest tumor of each patient, as well as lowest, highest, and average RF values over all lesions per patient were collected. Intra-patient inter-tumor heterogeneity metrics were calculated to measure the similarity between each patient lesions. After filtering predictors with univariable Cox p < 0.100 and analyzing their correlations, five survival machine-learning algorithms (stepwise Cox regression [SCR], LASSO Cox regression, random survival forests, gradient boosted machine [GBM], and deep learning [Deepsurv]) were trained in 100-times repeated 5-fold cross-validation (rCV) to predict PFS on three inputs: (i) clinicopathological variables, (ii) all radiomics-based and clinicopathological (full input), and (iii) uncorrelated radiomics-based and clinicopathological variables (uncorrelated input). The Models’ performances were evaluated using the concordance index (c-index). Overall, 140 patients were included (median age: 62.5 years, 36.4% women). In rCV, the highest c-index was reached with Deepsurv (c-index = 0.631, 95%CI = 0.625–0.647), followed by GBM (c-index = 0.603, 95%CI = 0.557–0.646), significantly outperforming standard SCR whatever its input (c-index range: 0.560–0.570, all p < 0.0001). Thus, single- and multi-site pre-treatment radiomics data provide valuable prognostic information for predicting PFS in MLUAD patients undergoing first-line CPI treatment when analyzed with advanced machine-learning survival algorithms. Full article

(This article belongs to the Special Issue Imaging and Molecular Biology as Biomarkers for Lung Cancer)

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17 pages, 4025 KiB

Open AccessEditor’s ChoiceArticle

CRISPR-Cas9 Knockout Screens Identify DNA Damage Response Pathways and BTK as Essential for Cisplatin Response in Diffuse Large B-Cell Lymphoma

by Issa Ismail Issa, Hanne Due, Rasmus Froberg Brøndum, Vidthdyan Veeravakaran, Hulda Haraldsdóttir, Cathrine Sylvester, Asta Brogaard, Soniya Dhanjal, Bernhard Schmierer and Karen Dybkær

Cancers 2024, 16(13), 2437; https://doi.org/10.3390/cancers16132437 - 2 Jul 2024

Cited by 3 | Viewed by 2348

Abstract

The recurrence of diffuse large B-cell lymphoma (DLBCL) has been observed in 40% of cases. The standard of care for refractory/relapsed DLBCL (RR-DLBCL) is platinum-based treatment prior to autologous stem cell transplantation; however, the prognosis for RR-DLBCL patients remains poor. Thus, to identify [...] Read more.

The recurrence of diffuse large B-cell lymphoma (DLBCL) has been observed in 40% of cases. The standard of care for refractory/relapsed DLBCL (RR-DLBCL) is platinum-based treatment prior to autologous stem cell transplantation; however, the prognosis for RR-DLBCL patients remains poor. Thus, to identify genes affecting the cisplatin response in DLBCL, cisplatin-based whole-genome CRISPR-Cas9 knockout screens were performed in this study. We discovered DNA damage response (DDR) pathways as enriched among identified sensitizing CRISPR-mediated gene knockouts. In line, the knockout of the nucleotide excision repair genes XPA and ERCC6 sensitized DLBCL cells to platinum drugs irrespective of proliferation rate, thus documenting DDR as essential for cisplatin sensitivity in DLBCL. Functional analysis revealed that the loss of XPA and ERCC6 increased DNA damage levels and altered cell cycle distribution. Interestingly, we also identified BTK, which is involved in B-cell receptor signaling, to affect cisplatin response. The knockout of BTK increased cisplatin sensitivity in DLBCL cells, and combinatory drug screens revealed a synergistic effect of the BTK inhibitor, ibrutinib, with platinum drugs at low concentrations. Applying local and external DLBCL cohorts, we addressed the clinical relevance of the genes identified in the CRISPR screens. BTK was among the most frequently mutated genes with a frequency of 3–5%, and XPA and ERCC6 were also mutated, albeit at lower frequencies. Furthermore, 27–54% of diagnostic DLBCL samples had mutations in pathways that can sensitize cells to cisplatin. In conclusion, this study shows that XPA and ERCC6, in addition to BTK, are essential for the response to platinum-based drugs in DLBCL. Full article

(This article belongs to the Section Molecular Cancer Biology)

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25 pages, 3138 KiB

Open AccessEditor’s ChoiceReview

Antibody-Drug Conjugates in Urothelial Cancer: From Scientific Rationale to Clinical Development

by Whi-An Kwon, Seo-Yeon Lee, Tae Yoong Jeong, Hyeon Hoe Kim and Min-Kyung Lee

Cancers 2024, 16(13), 2420; https://doi.org/10.3390/cancers16132420 - 30 Jun 2024

Cited by 6 | Viewed by 3025

Abstract

Antibody-drug conjugates (ADCs) have been a significant advancement in cancer therapy, particularly for urothelial cancer (UC). These innovative treatments, originally developed for hematological malignancies, use target-specific monoclonal antibodies linked to potent cytotoxic agents. This rational drug design efficiently delivers cancer cell-killing agents to [...] Read more.

Antibody-drug conjugates (ADCs) have been a significant advancement in cancer therapy, particularly for urothelial cancer (UC). These innovative treatments, originally developed for hematological malignancies, use target-specific monoclonal antibodies linked to potent cytotoxic agents. This rational drug design efficiently delivers cancer cell-killing agents to cells expressing specific surface proteins, which are abundant in UC owing to their high antigen expression. UC is an ideal candidate for ADC therapy, as it enhances on-target efficacy while mitigating systemic toxicity. In recent years, considerable progress has been made in understanding the biology and mechanisms of tumor progression in UC. However, despite the introduction of immune checkpoint inhibitors, advanced UC is characterized by rapid progression and poor survival rates. Targeted therapies that have been developed include the anti-nectin 4 ADC enfortumab vedotin and the fibroblast growth factor receptor inhibitor erdafitinib. Enfortumab vedotin has shown efficacy in prospective studies in patients with advanced UC, alone and in combination with pembrolizumab. The anti-Trop-2 ADC sacituzumab govitecan has also demonstrated effectiveness in single-armed studies. This review highlights the mechanism of action of ADCs, their application in mono- and combination therapies, primary mechanisms of resistance, and future perspectives for their clinical use in UC treatment. ADCs have proven to be an increasingly vital component of the therapeutic landscape for urothelial carcinoma, filling a gap in the treatment of this progressive disease. Full article

(This article belongs to the Special Issue Advances in Drug Delivery for Cancer Therapy)

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24 pages, 348 KiB

Open AccessEditor’s ChoiceReview

Bispecific Antibodies for the Management of Relapsed/Refractory Multiple Myeloma

by Paola Tacchetti, Simona Barbato, Katia Mancuso, Elena Zamagni and Michele Cavo

Cancers 2024, 16(13), 2337; https://doi.org/10.3390/cancers16132337 - 26 Jun 2024

Cited by 6 | Viewed by 3269

Abstract

Bispecific antibodies (BsAbs) are artificially engineered antibodies that can bind simultaneously to the CD3 subunit within the T-cell receptor complex and an antigen on tumor cells, leading to T-cell activation and tumor cell killing. BsAbs against BCMA or GPRC5D have shown impressive clinical [...] Read more.

Bispecific antibodies (BsAbs) are artificially engineered antibodies that can bind simultaneously to the CD3 subunit within the T-cell receptor complex and an antigen on tumor cells, leading to T-cell activation and tumor cell killing. BsAbs against BCMA or GPRC5D have shown impressive clinical activity in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), with some agents having already received regulatory approval after the third (by the European Medicines Agency, EMA) or fourth (by the Food and Drug Administration, FDA) line of therapy; the results of early-phase clinical trials targeting FcRH5 are also promising. Overall, BsAbs as monotherapy correlated with an ORR that exceeded 60%, with a high CR rate ranging between 25% and 50% and a median PFS of around 1 year among patients with a median of 4–6 prior lines of therapy. The main toxicities include cytokine release syndrome, cytopenias, hypogammaglobulinemia, and infections; on-target off-tumor adverse events involving the skin, mucosa, hair, and nails may also occur with anti-GPRC5D BsAbs. Active research to increase their efficacy and improve their tolerance is still in progress, including combination therapies and application in earlier treatment lines and the development of novel agents. A better understanding of the mechanisms of resistance is a challenge and could lead to more personalized approaches. Full article

(This article belongs to the Special Issue Immunotherapy in the Management of Hematologic Malignancy)

18 pages, 5955 KiB

Open AccessEditor’s ChoiceArticle

Inhibition of Histone Deacetylase Activity Increases Cisplatin Efficacy to Eliminate Metastatic Cells in Pediatric Liver Cancers

by Ruhi Gulati, Yasmeen Fleifil, Katherine Jennings, Alex Bondoc, Greg Tiao, James Geller, Lubov Timchenko and Nikolai Timchenko

Cancers 2024, 16(13), 2300; https://doi.org/10.3390/cancers16132300 - 22 Jun 2024

Cited by 4 | Viewed by 1436

Abstract

The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer [...] Read more.

The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer Associated Fibroblasts (CAFs) and neuron-like cells, which initiate cancer spread from liver to lungs. In this study, we found that these cells express high levels of HDAC1; therefore, we examined if histone deacetylase inhibition improves cisplatin anti-proliferative effects and reduces the formation of tumor clusters in pediatric liver cancer metastatic microenvironments. Methods: New cell lines were generated from primary hepatoblastoma liver tumors (hbl) and lung metastases (LM) of HBL patients. In addition, cell lines were generated from hepatocellular neoplasm, not otherwise specified (HCN-NOS) tumor samples, and hcc cell lines. Hbl, LM and hcc cells were treated with cisplatin, SAHA or in combination. The effect of these drugs on the number of cells, formation of tumor clusters and HDAC1-Sp5-p21 axis were examined. Results: Both HBL and HCC tissue specimens have increased HDAC1-Sp5 pathway activation, recapitulated in cell lines generated from the tumors. HDAC inhibition with vorinostat (SAHA) increases cisplatin efficacy to eliminate CAFs in hbl and in hcc cell lines. Although the neuron-like cells survive the combined treatments, proliferation was inhibited. Notably, combining SAHA with cisplatin overcame cisplatin resistance in an LM cell line from an aggressive case with multiple metastases. Underlying mechanisms of this enhanced inhibition include suppression of the HDAC1-Sp5 pathway and elevation of an inhibitor of proliferation p21. Similar findings were found with gemcitabine treatments suggesting that elimination of proliferative CAFs cells is a key event in the inhibition of mitotic microenvironment. Conclusions: Our studies demonstrate the synergistic benefits of HDAC inhibition and cisplatin to eliminate metastasis-initiating cells in pediatric liver cancers. Full article

(This article belongs to the Topic Individualized Molecular Mechanisms and Treatment in Tumor Metastasis)

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23 pages, 2134 KiB

Open AccessEditor’s ChoiceReview

The Anticancer Application of Delivery Systems for Honokiol and Magnolol

by Katarzyna Dominiak, Aleksandra Gostyńska, Michał Szulc and Maciej Stawny

Cancers 2024, 16(12), 2257; https://doi.org/10.3390/cancers16122257 - 18 Jun 2024

Cited by 4 | Viewed by 1719

Abstract

Cancer is a leading cause of death worldwide, and the effectiveness of treatment is consistently not at a satisfactory level. This review thoroughly examines the present knowledge and perspectives of honokiol (HON) in cancer therapeutics. The paper synthesizes critical insights into the molecular [...] Read more.

Cancer is a leading cause of death worldwide, and the effectiveness of treatment is consistently not at a satisfactory level. This review thoroughly examines the present knowledge and perspectives of honokiol (HON) in cancer therapeutics. The paper synthesizes critical insights into the molecular mechanisms underlying the observed anticancer effects, emphasizing both in vitro and in vivo studies. The effects of HON application, primarily in the common types of cancers, are presented. Because the therapeutic potential of HON may be limited by its physicochemical properties, appropriate delivery systems are sought to overcome this problem. This review discusses the effect of different nanotechnology-based delivery systems on the efficiency of HON. The data presented show that HON exhibits anticancer effects and can be successfully administered to the site of action. Honokiol exerts its anticancer activity through several mechanisms. Moreover, some authors used the combinations of classical anticancer drugs with HON. Such an approach is very interesting and worth further investigation. Understanding HON’s multiple molecular mechanisms would provide valuable insights into how HON might be developed as an effective therapeutic. Therefore, further research is needed to explore its specific applications and optimize its efficacy in diverse cancer types. Full article

(This article belongs to the Section Cancer Drug Development)

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18 pages, 1834 KiB

Open AccessEditor’s ChoiceReview

Resistance to Targeted Inhibitors of the PI3K/AKT/mTOR Pathway in Advanced Oestrogen-Receptor-Positive Breast Cancer

by Iseult M. Browne and Alicia F. C. Okines

Cancers 2024, 16(12), 2259; https://doi.org/10.3390/cancers16122259 - 18 Jun 2024

Cited by 9 | Viewed by 5656

Abstract

The PI3K/AKT/mTOR signalling pathway is one of the most frequently activated pathways in breast cancer and also plays a central role in the regulation of several physiologic functions. There are major efforts ongoing to exploit precision medicine by developing inhibitors that target the [...] Read more.

The PI3K/AKT/mTOR signalling pathway is one of the most frequently activated pathways in breast cancer and also plays a central role in the regulation of several physiologic functions. There are major efforts ongoing to exploit precision medicine by developing inhibitors that target the three kinases (PI3K, AKT, and mTOR). Although multiple compounds have been developed, at present, there are just three inhibitors approved to target this pathway in patients with advanced ER-positive, HER2-negative breast cancer: everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and capivasertib (AKT inhibitor). Like most targeted cancer drugs, resistance poses a major problem in the clinical setting and is a factor that has frequently limited the overall efficacy of these agents. Drug resistance can be categorised into intrinsic or acquired resistance depending on the timeframe it has developed within. Whereas intrinsic resistance exists prior to a specific treatment, acquired resistance is induced by a therapy. The majority of patients with ER-positive, HER2-negative advanced breast cancer will likely be offered an inhibitor of the PI3K/AKT/mTOR pathway at some point in their cancer journey, with the options available depending on the approval criteria in place and the cancer’s mutation status. Within this large cohort of patients, it is likely that most will develop resistance at some point, which makes this an area of interest and an unmet need at present. Herein, we review the common mechanisms of resistance to agents that target the PI3K/AKT/mTOR signalling pathway, elaborate on current management approaches, and discuss ongoing clinical trials attempting to mitigate this significant issue. We highlight the need for additional studies into AKT1 inhibitor resistance in particular. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

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16 pages, 2077 KiB

Open AccessEditor’s ChoiceReview

Dendritic Cells in Shaping Anti-Tumor T Cell Response

by Luciano Mazzoccoli and Bei Liu

Cancers 2024, 16(12), 2211; https://doi.org/10.3390/cancers16122211 - 13 Jun 2024

Cited by 12 | Viewed by 4480

Abstract

Among professional antigen-presenting cells, dendritic cells (DCs) orchestrate innate and adaptive immunity and play a pivotal role in anti-tumor immunity. DCs are a heterogeneous population with varying functions in the tumor microenvironment (TME). Tumor-associated DCs differentiate developmentally and functionally into three main subsets: [...] Read more.

Among professional antigen-presenting cells, dendritic cells (DCs) orchestrate innate and adaptive immunity and play a pivotal role in anti-tumor immunity. DCs are a heterogeneous population with varying functions in the tumor microenvironment (TME). Tumor-associated DCs differentiate developmentally and functionally into three main subsets: conventional DCs (cDCs), plasmacytoid DCs (pDCs), and monocyte-derived DCs (MoDCs). There are two major subsets of cDCs in TME, cDC1 and cDC2. cDC1 is critical for cross-presenting tumor antigens to activate cytotoxic CD8⁺ T cells and is also required for priming earlier CD4⁺ T cells in certain solid tumors. cDC2 is vital for priming anti-tumor CD4⁺ T cells in multiple tumor models. pDC is a unique subset of DCs and produces type I IFN through TLR7 and TLR9. Studies have shown that pDCs are related to immunosuppression in the TME through the secretion of immunosuppressive cytokines and by promoting regulatory T cells. MoDCs differentiate separately from monocytes in response to inflammatory cues and infection. Also, MoDCs can cross-prime CD8⁺ T cells. In this review, we summarize the subsets and functions of DCs. We also discuss the role of different DC subsets in shaping T cell immunity in TME and targeting DCs for potential immunotherapeutic benefits against cancer. Full article

(This article belongs to the Special Issue Evidence from the Real World Provides New Insights into the Evolving Landscape of Cancer Immunotherapy)

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17 pages, 320 KiB

Open AccessEditor’s ChoiceReview

Topical and Intralesional Immunotherapy for the Management of Basal Cell Carcinoma

by Aurora Fernández-Galván, Pedro Rodríguez-Jiménez, Beatriz González-Sixto, María Teresa Abalde-Pintos and Beatriz Butrón-Bris

Cancers 2024, 16(11), 2135; https://doi.org/10.3390/cancers16112135 - 4 Jun 2024

Cited by 2 | Viewed by 2010

Abstract

Basal Cell Carcinoma (BCC) is the most common type of cancer among the white population. Individuals with fair skin have an average lifetime risk of around 30% for developing BCC, and there is a noticeable upward trend in its incidence rate. The principal [...] Read more.

Basal Cell Carcinoma (BCC) is the most common type of cancer among the white population. Individuals with fair skin have an average lifetime risk of around 30% for developing BCC, and there is a noticeable upward trend in its incidence rate. The principal treatment objectives for BCC involve achieving the total excision of the tumor while maximizing the preservation of function and cosmesis. Surgery is considered the treatment of choice for BCC for two main reasons: it allows for the highest cure rates and facilitates histological control of resection margins. However, in the subgroup of patients with low-risk recurrence or medical contraindications for surgery, new non-surgical treatment alternatives can provide an excellent oncological and cosmetic outcome. An evident and justified instance of these local therapies occurred during the COVID-19 pandemic, a period when surgical interventions carried out in hospital settings were not a viable option. Full article

(This article belongs to the Special Issue Topical and Intralesional Immunotherapy for Skin Cancer)

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17 pages, 625 KiB

Open AccessEditor’s ChoiceReview

Targeting Neoantigens in Pancreatic Ductal Adenocarcinoma

by Gurkaranjot Singh, Drew Kutcher, Rajeshwar Lally and Vikrant Rai

Cancers 2024, 16(11), 2101; https://doi.org/10.3390/cancers16112101 - 31 May 2024

Cited by 5 | Viewed by 1979

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is currently the third leading cause of cancer-related death in the United States after lung and colon cancer. PDAC is estimated to be the second leading cause of cancer-related death [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is currently the third leading cause of cancer-related death in the United States after lung and colon cancer. PDAC is estimated to be the second leading cause of cancer-related death by 2030. The diagnosis at a late stage is the underlying cause for higher mortality and poor prognosis after surgery. Treatment resistance to chemotherapy and immunotherapy results in recurrence after surgery and poor prognosis. Neoantigen burden and CD8+ T-cell infiltration are associated with clinical outcomes in PDAC and paucity of neoantigen-reactive tumor-infiltrating lymphocytes may be the underlying cause for treatment resistance for immunotherapy. This suggests a need to identify additional neoantigens and therapies targeting these neoantigens to improve clinical outcomes in PDAC. In this review, we focus on describing the pathophysiology, current treatment strategies, and treatment resistance in PDAC followed by the need to target neoantigens in PDAC. Full article

(This article belongs to the Special Issue Current Clinical Studies of Pancreatic Ductal Adenocarcinoma)

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17 pages, 950 KiB

Open AccessEditor’s ChoiceArticle

Acceptance of Self-Sampling by Women Not Regularly Participating in Cervical Cancer Screening in Areas with Low Medical Density: A Qualitative Study within the French CapU4 Trial

by Johane Le Goff, Anne-Sophie Le Duc-Banaszuk, Caroline Lefeuvre, Adeline Pivert, Alexandra Ducancelle, Hélène De Pauw, Marc Arbyn, Aubeline Vinay and Franck Rexand-Galais

Cancers 2024, 16(11), 2066; https://doi.org/10.3390/cancers16112066 - 30 May 2024

Cited by 1 | Viewed by 1668

Abstract

Cervical cancer (CC) was diagnosed in 3159 women in France in 2023, and 1117 died from it. Organized screening for cervical cancer is potentially very effective for participating women. However, reaching under-screened populations remains a major challenge. The present qualitative study explored women’s [...] Read more.

Cervical cancer (CC) was diagnosed in 3159 women in France in 2023, and 1117 died from it. Organized screening for cervical cancer is potentially very effective for participating women. However, reaching under-screened populations remains a major challenge. The present qualitative study explored women’s opinions on what discourages or encourages them to participate in CC screening and assessed the acceptability of two experimental strategies (urinary or vaginal self-sampling kits) to increase the screening coverage in three rural French administrative departments with low medical density and/or low screening participation rates. Forty-eight semi-structured interviews and four focus groups were conducted by a team of psychologists. Results showed that the participants accepted at-home self-sampling to reach non-participating women in medically underserved areas. However, they suggested that the type of kit sent should be adapted to the patient’s profile (embarrassment from earlier exams, cultural aspects, fear of invasiveness, etc.), and that kits should be simple to use (in understandable language taking sociocultural aspects into account). Women wished to be assured that testing on self-samples is accurate and needed information about further actions in case of a positive result. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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21 pages, 3176 KiB

Open AccessEditor’s ChoiceArticle

Restricting Colorectal Cancer Cell Metabolism with Metformin: An Integrated Transcriptomics Study

by Ayla Orang, Shashikanth Marri, Ross A. McKinnon, Janni Petersen and Michael Z. Michael

Cancers 2024, 16(11), 2055; https://doi.org/10.3390/cancers16112055 - 29 May 2024

Cited by 4 | Viewed by 4035

Abstract

Background: Metformin is a first-line therapy for type 2 diabetes as it disrupts cellular metabolism. Despite the association between metformin and lower cancer incidence, the anti-tumour activity of the drug in colorectal cancer (CRC) is incompletely understood. This study identifies underlying molecular mechanisms [...] Read more.

Background: Metformin is a first-line therapy for type 2 diabetes as it disrupts cellular metabolism. Despite the association between metformin and lower cancer incidence, the anti-tumour activity of the drug in colorectal cancer (CRC) is incompletely understood. This study identifies underlying molecular mechanisms by which metformin slows colorectal cancer cell proliferation by investigating metformin-associated microRNA (miRNA) and target gene pairs implicated in signalling pathways. Methods: The present study analysed changes in miRNAs and the coding transcriptome in CRC cells treated with a sublethal dose of metformin, followed by the contextual validation of potential miRNA–target gene pairs. Results: Analyses of small RNA and transcriptome sequencing data revealed 104 miRNAs and 1221 mRNAs to be differentially expressed in CRC cells treated with metformin for 72 h. Interaction networks between differentially expressed miRNAs and putative target mRNAs were identified. Differentially expressed genes were mainly implicated in metabolism and signalling processes, such as the PI3K-Akt and MAPK/ERK pathways. Further validation of potential miRNA–target mRNA pairs revealed that metformin induced miR-2110 and miR-132-3p to target PIK3R3 and, consequently, regulate CRC cell proliferation, cell cycle progression and the PI3K-Akt signalling pathway. Metformin also induced miR-222-3p and miR-589-3p, which directly target STMN1 to inhibit CRC cell proliferation and cell cycle progression. Conclusions: This study identified novel changes in the coding transcriptome and small non-coding RNAs associated with metformin treatment of CRC cells. Integration of these datasets highlighted underlying mechanisms by which metformin impedes cell proliferation in CRC. Importantly, it identified the post-transcriptional regulation of specific genes that impact both metabolism and cell proliferation. Full article

(This article belongs to the Special Issue Targeting Metabolic Vulnerabilities in Cancer)

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12 pages, 911 KiB

Open AccessEditor’s ChoiceArticle

Diagnostic Accuracy of DNA-Methylation in Detection of Cervical Dysplasia: Findings from a Population-Based Screening Program

by Narcisa Muresu, Mariangela V. Puci, Giovanni Sotgiu, Illari Sechi, Manuela Usai, Andrea Cossu, Marianna Martinelli, Clementina Elvezia Cocuzza and Andrea Piana

Cancers 2024, 16(11), 1986; https://doi.org/10.3390/cancers16111986 - 23 May 2024

Cited by 2 | Viewed by 2073

Abstract

Background: Epigenetic biomarkers in cancer have emerged as promising tools for early detection, prognosis, and treatment response prediction. In cervical cells, hypermethylation of the host and viral HPV-genome increases with the severity of lesions, providing a useful biomarker in the triage of hr-HPV-positive [...] Read more.

Background: Epigenetic biomarkers in cancer have emerged as promising tools for early detection, prognosis, and treatment response prediction. In cervical cells, hypermethylation of the host and viral HPV-genome increases with the severity of lesions, providing a useful biomarker in the triage of hr-HPV-positive women and during treatment. The present study focuses on evaluating the clinical performance of the FAM19A4/miR124-2 methylation test in a population-based cervical screening program. Methods: Previously collected cervical samples, after bisulfite-converted DNA, were analyzed by PreCursor-M+ kit (distributed by Fujirebio Europe), for DNA methylation. The sensitivity, specificity, and negative/positive predictive values of DNA methylation were compared to histology, colposcopy, the HPV-DNA test, and cytology results. Results: Among the 61-sample set, the specificity of methylation vs. positive histology (≥CIN2) and colposcopy (≥G2) were 87% and 90%, whereas the sensitivity was 50% and 33.3%, respectively. The combination of methylation analysis with standard methods increases diagnostic accuracy. Conclusions: Overall, we found a good specificity of DNA methylation in comparison to currently used techniques. Further larger studies could support the use of FAM19A4/miR124-2 as reliable biomarkers in the prevention of cervical cancer as triage in the screening protocol. Full article

(This article belongs to the Special Issue Cervical Cancer: Risk Factors, Screening, and Prevention Strategies)

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25 pages, 3965 KiB

Open AccessEditor’s ChoiceArticle

Multidrug-Resistant Profiles in Non-Small Cell Lung Carcinoma Patient-Derived Cells: Implications for Personalized Approaches with Tyrosine Kinase Inhibitors

by Jelena Dinić, Miodrag Dragoj, Sofija Jovanović Stojanov, Ana Stepanović, Ema Lupšić, Milica Pajović, Thomas Mohr, Sofija Glumac, Dragana Marić, Maja Ercegovac, Ana Podolski-Renić and Milica Pešić

Cancers 2024, 16(11), 1984; https://doi.org/10.3390/cancers16111984 - 23 May 2024

Cited by 2 | Viewed by 1708

Abstract

The impact of tyrosine kinase inhibitors (TKIs) on multidrug resistance (MDR) in non-small cell lung carcinoma (NSCLC) is a critical aspect of cancer therapy. While TKIs effectively target specific signaling pathways of cancer cells, they can also act as substrates for ABC transporters, [...] Read more.

The impact of tyrosine kinase inhibitors (TKIs) on multidrug resistance (MDR) in non-small cell lung carcinoma (NSCLC) is a critical aspect of cancer therapy. While TKIs effectively target specific signaling pathways of cancer cells, they can also act as substrates for ABC transporters, potentially triggering MDR. The aim of our study was to evaluate the response of 17 patient-derived NSCLC cultures to 10 commonly prescribed TKIs and to correlate these responses with patient mutational profiles. Using an ex vivo immunofluorescence assay, we analyzed the expression of the MDR markers ABCB1, ABCC1, and ABCG2, and correlated these data with the genetic profiles of patients for a functional diagnostic approach. NSCLC cultures responded differently to TKIs, with erlotinib showing good efficacy regardless of mutation burden or EGFR status. However, the modulation of MDR mechanisms by erlotinib, such as increased ABCG2 expression, highlights the challenges associated with erlotinib treatment. Other TKIs showed limited efficacy, highlighting the variability of response in NSCLC. Genetic alterations in signaling pathways associated with drug resistance and sensitivity, including TP53 mutations, likely contributed to the variable responses to TKIs. The relationships between ABC transporter expression, gene alterations, and response to TKIs did not show consistent patterns. Our results suggest that in addition to mutational status, performing functional sensitivity screening is critical for identifying appropriate treatment strategies with TKIs. These results underscore the importance of considering drug sensitivity, off-target effects, MDR risks, and patient-specific genetic profiles when optimizing NSCLC treatment and highlight the potential for personalized approaches, especially in early stages. Full article

(This article belongs to the Special Issue Cancer Chemotherapy Resistance)

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12 pages, 565 KiB

Open AccessEditor’s ChoiceReview

The Role of Biomarkers in Lung Cancer Screening

by Efimia Boutsikou, Georgia Hardavella, Eleni Fili, Aikaterini Bakiri, Stylianos Gaitanakis, Alexandra Kote, Konstantinos Samitas and Ioannis Gkiozos

Cancers 2024, 16(11), 1980; https://doi.org/10.3390/cancers16111980 - 23 May 2024

Cited by 6 | Viewed by 1656

Abstract

Background: Lung Cancer Screening (LCS) is an evolving field with variations in its implementation in various countries. There are only scarce data from National LCS programs. Aim: We aim to provide an up-to-date overview of the current evidence regarding the use of biomarkers [...] Read more.

Background: Lung Cancer Screening (LCS) is an evolving field with variations in its implementation in various countries. There are only scarce data from National LCS programs. Aim: We aim to provide an up-to-date overview of the current evidence regarding the use of biomarkers in LCS. Materials and Methods: A multidisciplinary Task Force experts’ panel collaborated and conducted a systematic literature search, followed by screening, review and synthesis of available evidence. Results: Biomarkers in LCS could be used to improve risk stratification in high-risk participants, improve clarification regarding indeterminate lung nodules and avoid overdiagnosis in suspicious lung findings. Currently, there seem to be promising biomarkers (blood/serum/breath) that have been studied in various trials; however, there is still a lack of solid evidence in clinical validation that would pave the way for their integration into LCS programs. Conclusions: Biomarkers are the next logical step in improving the LCS pathway and its efficiency by playing an adjuvant role in a minimally invasive way. National LCS programs and pilot studies should integrate biomarkers to validate their accuracy in real-life LCS participants. Full article

(This article belongs to the Special Issue Recent Advances in Trachea, Bronchus and Lung Cancer Management)

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15 pages, 1635 KiB

Open AccessEditor’s ChoiceSystematic Review

Sex Differences in Anxiety and Depression Conditions among Cancer Patients: A Systematic Review and Meta-Analysis

by Elsa Vitale, Kurvatteppa Halemani, Asha Shetty, Yun-Chen Chang, Wen-Yu Hu, Raffaella Massafra and Annamaria Moretti

Cancers 2024, 16(11), 1969; https://doi.org/10.3390/cancers16111969 - 22 May 2024

Cited by 4 | Viewed by 1958

Abstract

(1) Background: Evidence suggested inconsistent results in anxiety and depression scores among female and male cancer patients. The present systematic review and meta-analysis aimed to assess how anxiety and depression conditions among cancer patients vary according to sex. (2) Methods: This systematic review [...] Read more.

(1) Background: Evidence suggested inconsistent results in anxiety and depression scores among female and male cancer patients. The present systematic review and meta-analysis aimed to assess how anxiety and depression conditions among cancer patients vary according to sex. (2) Methods: This systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). The protocol was registered in PROSPERO with id no. CRD42024512553. The search strategy involved combining keywords using Boolean operators, including “Anxiety”, “Cancer”, and “Depression”, across several databases: Embase, PubMed, Scopus, and Web of Science. The outcomes were evaluated using the Hospital Anxiety and Depression Scale (HADS). (3) Results: Data were collected from five studies, enrolling a total of 6317 cancer patients, of whom 2961 were females and 3356 males. For each study, HADS-A and HADS-D scores were considered, also differentiating HADS scores according to cancer typology, and then three different meta-analyses were performed. Generally, females reported significantly higher levels of depression scores than males and, conversely, males reported significantly greater levels of anxiety than females. (4) Conclusions: Previous studies suggested higher rates of depression and anxiety conditions in females than in males, but the present data highlighted controversial findings, since males reported significantly higher levels of anxiety than females. In this scenario, the theoretical approach justified females being more open than males to expressing anxiety or depression conditions. It would be necessary for healthcare professionals to improve effective measures purposed at assessing and mitigating depressive symptoms in cases of advanced cancer, thereby improving their mental health, given the high rates of depression in advanced cancer patients, due to the difficulty level of performing their daily living activities, which deteriorate further over time. Full article

(This article belongs to the Special Issue Updates on Depression among Cancer Patients)

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17 pages, 775 KiB

Open AccessEditor’s ChoiceReview

Intralesional and Infusional Updates for Metastatic Melanoma

by Michelle M. Dugan, Adrienne B. Shannon, Danielle K. DePalo, Matthew C. Perez and Jonathan S. Zager

Cancers 2024, 16(11), 1957; https://doi.org/10.3390/cancers16111957 - 22 May 2024

Cited by 3 | Viewed by 1903

Abstract

Locoregionally advanced and metastatic melanoma represent a challenging clinical problem, but in the era of immune checkpoint blockade and intralesional and infusional therapies, more options are available for use. Isolated limb infusion (ILI) was first introduced in the 1990s for the management of [...] Read more.

Locoregionally advanced and metastatic melanoma represent a challenging clinical problem, but in the era of immune checkpoint blockade and intralesional and infusional therapies, more options are available for use. Isolated limb infusion (ILI) was first introduced in the 1990s for the management of advanced melanoma, followed by the utilization of isolated extremity perfusion (ILP). Following this, intralesional oncolytic viruses, xanthene dyes, and cytokines were introduced for the management of in-transit metastases as well as unresectable, advanced melanoma. In 2015, the Food and Drug Administration (FDA) approved the first oncolytic intralesional therapy, talimogene laherparepvec (T-VEC), for the treatment of advanced melanoma. Additionally, immune checkpoint inhibition has demonstrated efficacy in the management of advanced melanomas, and this improvement in outcomes has been extrapolated to aid in the management of in-transit metastatic disease. Finally, percutaneous hepatic perfusion (PHP), also approved by the FDA, has been reported to have a significant impact on the treatment of hepatic disease in uveal melanoma. While some of these treatments have less utility due to inferior outcomes as well as higher toxicity profiles, there are selective patient profiles for which these therapies carry a role. This review highlights intralesional and infusional therapies for the management of metastatic melanoma. Full article

(This article belongs to the Special Issue Contemporary Surgical Management of Melanoma)

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20 pages, 1932 KiB

Open AccessEditor’s ChoiceReview

The Transformative Role of 3D Culture Models in Triple-Negative Breast Cancer Research

by Xavier S. Bittman-Soto, Evelyn S. Thomas, Madeline E. Ganshert, Laura L. Mendez-Santacruz and J. Chuck Harrell

Cancers 2024, 16(10), 1859; https://doi.org/10.3390/cancers16101859 - 13 May 2024

Cited by 4 | Viewed by 4690

Abstract

Advancements in cell culturing techniques have allowed the development of three-dimensional (3D) cell culture models sourced directly from patients’ tissues and tumors, faithfully replicating the native tissue environment. These models provide a more clinically relevant platform for studying disease progression and treatment responses [...] Read more.

Advancements in cell culturing techniques have allowed the development of three-dimensional (3D) cell culture models sourced directly from patients’ tissues and tumors, faithfully replicating the native tissue environment. These models provide a more clinically relevant platform for studying disease progression and treatment responses compared to traditional two-dimensional (2D) models. Patient-derived organoids (PDOs) and patient-derived xenograft organoids (PDXOs) emerge as innovative 3D cancer models capable of accurately mimicking the tumor’s unique features, enhancing our understanding of tumor complexities, and predicting clinical outcomes. Triple-negative breast cancer (TNBC) poses significant clinical challenges due to its aggressive nature, propensity for early metastasis, and limited treatment options. TNBC PDOs and PDXOs have significantly contributed to the comprehension of TNBC, providing novel insights into its underlying mechanism and identifying potential therapeutic targets. This review explores the transformative role of various 3D cancer models in elucidating TNBC pathogenesis and guiding novel therapeutic strategies. It also provides an overview of diverse 3D cell culture models, derived from cell lines and tumors, highlighting their advantages and culturing challenges. Finally, it delves into live-cell imaging techniques, endpoint assays, and alternative cell culture media and methodologies, such as scaffold-free and scaffold-based systems, essential for advancing 3D cancer model research and development. Full article

(This article belongs to the Special Issue Advances in Triple-Negative Breast Cancer)

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23 pages, 2587 KiB

Open AccessEditor’s ChoiceReview

Hepatocellular Carcinoma and the Multifaceted Relationship with Its Microenvironment: Attacking the Hepatocellular Carcinoma Defensive Fortress

by Linda Galasso, Lucia Cerrito, Valeria Maccauro, Fabrizio Termite, Maria Elena Ainora, Antonio Gasbarrini and Maria Assunta Zocco

Cancers 2024, 16(10), 1837; https://doi.org/10.3390/cancers16101837 - 11 May 2024

Cited by 2 | Viewed by 1752

Abstract

Hepatocellular carcinoma is a malignant tumor that originates from hepatocytes in an inflammatory substrate due to different degrees of liver fibrosis up to cirrhosis. In recent years, there has been growing interest in the role played by the complex interrelationship between hepatocellular carcinoma [...] Read more.

Hepatocellular carcinoma is a malignant tumor that originates from hepatocytes in an inflammatory substrate due to different degrees of liver fibrosis up to cirrhosis. In recent years, there has been growing interest in the role played by the complex interrelationship between hepatocellular carcinoma and its microenvironment, capable of influencing tumourigenesis, neoplastic growth, and its progression or even inhibition. The microenvironment is made up of an intricate network of mesenchymal cells, immune system cells, extracellular matrix, and growth factors, as well as proinflammatory cytokines and translocated bacterial products coming from the intestinal microenvironment via the enterohepatic circulation. The aim of this paper is to review the role of the HCC microenvironment and describe the possible implications in the choice of the most appropriate therapeutic scheme in the prediction of tumor response or resistance to currently applied treatments and in the possible development of future therapeutic perspectives, in order to circumvent resistance and break down the tumor’s defensive fort. Full article

(This article belongs to the Special Issue The Evolving Treatment and Clinical Trials of Hepatocellular Carcinoma)

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12 pages, 1826 KiB

Open AccessEditor’s ChoiceSystematic Review

Prognostic Significance of the Royal Marsden Hospital (RMH) Score in Patients with Cancer: A Systematic Review and Meta-Analysis

by Taha Koray Sahin, Alessandro Rizzo, Sercan Aksoy and Deniz Can Guven

Cancers 2024, 16(10), 1835; https://doi.org/10.3390/cancers16101835 - 11 May 2024

Cited by 116 | Viewed by 3103

Abstract

Background: Cancer remains a leading cause of death globally, necessitating the identification of prognostic biomarkers to guide treatment decisions. The Royal Marsden Hospital (RMH) score, based on readily available blood tests and clinical features, has emerged as a prognostic tool, although its performance [...] Read more.

Background: Cancer remains a leading cause of death globally, necessitating the identification of prognostic biomarkers to guide treatment decisions. The Royal Marsden Hospital (RMH) score, based on readily available blood tests and clinical features, has emerged as a prognostic tool, although its performance across variable clinical scenarios is not thoroughly delineated. Therefore, we aimed to systematically assess the association between RMH score and survival in cancer patients. Methods: We conducted a systematic literature search across Pubmed, Scopus, and Web of Science databases for studies published up to 15 February 2024. We performed a meta-analysis with the generic inverse variance method with a random-effects model and reported hazard ratios (HR) with 95% confidence intervals (CI). Results: Nineteen studies encompassing 127,230 patients were included. A higher RMH score was significantly associated with worse overall survival (OS) (HR: 2.09, 95% CI: 1.87–2.33, p < 0.001) and progression-free survival (PFS) (HR: 1.80, 95% CI: 1.48–2.18, p < 0.001). This association was consistent across various subgroups, including study population (clinical trial vs. real-world cohort), geographic region, and tumor type. Conclusion: This meta-analysis, including over a hundred thousand patients, demonstrates a negative association between a higher RMH score and survival in cancer patients. The RMH score holds promise as a readily available prognostic tool across diverse cancer types and clinical settings. Future research should focus on validating and refining this score to aid clinical decision-making. Full article

(This article belongs to the Special Issue Novel Prognostic Biomarkers in Human Cancers: From Discovery to Application)

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18 pages, 1077 KiB

Open AccessEditor’s ChoiceReview

Implementation of Artificial Intelligence in Personalized Prognostic Assessment of Lung Cancer: A Narrative Review

by Filippo Lococo, Galal Ghaly, Marco Chiappetta, Sara Flamini, Jessica Evangelista, Emilio Bria, Alessio Stefani, Emanuele Vita, Antonella Martino, Luca Boldrini, Carolina Sassorossi, Annalisa Campanella, Stefano Margaritora and Abdelrahman Mohammed

Cancers 2024, 16(10), 1832; https://doi.org/10.3390/cancers16101832 - 10 May 2024

Cited by 14 | Viewed by 4648

Abstract

Artificial Intelligence (AI) has revolutionized the management of non-small-cell lung cancer (NSCLC) by enhancing different aspects, including staging, prognosis assessment, treatment prediction, response evaluation, recurrence/prognosis prediction, and personalized prognostic assessment. AI algorithms may accurately classify NSCLC stages using machine learning techniques and deep [...] Read more.

Artificial Intelligence (AI) has revolutionized the management of non-small-cell lung cancer (NSCLC) by enhancing different aspects, including staging, prognosis assessment, treatment prediction, response evaluation, recurrence/prognosis prediction, and personalized prognostic assessment. AI algorithms may accurately classify NSCLC stages using machine learning techniques and deep imaging data analysis. This could potentially improve precision and efficiency in staging, facilitating personalized treatment decisions. Furthermore, there are data suggesting the potential application of AI-based models in predicting prognosis in terms of survival rates and disease progression by integrating clinical, imaging and molecular data. In the present narrative review, we will analyze the preliminary studies reporting on how AI algorithms could predict responses to various treatment modalities, such as surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. There is robust evidence suggesting that AI also plays a crucial role in predicting the likelihood of tumor recurrence after surgery and the pattern of failure, which has significant implications for tailoring adjuvant treatments. The successful implementation of AI in personalized prognostic assessment requires the integration of different data sources, including clinical, molecular, and imaging data. Machine learning (ML) and deep learning (DL) techniques enable AI models to analyze these data and generate personalized prognostic predictions, allowing for a precise and individualized approach to patient care. However, challenges relating to data quality, interpretability, and the ability of AI models to generalize need to be addressed. Collaboration among clinicians, data scientists, and regulators is critical for the responsible implementation of AI and for maximizing its benefits in providing a more personalized prognostic assessment. Continued research, validation, and collaboration are essential to fully exploit the potential of AI in NSCLC management and improve patient outcomes. Herein, we have summarized the state of the art of applications of AI in lung cancer for predicting staging, prognosis, and pattern of recurrence after treatment in order to provide to the readers a large comprehensive overview of this challenging issue. Full article

(This article belongs to the Special Issue Innovative Prognostic Factors and Follow-Up of Localized Thoracic Malignancies)

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20 pages, 1207 KiB

Open AccessEditor’s ChoiceReview

Driver Mutations in Pancreatic Cancer and Opportunities for Targeted Therapy

by Olamide T. Olaoba, Temitope I. Adelusi, Ming Yang, Tessa Maidens, Eric T. Kimchi, Kevin F. Staveley-O’Carroll and Guangfu Li

Cancers 2024, 16(10), 1808; https://doi.org/10.3390/cancers16101808 - 9 May 2024

Cited by 6 | Viewed by 3768

Abstract

Pancreatic cancer is the sixth leading cause of cancer-related mortality globally. As the most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) represents up to 95% of all pancreatic cancer cases, accounting for more than 300,000 deaths annually. Due to the lack [...] Read more.

Pancreatic cancer is the sixth leading cause of cancer-related mortality globally. As the most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) represents up to 95% of all pancreatic cancer cases, accounting for more than 300,000 deaths annually. Due to the lack of early diagnoses and the high refractory response to the currently available treatments, PDAC has a very poor prognosis, with a 5-year overall survival rate of less than 10%. Targeted therapy and immunotherapy are highly effective and have been used for the treatment of many types of cancer; however, they offer limited benefits in pancreatic cancer patients due to tumor-intrinsic and extrinsic factors that culminate in drug resistance. The identification of key factors responsible for PDAC growth and resistance to different treatments is highly valuable in developing new effective therapeutic strategies. In this review, we discuss some molecules which promote PDAC initiation and progression, and their potential as targets for PDAC treatment. We also evaluate the challenges associated with patient outcomes in clinical trials and implications for future research. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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9 pages, 240 KiB

Open AccessEditor’s ChoiceReview

Efficacy and Safety of Cemiplimab for the Management of Non-Melanoma Skin Cancer: A Drug Safety Evaluation

by Luca Potestio, Massimiliano Scalvenzi, Aimilios Lallas, Fabrizio Martora, Luigi Guerriero, Luigi Fornaro, Laura Marano and Alessia Villani

Cancers 2024, 16(9), 1732; https://doi.org/10.3390/cancers16091732 - 29 Apr 2024

Cited by 5 | Viewed by 1891

Abstract

Non-melanoma skin cancer includes several types of cutaneous tumors, with basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) as the commonest. Among the available therapeutic options, surgical excision is the mainstay of treatment for both tumors. However, tumor features and patients’ [...] Read more.

Non-melanoma skin cancer includes several types of cutaneous tumors, with basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) as the commonest. Among the available therapeutic options, surgical excision is the mainstay of treatment for both tumors. However, tumor features and patients’ comorbidities may limit the use of these techniques, making the treatment challenging. As regards BCC, even if hedgehog inhibitors revolutionized the therapeutic scenario, there are still patients unresponsive or intolerant to these drugs. In this context, cemiplimab has been approved as second-line treatment. As regards SCC, cemiplimab was the first systemic therapy approved. The objective of this manuscript was to investigate the efficacy and safety of cemiplimab for the management of BCC and cSCC. Cemiplimab has a durable and significant effect for the management of BCC and CSCC, with a favorable safety profile. Different specialists including oncologists, radiologists, dermatologists, and surgeons are required to guarantee an integrated approach, leading to the best management of patients. Moreover, the collaboration among specialists will allow them to best manage the TEAEs, reducing the risk of treatment suspension or discontinuation. Certainly, ongoing studies and more and more emerging real-world evidence, will allow us to better characterize the role of cemiplimab for the management of advanced non-melanoma skin cancer. Full article

(This article belongs to the Special Issue Research Progress of Cutaneous Squamous and Basal Cell Carcinomas (Volume II))

14 pages, 1361 KiB

Open AccessEditor’s ChoiceArticle

High Serum Levels of CCL20 Are Associated with Recurrence and Unfavorable Overall Survival in Advanced Melanoma Patients Receiving Immunotherapy

by Julian Kött, Inka Lilott Hoehne, Isabel Heidrich, Noah Zimmermann, Kim-Lea Reese, Tim Zell, Glenn Geidel, Alessandra Rünger, Stefan W. Schneider, Klaus Pantel, Daniel J. Smit and Christoffer Gebhardt

Cancers 2024, 16(9), 1737; https://doi.org/10.3390/cancers16091737 - 29 Apr 2024

Cited by 2 | Viewed by 2409

Abstract

Background: Immune checkpoint inhibition has revolutionized melanoma therapy, but many patients show primary or secondary resistance. Biomarkers are, therefore, urgently required to predict response prior to the initiation of therapy and to monitor disease progression. Methods: In this prospective study, we analyzed the [...] Read more.

Background: Immune checkpoint inhibition has revolutionized melanoma therapy, but many patients show primary or secondary resistance. Biomarkers are, therefore, urgently required to predict response prior to the initiation of therapy and to monitor disease progression. Methods: In this prospective study, we analyzed the serum C-C motif chemokine ligand 20 (CCL20) concentration using an enzyme-linked immunosorbent assay. Blood was obtained at baseline before the initiation of immunotherapy with anti-PD-1 monotherapy or Nivolumab and Ipilimumab in advanced melanoma patients (stages III and IV) enrolled at the University Medical Center Hamburg-Eppendorf. The CCL20 levels were correlated with clinico-pathological parameters and disease-related outcomes. Results: An increased C-C motif chemokine ligand 20 (CCL20) concentration (≥0.34 pg/mL) at baseline was associated with a significantly impaired progression-free survival (PFS) in the high-CCL20 group (3 months (95% CI: 2–6 months) vs. 11 months (95% CI: 6–26 months)) (p = 0.0033) and could be identified as an independent negative prognostic factor for PFS in univariate (Hazard Ratio (HR): 1.98, 95% CI 1.25–3.12, p = 0.004) and multivariate (HR: 1.99, 95% CI 1.21–3.29, p = 0.007) Cox regression analysis, which was associated with a higher risk than S100 (HR: 1.74). Moreover, high CCL20 levels were associated with impaired overall survival (median OS not reached for low-CCL20 group, p = 0.042) with an HR of 1.85 (95% CI 1.02–3.37, p = 0.043) in univariate analysis similar to the established prognostic marker S100 (HR: 1.99, 95% CI: 1.02–3.88, p = 0.043). Conclusions: CCL20 may represent a novel blood-based biomarker for the prediction of resistance to immunotherapy that can be used in combination with established strong clinical predictors (e.g., ECOG performance score) and laboratory markers (e.g., S100) in advanced melanoma patients. Future prospective randomized trials are needed to establish CCL20 as a liquid biopsy-based biomarker in advanced melanoma. Full article

(This article belongs to the Special Issue Novel Developments on Skin Cancer Diagnostics and Treatment)

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16 pages, 1764 KiB

Open AccessEditor’s ChoiceArticle

Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors

by Ryan A. Denu, Cissimol P. Joseph, Elizabeth S. Urquiola, Precious S. Byrd, Richard K. Yang, Ravin Ratan, Maria Alejandra Zarzour, Anthony P. Conley, Dejka M. Araujo, Vinod Ravi, Elise F. Nassif Haddad, Michael S. Nakazawa, Shreyaskumar Patel, Wei-Lien Wang, Alexander J. Lazar and Neeta Somaiah

Cancers 2024, 16(9), 1707; https://doi.org/10.3390/cancers16091707 - 27 Apr 2024

Cited by 2 | Viewed by 3225

Abstract

Objective: The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT, PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack [...] Read more.

Objective: The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT, PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack alterations in KIT, PDGFRA, and SDH. We aimed to further characterize the clinical and genomic characteristics of these so-called “triple-negative” GISTs. Methods: We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify “triple-negative” patients. Results: Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5–191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with a BRAF V600E mutation and two with NF1 loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two with TP53 LOF mutations, one with NTRK3 fusion (ETV6-NTRK3), one with PTEN deletion, one with FGFR1 gain-of-function (GOF) mutation (K654E), one with CHEK2 LOF mutation (T367fs*), one with Aurora kinase A fusion (AURKA-CSTF1), and one with FANCA deletion. Patients had better responses with molecularly targeted therapies than with imatinib. Conclusions: Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared to KIT/PDGFRA-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy. Full article

(This article belongs to the Special Issue Genome Sequencing of Cancer: Identifying Targets and Biomarkers for Therapy)

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22 pages, 323 KiB

Open AccessEditor’s ChoiceReview

Advances in Molecular Understanding of Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis: Towards Precision Medicine

by Hammad Tashkandi and Ismail Elbaz Younes

Cancers 2024, 16(9), 1679; https://doi.org/10.3390/cancers16091679 - 26 Apr 2024

Cited by 4 | Viewed by 5693

Abstract

Myeloproliferative neoplasms (MPNs), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), are characterized by the clonal proliferation of hematopoietic stem cells leading to an overproduction of hematopoietic cells. The last two decades have seen significant advances in our understanding of [...] Read more.

Myeloproliferative neoplasms (MPNs), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), are characterized by the clonal proliferation of hematopoietic stem cells leading to an overproduction of hematopoietic cells. The last two decades have seen significant advances in our understanding of the molecular pathogenesis of these diseases, with the discovery of key mutations in the JAK2, CALR, and MPL genes being pivotal. This review provides a comprehensive update on the molecular landscape of PV, ET, and PMF, highlighting the diagnostic, prognostic, and therapeutic implications of these genetic findings. We delve into the challenges of diagnosing and treating patients with prognostic mutations, clonal evolution, and the impact of emerging technologies like next-generation sequencing and single-cell genomics on the field. The future of MPN management lies in leveraging these molecular insights to develop personalized treatment strategies, aiming for precision medicine that optimizes outcomes for patients. This article synthesizes current knowledge on molecular diagnostics in MPNs, underscoring the critical role of genetic profiling in enhancing patient care and pointing towards future research directions that promise to further refine our approach to these complex disorders. Full article

(This article belongs to the Special Issue Molecular and Genetic Diagnosis and Targeted Therapy of Myeloproliferative Neoplasms)

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29 pages, 1077 KiB

Open AccessEditor’s ChoiceReview

Deregulation of New Cell Death Mechanisms in Leukemia

by Gregorio Favale, Federica Donnarumma, Vincenza Capone, Laura Della Torre, Antonio Beato, Daniela Carannante, Giulia Verrilli, Asmat Nawaz, Francesco Grimaldi, Maria Carla De Simone, Nunzio Del Gaudio, Wouter Leonard Megchelenbrink, Michele Caraglia, Rosaria Benedetti, Lucia Altucci and Vincenzo Carafa

Cancers 2024, 16(9), 1657; https://doi.org/10.3390/cancers16091657 - 25 Apr 2024

Cited by 1 | Viewed by 2089

Abstract

Hematological malignancies are among the top five most frequent forms of cancer in developed countries worldwide. Although the new therapeutic approaches have improved the quality and the life expectancy of patients, the high rate of recurrence and drug resistance are the main issues [...] Read more.

Hematological malignancies are among the top five most frequent forms of cancer in developed countries worldwide. Although the new therapeutic approaches have improved the quality and the life expectancy of patients, the high rate of recurrence and drug resistance are the main issues for counteracting blood disorders. Chemotherapy-resistant leukemic clones activate molecular processes for biological survival, preventing the activation of regulated cell death pathways, leading to cancer progression. In the past decade, leukemia research has predominantly centered around modulating the well-established processes of apoptosis (type I cell death) and autophagy (type II cell death). However, the development of therapy resistance and the adaptive nature of leukemic clones have rendered targeting these cell death pathways ineffective. The identification of novel cell death mechanisms, as categorized by the Nomenclature Committee on Cell Death (NCCD), has provided researchers with new tools to overcome survival mechanisms and activate alternative molecular pathways. This review aims to synthesize information on these recently discovered RCD mechanisms in the major types of leukemia, providing researchers with a comprehensive overview of cell death and its modulation. Full article

(This article belongs to the Special Issue Emerging Insights into Cell Death in Cancer)

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12 pages, 834 KiB

Open AccessEditor’s ChoiceArticle

The Current Achievements of Multi-Gene Panel Tests in Clinical Settings for Patients with Non-Small-Cell Lung Cancer

by Tadashi Sakaguchi, Akemi Iketani, Seiya Esumi, Maki Esumi, Yuta Suzuki, Kentaro Ito, Kentaro Fujiwara, Yoichi Nishii, Koji Katsuta, Hiroki Yasui, Osamu Taguchi and Osamu Hataji

Cancers 2024, 16(9), 1670; https://doi.org/10.3390/cancers16091670 - 25 Apr 2024

Cited by 6 | Viewed by 2058

Abstract

Some multi-gene panel tests have been implemented in clinical settings to guide targeted therapy in non-small-cell lung cancer (NSCLC) in Japan. The current performance of multi-gene panel tests under the condition that the Oncomine Dx Target Test (ODxTT) and Amoy Dx^® Pan [...] Read more.

Some multi-gene panel tests have been implemented in clinical settings to guide targeted therapy in non-small-cell lung cancer (NSCLC) in Japan. The current performance of multi-gene panel tests under the condition that the Oncomine Dx Target Test (ODxTT) and Amoy Dx^® Pan Lung Cancer PCR panel (AmoyDx-multi) are available remains relatively unknown. We retrospectively reviewed consecutive patients with NSCLC, whose FFPE samples were considered for genetic testing. We assessed the submission rates, the success rates, and the driver oncogene detection rates of multi-gene panel tests. A total of 225 patients were histologically newly diagnosed with NSCLC or diagnosed with a recurrence of NSCLC without a previous multi-gene panel test at our institution. Among the 225 patients, the FFPE samples of 212 patients (94.2%) were submitted for multi-gene panel testing, including 191 samples (84.9%) for the ODxTT and 21 samples (9.3%) for the AmoyDx-multi. Among the 212 samples submitted to multi-gene panel tests, the success rate was 99.5% (211/212). The detection rate of driver oncogene alterations for all histologies was 52.4% (111/212), and that for adenocarcinoma was 69.7% (106/152). A favorable submission rate and success rate of multi-gene panel tests were shown, along with a favorable detection rate in recent clinical settings. Full article

(This article belongs to the Section Cancer Biomarkers)

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27 pages, 965 KiB

Open AccessEditor’s ChoiceReview

Clinical Prediction Models for Prognosis of Colorectal Liver Metastases: A Comprehensive Review of Regression-Based and Machine Learning Models

by Stamatios Kokkinakis, Ioannis A. Ziogas, Jose D. Llaque Salazar, Dimitrios P. Moris and Georgios Tsoulfas

Cancers 2024, 16(9), 1645; https://doi.org/10.3390/cancers16091645 - 25 Apr 2024

Cited by 4 | Viewed by 2083

Abstract

Colorectal liver metastasis (CRLM) is a disease entity that warrants special attention due to its high frequency and potential curability. Identification of “high-risk” patients is increasingly popular for risk stratification and personalization of the management pathway. Traditional regression-based methods have been used to [...] Read more.

Colorectal liver metastasis (CRLM) is a disease entity that warrants special attention due to its high frequency and potential curability. Identification of “high-risk” patients is increasingly popular for risk stratification and personalization of the management pathway. Traditional regression-based methods have been used to derive prediction models for these patients, and lately, focus has shifted to artificial intelligence-based models, with employment of variable supervised and unsupervised techniques. Multiple endpoints, like overall survival (OS), disease-free survival (DFS) and development or recurrence of postoperative complications have all been used as outcomes in these studies. This review provides an extensive overview of available clinical prediction models focusing on the prognosis of CRLM and highlights the different predictor types incorporated in each model. An overview of the modelling strategies and the outcomes chosen is provided. Specific patient and treatment characteristics included in the models are discussed in detail. Model development and validation methods are presented and critically appraised, and model performance is assessed within a proposed framework. Full article

(This article belongs to the Special Issue Advanced Research in Oncology in 2024)

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14 pages, 1677 KiB

Open AccessEditor’s ChoiceArticle

tRNA-Derived Fragments as Biomarkers in Bladder Cancer

by Olaf Strømme, Kathleen A. Heck, Gaute Brede, Håvard T. Lindholm, Marit Otterlei and Carl-Jørgen Arum

Cancers 2024, 16(8), 1588; https://doi.org/10.3390/cancers16081588 - 20 Apr 2024

Cited by 4 | Viewed by 2322

Abstract

Bladder cancer (BC) diagnosis is reliant on cystoscopy, an invasive procedure associated with urinary tract infections. This has sparked interest in identifying noninvasive biomarkers in body fluids such as blood and urine. A source of biomarkers in these biofluids are extracellular vesicles (EVs), [...] Read more.

Bladder cancer (BC) diagnosis is reliant on cystoscopy, an invasive procedure associated with urinary tract infections. This has sparked interest in identifying noninvasive biomarkers in body fluids such as blood and urine. A source of biomarkers in these biofluids are extracellular vesicles (EVs), nanosized vesicles that contain a wide array of molecular cargo, including small noncoding RNA such as transfer RNA-derived fragments (tRF) and microRNA. Here, we performed small-RNA next-generation sequencing from EVs from urine and serum, as well as from serum supernatant. RNA was extracted from 15 non-cancer patients (NCPs) with benign findings in cystoscopy and 41 patients with non-muscle invasive BC. Urine and serum were collected before transurethral resection of bladder tumors (TUR-b) and at routine post-surgery check-ups. We compared levels of tRFs in pre-surgery samples to samples from NCPs and post-surgery check-ups. To further verify our findings, samples from 10 patients with stage T1 disease were resequenced. When comparing tRF expression in urine EVs between T1 stage BC patients and NCPs, 14 differentially expressed tRFs (DEtRFs) were identified. In serum supernatant, six DEtRFs were identified among stage T1 patients when comparing pre-surgery to post-surgery samples and four DEtRFs were found when comparing pre-surgery samples to NCPs. By performing a blast search, we found that sequences of DEtRFs aligned with genomic sequences pertaining to processes relevant to cancer development, such as enhancers, regulatory elements and CpG islands. Our findings display a number of tRFs that may hold potential as biomarkers for the diagnosis and recurrence-free survival of BC. Full article

(This article belongs to the Section Cancer Biomarkers)

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26 pages, 1409 KiB

Open AccessEditor’s ChoiceReview

Hepatocellular Carcinoma: Current Drug Therapeutic Status, Advances and Challenges

by Shunzhen Zheng, Siew Wee Chan, Fei Liu, Jun Liu, Pierce Kah Hoe Chow, Han Chong Toh and Wanjin Hong

Cancers 2024, 16(8), 1582; https://doi.org/10.3390/cancers16081582 - 20 Apr 2024

Cited by 13 | Viewed by 5056

Abstract

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for ~90% of liver neoplasms. It is the second leading cause of cancer-related deaths and the seventh most common cancer worldwide. Although there have been rapid developments in the treatment of [...] Read more.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for ~90% of liver neoplasms. It is the second leading cause of cancer-related deaths and the seventh most common cancer worldwide. Although there have been rapid developments in the treatment of HCC over the past decade, the incidence and mortality rates of HCC remain a challenge. With the widespread use of the hepatitis B vaccine and antiviral therapy, the etiology of HCC is shifting more toward metabolic-associated steatohepatitis (MASH). Early-stage HCC can be treated with potentially curative strategies such as surgical resection, liver transplantation, and radiofrequency ablation, improving long-term survival. However, most HCC patients, when diagnosed, are already in the intermediate or advanced stages. Molecular targeted therapy, followed by immune checkpoint inhibitor immunotherapy, has been a revolution in HCC systemic treatment. Systemic treatment of HCC especially for patients with compromised liver function is still a challenge due to a significant resistance to immune checkpoint blockade, tumor heterogeneity, lack of oncogenic addiction, and lack of effective predictive and therapeutic biomarkers. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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37 pages, 2553 KiB

Open AccessEditor’s ChoiceReview

Current State of Melanoma Therapy and Next Steps: Battling Therapeutic Resistance

by Anna Fateeva, Kevinn Eddy and Suzie Chen

Cancers 2024, 16(8), 1571; https://doi.org/10.3390/cancers16081571 - 19 Apr 2024

Cited by 12 | Viewed by 4450

Abstract

Melanoma is the most aggressive and deadly form of skin cancer due to its high propensity to metastasize to distant organs. Significant progress has been made in the last few decades in melanoma therapeutics, most notably in targeted therapy and immunotherapy. These approaches [...] Read more.

Melanoma is the most aggressive and deadly form of skin cancer due to its high propensity to metastasize to distant organs. Significant progress has been made in the last few decades in melanoma therapeutics, most notably in targeted therapy and immunotherapy. These approaches have greatly improved treatment response outcomes; however, they remain limited in their abilities to hinder disease progression due, in part, to the onset of acquired resistance. In parallel, intrinsic resistance to therapy remains an issue to be resolved. In this review, we summarize currently available therapeutic options for melanoma treatment and focus on possible mechanisms that drive therapeutic resistance. A better understanding of therapy resistance will provide improved rational strategies to overcome these obstacles. Full article

(This article belongs to the Section Cancer Therapy)

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15 pages, 2352 KiB

Open AccessEditor’s ChoiceArticle

A Novel ceRNET Relying on the lncRNA JPX, miR-378a-3p, and Its mRNA Targets in Lung Cancer

by Nicola Mosca, Mariaceleste Pezzullo, Ilenia De Leo, Anna Truda, Giovanna Marchese, Aniello Russo and Nicoletta Potenza

Cancers 2024, 16(8), 1526; https://doi.org/10.3390/cancers16081526 - 17 Apr 2024

Cited by 2 | Viewed by 2235

Abstract

Lung cancer is the leading cause of cancer-related death worldwide. Non-coding RNAs are emerging as critical players for the onset and progression of cancer. Analyses of three different datasets revealed that the lncRNA JPX was overexpressed in adenocarcinoma tissues in comparison to normal [...] Read more.

Lung cancer is the leading cause of cancer-related death worldwide. Non-coding RNAs are emerging as critical players for the onset and progression of cancer. Analyses of three different datasets revealed that the lncRNA JPX was overexpressed in adenocarcinoma tissues in comparison to normal lungs, as expected for an oncogene. Intriguingly, the predicted binding miR-378a-3p showed a significant inverse correlation with JPX expression. The lncRNA/miRNA physical interaction was validated by reporter vectors. Then, the oncogenic activity of JPX, the tumor-suppressive role of miR-378a-3p, and the contribution of their functional interaction to cancer hallmarks were demonstrated using assays for cell proliferation, migration, invasion, and 3D-spheroid formation. Finally, molecular circuits were investigated by boosting the expression of both JPX and miR-378a-3p, singularly and in combination, demonstrating that JPX counteracted miR-378a-3p silencing activity toward its oncogenic targets GLUT1, NRP1, YY1, and Wnt5a. Overall, the data unveil a novel ceRNET (competing endogenous RNA network), wherein JPX acts as a ceRNA by binding to miR-378a-3p, thus reducing the miRNA silencing activity toward its downstream targets, and eliciting oncogenic pathways driving lung cancer. The knowledge of the network may pave the way to develop new diagnostic panels, and innovative RNA-targeted and RNA-based therapeutic strategies. Full article

(This article belongs to the Special Issue RNA in Non-Small-Cell Lung Cancer)

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