Cancers

16 pages, 2818 KiB

Open AccessArticle

Impact of Optimized Ku–DNA Binding Inhibitors on the Cellular and In Vivo DNA Damage Response

by Pamela L. Mendoza-Munoz, Narva Deshwar Kushwaha, Dineshsinha Chauhan, Karim Ben Ali Gacem, Joy E. Garrett, Joseph R. Dynlacht, Jean-Baptiste Charbonnier, Navnath S. Gavande and John J. Turchi

Cancers 2024, 16(19), 3286; https://doi.org/10.3390/cancers16193286 (registering DOI) - 26 Sep 2024

Abstract

Background: DNA-dependent protein kinase (DNA-PK) is a validated cancer therapeutic target involved in DNA damage response (DDR) and non-homologous end-joining (NHEJ) repair of DNA double-strand breaks (DSBs). Ku serves as a sensor of DSBs by binding to DNA ends and activating DNA-PK. [...] Read more.

Background: DNA-dependent protein kinase (DNA-PK) is a validated cancer therapeutic target involved in DNA damage response (DDR) and non-homologous end-joining (NHEJ) repair of DNA double-strand breaks (DSBs). Ku serves as a sensor of DSBs by binding to DNA ends and activating DNA-PK. Inhibition of DNA-PK is a common strategy to block DSB repair and improve efficacy of ionizing radiation (IR) therapy and radiomimetic drug therapies. We have previously developed Ku–DNA binding inhibitors (Ku-DBis) that block in vitro and cellular NHEJ activity, abrogate DNA-PK autophosphorylation, and potentiate cellular sensitivity to IR. Results and Conclusions: Here we report the discovery of oxindole Ku-DBis with improved cellular uptake and retained potent Ku-inhibitory activity. Variable monotherapy activity was observed in a panel of non-small cell lung cancer (NSCLC) cell lines, with ATM-null cells being the most sensitive and showing synergy with IR. BRCA1-deficient cells were resistant to single-agent treatment and antagonistic when combined with DSB-generating therapies. In vivo studies in an NSCLC xenograft model demonstrated that the Ku-DBi treatment blocked IR-dependent DNA-PKcs autophosphorylation, modulated DDR, and reduced tumor cell proliferation. This represents the first in vivo demonstration of a Ku-targeted DNA-binding inhibitor impacting IR response and highlights the potential therapeutic utility of Ku-DBis for cancer treatment. Full article

(This article belongs to the Special Issue Incorporating DNA Damage Response (DDR) Mechanisms in Cancer Systems: 2nd Edition)

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32 pages, 5874 KiB

Open AccessReview

Deep Learning for Image Analysis in the Diagnosis and Management of Esophageal Cancer

by Charalampos Theocharopoulos, Spyridon Davakis, Dimitrios C. Ziogas, Achilleas Theocharopoulos, Dimitra Foteinou, Adam Mylonakis, Ioannis Katsaros, Helen Gogas and Alexandros Charalabopoulos

Cancers 2024, 16(19), 3285; https://doi.org/10.3390/cancers16193285 (registering DOI) - 26 Sep 2024

Abstract

Esophageal cancer has a dismal prognosis and necessitates a multimodal and multidisciplinary approach from diagnosis to treatment. High-definition white-light endoscopy and histopathological confirmation remain the gold standard for the definitive diagnosis of premalignant and malignant lesions. Artificial intelligence using deep learning (DL) methods [...] Read more.

Esophageal cancer has a dismal prognosis and necessitates a multimodal and multidisciplinary approach from diagnosis to treatment. High-definition white-light endoscopy and histopathological confirmation remain the gold standard for the definitive diagnosis of premalignant and malignant lesions. Artificial intelligence using deep learning (DL) methods for image analysis constitutes a promising adjunct for the clinical endoscopist that could effectively decrease BE overdiagnosis and unnecessary surveillance, while also assisting in the timely detection of dysplastic BE and esophageal cancer. A plethora of studies published during the last five years have consistently reported highly accurate DL algorithms with comparable or superior performance compared to endoscopists. Recent efforts aim to expand DL utilization into further aspects of esophageal neoplasia management including histologic diagnosis, segmentation of gross tumor volume, pretreatment prediction and post-treatment evaluation of patient response to systemic therapy and operative guidance during minimally invasive esophagectomy. Our manuscript serves as an introduction to the growing literature of DL applications for image analysis in the management of esophageal neoplasia, concisely presenting all currently published studies. We also aim to guide the clinician across basic functional principles, evaluation metrics and limitations of DL for image recognition to facilitate the comprehension and critical evaluation of the presented studies. Full article

(This article belongs to the Special Issue Applications of Machine and Deep Learning in Thoracic Malignancies)

14 pages, 1551 KiB

Open AccessReview

Current Status and Future Perspectives of Preoperative and Intraoperative Marking in Thoracic Surgery

by Toyofumi Fengshi Chen-Yoshikawa, Shota Nakamura, Harushi Ueno, Yuka Kadomatsu, Taketo Kato and Tetsuya Mizuno

Cancers 2024, 16(19), 3284; https://doi.org/10.3390/cancers16193284 - 26 Sep 2024

Abstract

The widespread implementation of lung cancer screening and thin-slice computed tomography (CT) has led to the more frequent detection of small nodules, which are commonly referred to thoracic surgeons. Surgical resection is the final diagnostic and treatment option for such nodules; however, surgeons [...] Read more.

The widespread implementation of lung cancer screening and thin-slice computed tomography (CT) has led to the more frequent detection of small nodules, which are commonly referred to thoracic surgeons. Surgical resection is the final diagnostic and treatment option for such nodules; however, surgeons must perform preoperative or intraoperative markings for the identification of such nodules and their precise resection. Historically, hook-wire marking has been performed more frequently worldwide; however, lethal complications, such as air embolism, have been reported. Therefore, several surgeons have recently attempted to develop novel preoperative and intraoperative markers. For example, transbronchial markings, such as virtual-assisted lung mapping and intraoperative markings using cone-beam computed tomography, have been developed. This review explores various marking methods that have been practically applied for a better understanding of preoperative and intraoperative markings in thoracic surgery. Recently, several attempts have been made to perform intraoperative molecular imaging and dynamic virtual three-dimensional computed tomography for the localization, diagnosis, and margin assessment of small nodules. In this narrative review, the current status and future perspectives of preoperative and intraoperative markings in thoracic surgery are examined for a better understanding of these techniques. Full article

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

22 pages, 28589 KiB

Open AccessReview

Unveiling the Inflammatory Landscape of Recurrent Glioblastoma through Histological-Based Assessments

by Nicholas B. Dadario, Deborah M. Boyett, Damian E. Teasley, Peter J. Chabot, Nathan J. Winans, Michael G. Argenziano, Colin P. Sperring, Peter Canoll and Jeffrey N. Bruce

Cancers 2024, 16(19), 3283; https://doi.org/10.3390/cancers16193283 - 26 Sep 2024

Abstract

The glioblastoma (GBM) tumor microenvironment consists of a heterogeneous mixture of neoplastic and non-neoplastic cells, including immune cells. Tumor recurrence following standard-of-care therapy results in a rich landscape of inflammatory cells throughout the glioma-infiltrated cortex. Immune cells consisting of glioma-associated macrophages and microglia [...] Read more.

The glioblastoma (GBM) tumor microenvironment consists of a heterogeneous mixture of neoplastic and non-neoplastic cells, including immune cells. Tumor recurrence following standard-of-care therapy results in a rich landscape of inflammatory cells throughout the glioma-infiltrated cortex. Immune cells consisting of glioma-associated macrophages and microglia (GAMMs) overwhelmingly constitute the bulk of the recurrent glioblastoma (rGBM) microenvironment, in comparison to the highly cellular and proliferative tumor microenvironment characteristic of primary GBM. These immune cells dynamically interact within the tumor microenvironment and can contribute to disease progression and therapy resistance while also providing novel targets for emerging immunotherapies. Within these varying contexts, histological-based assessments of immune cells in rGBM, including immunohistochemistry (IHC) and immunofluorescence (IF), offer a critical way to visualize and examine the inflammatory landscape. Here, we exhaustively review the available body of literature on the inflammatory landscape in rGBM as identified through histological-based assessments. We highlight the heterogeneity of immune cells throughout the glioma-infiltrated cortex with a focus on microglia and macrophages, drawing insights from canonical and novel immune-cell histological markers to estimate cell phenotypes and function. Lastly, we discuss opportunities for immunomodulatory treatments aiming to harness the inflammatory landscape in rGBM. Full article

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21 pages, 5846 KiB

Open AccessArticle

A Proteomic Analysis of Nasopharyngeal Carcinoma in a Moroccan Subpopulation

by Ayman Reffai, Michelle Hori, Ravali Adusumilli, Abel Bermudez, Abdelilah Bouzoubaa, Sharon Pitteri, Mohcine Bennani Mechita and Parag Mallick

Cancers 2024, 16(19), 3282; https://doi.org/10.3390/cancers16193282 (registering DOI) - 26 Sep 2024

Abstract

Background: Nasopharyngeal carcinoma (NPC) is a distinct cancer of the head and neck that is highly prevalent in Southeast Asia and North Africa. Though an extensive analysis of environmental and genetic contributors has been performed, very little is known about the proteome of [...] Read more.

Background: Nasopharyngeal carcinoma (NPC) is a distinct cancer of the head and neck that is highly prevalent in Southeast Asia and North Africa. Though an extensive analysis of environmental and genetic contributors has been performed, very little is known about the proteome of this disease. A proteomic analysis of formalin-fixed paraffin-embedded (FFPE) tissues can provide valuable information on protein expression and molecular patterns for both increasing our understanding of the disease and for biomarker discovery. To date, very few NPC proteomic studies have been performed, and none focused on patients from Morocco and North Africa. Methods: Label-free Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS) was used to perform a proteomic analysis of FFPE tissue samples from a cohort of 41 NPC tumor samples of Morocco and North Africa origins. The LC-MS/MS data from this cohort were analyzed alongside 21 healthy controls using MaxQuant 2.4.2.0. A differential expression analysis was performed using the MSstats package in R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotations were carried out using the DAVID bioinformatic tool. Results: 3341 proteins were identified across our NPC cases, revealing three main clusters and five DEPs with prognostic significance. The sex disparity of NPC was investigated from a proteomic perspective in which 59 DEPs were found between males and females, with significantly enriched terms associated with the immune response and gene expression. Furthermore, 26 DEPs were observed between patients with early and advanced stages of NPC with a significant cluster related to the immune response, implicating up-regulated DEPs such as IGHA, IGKC, and VAT1. Across both datasets, 6532 proteins were quantified between NPC patients and healthy controls. Among them, 1507 differentially expressed proteins (DEPs) were observed. GO and KEGG pathway analyses showed enriched terms of DEPs related to increased cellular activity, cell proliferation, and survival. PI3K and MAPK proteins as well as RAC1 BCL2 and PPIA were found to be overexpressed between cancer tissues and healthy controls. EBV infection was also one of the enriched pathways implicating its latent genes like LMP1 and LMP2 that activate several proteins and signaling pathways including NF-Kappa B, MAPK, and JAK-STAT pathways. Conclusion: Our findings unveil the proteomic landscape of NPC for the first time in the Moroccan population. These studies additionally may provide a foundation for identifying potential biomarkers. Further research is still needed to help develop tools for the early diagnosis and treatment of NPC in Moroccan and North African populations. Full article

(This article belongs to the Special Issue New Insights into Clinical and Translational Research in Nasopharyngeal Carcinoma)

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12 pages, 996 KiB

Open AccessArticle

Surgical Technique and Implementation of Total Minimally Invasive (Laparo-Thoracoscopic) Ivor Lewis Esophagectomy for Cancer

by Francesco Puccetti, Silvia Battaglia, Agnese Carresi, Lorenzo Cinelli, Stefano Turi, Ugo Elmore, Riccardo Rosati and the OSR CCeR Collaborative

Cancers 2024, 16(19), 3281; https://doi.org/10.3390/cancers16193281 - 26 Sep 2024

Abstract

Background/Objectives: Esophagectomy represents a major oncological operation due to the surgical involvement of both the abdominal and thoracic cavities. The minimally invasive technique has been developed to minimize the operative impact on patients undergoing esophageal resections, often presenting with nutritional deterioration and poor [...] Read more.

Background/Objectives: Esophagectomy represents a major oncological operation due to the surgical involvement of both the abdominal and thoracic cavities. The minimally invasive technique has been developed to minimize the operative impact on patients undergoing esophageal resections, often presenting with nutritional deterioration and poor functional reserves. Methods: The present article provides an illustrative description of the total minimally invasive (laparo-thoracoscopic) Ivor Lewis esophagectomy for cancer integrated with complementary components of perioperative clinical management. This standardized surgical technique of two-field esophagectomy (i.e., laparoscopy and thoracoscopy) was depicted based on the experience of a tertiary center for esophageal cancer care with more than 1500 cases operated on, and in accordance with the SUPER reporting guidelines. Results and conclusions: The accomplishment of the following descriptive and illustrative content allowed the development of remarks on the strengths and possible flaws of this specific procedure, providing a measurable opportunity to absorb technical details of the most widespread surgical resection for esophageal cancer worldwide. Full article

(This article belongs to the Special Issue Technical Advances in Esophageal Cancer Treatment)

10 pages, 3002 KiB

Open AccessCommentary

IDH2 Inhibitors Gain a Wildcard Status in the Cancer Therapeutics Competition

by Roberto Piva, Nariman Gharari, Maria Labrador and Sylvie Mader

Cancers 2024, 16(19), 3280; https://doi.org/10.3390/cancers16193280 (registering DOI) - 26 Sep 2024

Abstract

The metabolic reprogramming characteristic of cancer cells, including the Warburg effect, has long been recognized as a hallmark of malignancy. This commentary explores three recent investigations focusing on the role of wild-type IDH2 in cancer and immune cell function. The first publication identifies [...] Read more.

The metabolic reprogramming characteristic of cancer cells, including the Warburg effect, has long been recognized as a hallmark of malignancy. This commentary explores three recent investigations focusing on the role of wild-type IDH2 in cancer and immune cell function. The first publication identifies wild-type IDH2 as a crucial factor in the survival of triple-negative breast cancer (TNBC) cells, with its inhibition leading to disrupted energy metabolism, reduced tumor growth, and enhanced apoptosis. The second analysis examines the role of IDH2 in CD8+ T cells, revealing that its inhibition promotes the differentiation of memory T cells, thereby enhancing the efficacy of cell-based immunotherapies like CAR T cells. A third investigation supports these findings, demonstrating that IDH2 inhibition in CAR T cells reduces exhaustion, enhances memory T cell formation, and improves anti-tumor efficacy. Collectively, these reports highlight wild-type IDH2 as a promising therapeutic target, with potential applications as a two-edged sword in both cancer treatment and immunotherapy. The development of specific wild-type IDH2 inhibitors could offer new avenues for therapy, particularly in tumors reliant on IDH2 activity as well as in enhancing the effectiveness of CAR T cell therapies. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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26 pages, 8944 KiB

Open AccessArticle

Genotoxic and Anti-Migratory Effects of Camptothecin Combined with Celastrol or Resveratrol in Metastatic and Stem-like Cells of Colon Cancer

by Helena Moreira, Anna Szyjka, Dorota Bęben, Oliwia Siwiela, Anna Radajewska, Nadia Stankiewicz, Małgorzata Grzesiak, Benita Wiatrak, Fathi Emhemmed, Christian D. Muller and Ewa Barg

Cancers 2024, 16(19), 3279; https://doi.org/10.3390/cancers16193279 (registering DOI) - 26 Sep 2024

Abstract

Background: Colorectal cancer is one of the leading and most lethal neoplasms. Standard chemotherapy is ineffective, especially in metastatic cancer, and does not target cancer stem cells. A promising approach to improve cancer treatment is the combination therapy of standard cytostatic drugs [...] Read more.

Background: Colorectal cancer is one of the leading and most lethal neoplasms. Standard chemotherapy is ineffective, especially in metastatic cancer, and does not target cancer stem cells. A promising approach to improve cancer treatment is the combination therapy of standard cytostatic drugs with natural compounds. Several plant-derived compounds have been proven to possess anticancer properties, including the induction of apoptosis and inhibition of cancer invasion. This study was focused on investigating in vitro the combination of camptothecin (CPT) with celastrol (CEL) or resveratrol (RSV) as a potential strategy to target metastatic (LOVO) and stem-like (LOVO/DX) colon cancer cells. Methods: The genotoxic effects that drive cancer cells into death-inducing pathways and the ability to inhibit the migratory properties of cancer cells were evaluated. The γH2AX+ assay and Fast-Halo Assay (FHA) were used to evaluate genotoxic effects, the annexin-V apoptosis assay to rate the level of apoptosis, and the scratch test to assess antimigratory capacity. Results: The results showed that both combinations CPT-CEL and CPT-RSV improve general genotoxicity of CPT alone on metastatic cells and CSCs. However, the assessment of specific double-stranded breaks (DSBs) indicated a better efficacy of the CPT-CEL combination on LOVO cells and CPT-RSV in LOVO/DX cells. Interestingly, the combinations CPT-CEL and CPT-RSV did not improve the pro-apoptotic effect of CPT alone, with both LOVO and LOVO/DX cells suggesting activation of different cell death mechanisms. Furthermore, it was found that the combinations of CPT-CEL and CPT-RSV improve the inhibitory effect of camptothecin on cell migration. Conclusions: These findings suggest the potential utility of combining camptothecin with celastrol or resveratrol in the treatment of colon cancer, including more aggressive forms of the disease. So far, no studies evaluating the effects of combinations of these compounds have been published in the available medical databases. Full article

(This article belongs to the Section Cancer Drug Development)

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15 pages, 1969 KiB

Open AccessArticle

Proteomic Profiling Identifies Predictive Signatures for Progression Risk in Patients with Advanced-Stage Follicular Lymphoma

by Jonas Klejs Hemmingsen, Marie Hairing Enemark, Emma Frasez Sørensen, Kristina Lystlund Lauridsen, Stephen Jacques Hamilton-Dutoit, Robert Kridel, Bent Honoré and Maja Ludvigsen

Cancers 2024, 16(19), 3278; https://doi.org/10.3390/cancers16193278 - 26 Sep 2024

Abstract

Background: Follicular lymphoma (FL) is characterized by an indolent nature and generally favorable prognosis, yet poses a particular clinical challenge, since disease progression is observed in a notable subset of patients. Currently, it is not possible to anticipate which patients will be at [...] Read more.

Background: Follicular lymphoma (FL) is characterized by an indolent nature and generally favorable prognosis, yet poses a particular clinical challenge, since disease progression is observed in a notable subset of patients. Currently, it is not possible to anticipate which patients will be at risk of progression, highlighting the need for reliable predictive biomarkers that can be detected early in the disease. Methods: We applied tandem-mass-tag labelled nano-liquid chromatography tandem mass spectrometry (nLC-MS/MS) on 48 diagnostic formalin-fixed, paraffin-embedded tumor samples from patients with advanced-stage FL. Of these, 17 experienced subsequent progression (subsequently-progressing, sp-FL) while 31 did not (non-progressing, np-FL). Results: We identified 99 proteins that were significantly differentially expressed between sp-FL samples and np-FL samples (p < 0.05; log₂-fold changes between 0.2 and −1.3). Based on this subset of proteins, we classified patients into high-risk and low-risk subgroups using unsupervised machine learning techniques. Pathway analyses of the identified proteins revealed aberrancies within the immune system and cellular energy metabolism. In addition, two proteins were selected for immunohistochemical evaluation, namely stimulator of interferon genes 1 (STING1) and isocitrate dehydrogenase 2 (IDH2). Notably, IDH2 retained significantly lower expression levels in sp-FL samples compared with np-FL samples (p = 0.034). Low IDH2 expression correlated with shorter progression-free survival (PFS, p = 0.020). Conclusions: This study provides evidence for some of the biological mechanisms likely to be involved in FL progression and, importantly, identifies potential predictive biomarkers for improvement of risk stratification up-front at time of FL diagnosis. Full article

(This article belongs to the Section Methods and Technologies Development)

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15 pages, 3318 KiB

Open AccessArticle

Xeroderma Pigmentosum Type C Primary Skin Fibroblasts Overexpress HGF and Promote Squamous Cell Carcinoma Invasion in the Absence of Genotoxic Stress

by Sahar Al-qaraghuli, Yannick Gache, Maria Goncalves-Maia, Damien Alcor, Elodie Muzotte, Walid Mahfouf, Hamid-Reza Rezvani and Thierry Magnaldo

Cancers 2024, 16(19), 3277; https://doi.org/10.3390/cancers16193277 - 26 Sep 2024

Abstract

Xeroderma pigmentosum (XP) is a very rare recessive disease caused by the incapacity to resolve ultraviolet-induced DNA lesions through Nucleotide Excision Repair (NER). Most XP patients suffer from aggressive skin carcinoma and melanoma at a very early age (<8). Our previous results showed [...] Read more.

Xeroderma pigmentosum (XP) is a very rare recessive disease caused by the incapacity to resolve ultraviolet-induced DNA lesions through Nucleotide Excision Repair (NER). Most XP patients suffer from aggressive skin carcinoma and melanoma at a very early age (<8). Our previous results showed that primary XP fibroblasts isolated from healthy (non-photo-exposed) skin negatively impact the extracellular matrix and fail to activate the innate immune system. Here, we show for the first time that XP-C fibroblasts also play a major role in cancer cell invasion ex vivo and in vivo through the overexpression of Hepatocyte Growth Factor/Scatter Factor (HGF/SF) in the absence of genotoxic attacks. The use of inhibitors of the activation of the HGF/SF pathway counteracted the effects of XP fibroblasts on the growth of cancer cells, suggesting new perspectives in the care of XP patients. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in France)

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14 pages, 1500 KiB

Open AccessSystematic Review

Stereotactic Body Radiotherapy (SBRT) for the Treatment of Primary Localized Renal Cell Carcinoma: A Systematic Review and Meta-Analysis

by Agata Suleja, Mateusz Bilski, Ekaterina Laukhtina, Tamás Fazekas, Akihiro Matsukawa, Ichiro Tsuboi, Stefano Mancon, Robert Schulz, Timo F. W. Soeterik, Mikołaj Przydacz, Łukasz Nyk, Paweł Rajwa, Wojciech Majewski, Riccardo Campi, Shahrokh F. Shariat and Marcin Miszczyk

Cancers 2024, 16(19), 3276; https://doi.org/10.3390/cancers16193276 - 26 Sep 2024

Abstract

Context: Surgery is the gold standard for the local treatment of primary renal cell carcinoma (RCC), but alternatives are emerging. We conducted a systematic review and meta-analysis to assess the results of prospective studies using definitive stereotactic body radiotherapy (SBRT) to treat primary [...] Read more.

Context: Surgery is the gold standard for the local treatment of primary renal cell carcinoma (RCC), but alternatives are emerging. We conducted a systematic review and meta-analysis to assess the results of prospective studies using definitive stereotactic body radiotherapy (SBRT) to treat primary localised RCC. Evidence acquisition: This review was prospectively registered in PROSPERO (CRD42023447274). We searched PubMed, Embase, Scopus, and Google Scholar for reports of prospective studies published since 2003, describing the outcomes of SBRT for localised RCC. Meta-analyses were performed for local control (LC), overall survival (OS), and rates of adverse events (AEs) using generalised linear mixed models (GLMMs). Outcomes were presented as rates with corresponding 95% confidence intervals (95% CIs). Risk-of-bias was assessed using the ROBINS-I tool. Evidence synthesis: Of the 2983 records, 13 prospective studies (n = 308) were included in the meta-analysis. The median diameter of the irradiated tumours ranged between 1.9 and 5.5 cm in individual studies. Grade ≥ 3 AEs were reported in 15 patients, and their estimated rate was 0.03 (95%CI: 0.01–0.11; n = 291). One- and two-year LC rates were 0.98 (95%CI: 0.95–0.99; n = 293) and 0.97 (95%CI: 0.93–0.99; n = 253), while one- and two-year OS rates were 0.95 (95%CI: 0.88–0.98; n = 294) and 0.86 (95%CI: 0.77–0.91; n = 224). There was no statistically significant heterogeneity, and the estimations were consistent after excluding studies at a high risk of bias in a sensitivity analysis. Major limitations include a relatively short follow-up, inhomogeneous reporting of renal function deterioration, and a lack of prospective comparative evidence. Conclusions: The short-term results suggest that SBRT is a valuable treatment method for selected inoperable patients (or those who refuse surgery) with localised RCC associated with low rates of high-grade AEs and excellent LC. However, until the long-term data from randomised controlled trials are available, surgical management remains a standard of care in operable patients. Full article

(This article belongs to the Special Issue Clinical and Translational Updates in Renal Cell Carcinoma)

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11 pages, 226 KiB

Open AccessReview

Mechanisms by Which Pharmacotherapy May Impact Cancer Risk among Individuals with Overweight and Obesity

by Edward R. Sauter and Tanya Agurs-Collins

Cancers 2024, 16(19), 3275; https://doi.org/10.3390/cancers16193275 - 26 Sep 2024

Abstract

Diets geared to reduce cancer risk in overweight and obese individuals focus on (1) caloric restriction (every day, some days, or most hours of each day); (2) changes in macronutrient intake; or (3) a combination of the prior two strategies. Diets generally fail [...] Read more.

Diets geared to reduce cancer risk in overweight and obese individuals focus on (1) caloric restriction (every day, some days, or most hours of each day); (2) changes in macronutrient intake; or (3) a combination of the prior two strategies. Diets generally fail because of nonadherence or due to limited sustained weight loss. This is in contrast to a diet supplemented with a weight loss medication, so long as the participant continues the medication or after bariatric surgery, in which adherence tends to be much higher. Among individuals who regain weight after surgery, weight loss medications are proving beneficial in maintaining weight loss. Both maximum and sustained weight loss are essential for all forms of effective metabolic improvement, including cancer risk reduction. The focus of this report is to assess the state of research on the consequence of pharmacotherapy use on weight loss and proposed weight loss-independent effects on subsequent cancer risk reduction, including the potential role of medication use in conjunction with metabolic (bariatric) surgery (MBS). Finally, we present Notices of Funding Opportunities (NOFOs) by the National Cancer Institute (NCI) to better understand the mechanism(s) that are driving the efficacy of pharmacotherapy in cancer risk reduction. Full article

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

15 pages, 1899 KiB

Open AccessArticle

Vascular Biomarkers for Pulmonary Nodule Malignancy: Arteries vs. Veins

by Tong Yu, Xiaoyan Zhao, Joseph K. Leader, Jing Wang, Xin Meng, James Herman, David Wilson and Jiantao Pu

Cancers 2024, 16(19), 3274; https://doi.org/10.3390/cancers16193274 - 26 Sep 2024

Abstract

Objective: This study aims to investigate the association between the arteries and veins surrounding a pulmonary nodule and its malignancy. Methods: A dataset of 146 subjects from a LDCT lung cancer screening program was used in this study. AI algorithms were used to [...] Read more.

Objective: This study aims to investigate the association between the arteries and veins surrounding a pulmonary nodule and its malignancy. Methods: A dataset of 146 subjects from a LDCT lung cancer screening program was used in this study. AI algorithms were used to automatically segment and quantify nodules and their surrounding macro-vasculature. The macro-vasculature was differentiated into arteries and veins. Vessel branch count, volume, and tortuosity were quantified for arteries and veins at different distances from the nodule surface. Univariate and multivariate logistic regression (LR) analyses were performed, with a special emphasis on the nodules with diameters ranging from 8 to 20 mm. ROC-AUC was used to assess the performance based on the k-fold cross-validation method. Average feature importance was evaluated in several machine learning models. Results: The LR models using macro-vasculature features achieved an AUC of 0.78 (95% CI: 0.71–0.86) for all nodules and an AUC of 0.67 (95% CI: 0.54–0.80) for nodules between 8–20 mm. Models including macro-vasculature features, demographics, and CT-derived nodule features yielded an AUC of 0.91 (95% CI: 0.87–0.96) for all nodules and an AUC of 0.82 (95% CI: 0.71–0.92) for nodules between 8–20 mm. In terms of feature importance, arteries within 5.0 mm from the nodule surface were the highest-ranked among macro-vasculature features and retained their significance even with the inclusion of demographics and CT-derived nodule features. Conclusions: Arteries within 5.0 mm from the nodule surface emerged as a potential biomarker for effectively discriminating between malignant and benign nodules. Full article

(This article belongs to the Collection Oncology: State-of-the-Art Research in the USA)

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30 pages, 1567 KiB

Open AccessReview

Barriers to T Cell Functionality in the Glioblastoma Microenvironment

by Noor E. Nader, Stephen C. Frederico, Tracy Miller, Sakibul Huq, Xiaoran Zhang, Gary Kohanbash and Constantinos G. Hadjipanayis

Cancers 2024, 16(19), 3273; https://doi.org/10.3390/cancers16193273 - 26 Sep 2024

Abstract

Glioblastoma (GBM) is an aggressive primary brain tumor depicted by a cold tumor microenvironment, low immunogenicity, and limited effective therapeutic interventions. Its location in the brain, a highly immune-selective organ, acts as a barrier, limiting immune access and promoting GBM dissemination, despite therapeutic [...] Read more.

Glioblastoma (GBM) is an aggressive primary brain tumor depicted by a cold tumor microenvironment, low immunogenicity, and limited effective therapeutic interventions. Its location in the brain, a highly immune-selective organ, acts as a barrier, limiting immune access and promoting GBM dissemination, despite therapeutic interventions. Currently, chemotherapy and radiation combined with surgical resection are the standard of care for GBM treatment. Although immune checkpoint blockade has revolutionized the treatment of solid tumors, its observed success in extracranial tumors has not translated into a significant survival benefit for GBM patients. To develop effective immunotherapies for GBM, it is vital to tailor treatments to overcome the numerous immunosuppressive barriers that inhibit T cell responses to these tumors. In this review, we address the unique physical and immunological barriers that make GBM challenging to treat. Additionally, we explore potential therapeutic mechanisms, studied in central nervous system (CNS) and non-CNS cancers, that may overcome these barriers. Furthermore, we examine current and promising immunotherapy clinical trials and immunotherapeutic interventions for GBM. By highlighting the array of challenges T cell-based therapies face in GBM, we hope this review can guide investigators as they develop future immunotherapies for this highly aggressive malignancy. Full article

(This article belongs to the Collection Deciphering the Crosstalk between Tumor Cells and Their Microenvironment: From Molecular Aspects to Therapeutic Implications)

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16 pages, 3849 KiB

Open AccessArticle

Autophagy Blockage Up-Regulates HLA-Class-I Molecule Expression in Lung Cancer and Enhances Anti-PD-L1 Immunotherapy Efficacy

by Erasmia Xanthopoulou, Ioannis Lamprou, Achilleas G. Mitrakas, Georgios D. Michos, Christos E. Zois, Alexandra Giatromanolaki, Adrian L. Harris and Michael I. Koukourakis

Cancers 2024, 16(19), 3272; https://doi.org/10.3390/cancers16193272 - 26 Sep 2024

Abstract

Background/Objectives: Immune checkpoint inhibitors have an established role in non-small cell lung cancer (NSCLC) therapy. The loss of HLA-class-I expression allows cancer cell evasion from immune surveillance, disease progression, and failure of immunotherapy. The restoration of HLA-class-I expression may prove to be a [...] Read more.

Background/Objectives: Immune checkpoint inhibitors have an established role in non-small cell lung cancer (NSCLC) therapy. The loss of HLA-class-I expression allows cancer cell evasion from immune surveillance, disease progression, and failure of immunotherapy. The restoration of HLA-class-I expression may prove to be a game-changer in current immunotherapy strategies. Autophagic activity has been recently postulated to repress HLA-class-I expression in cancer cells. Methods: NSCLC cell lines (A549 and H1299) underwent late-stage (chloroquine and bafilomycin) and early-stage autophagy blockage (ULK1 inhibitors and MAP1LC3A silencing). The HLA-class-I expression was assessed with flow cytometry, a Western blot, and RT-PCR. NSCLC tissues were examined for MAP1LC3A and HLA-class-I expression using double immunohistochemistry. CD8+ T-cell cytotoxicity was examined in cancer cells pre-incubated with chloroquine and anti-PD-L1 monoclonal antibodies (Moabs); Results: A striking increase in HLA-class-I expression following incubation with chloroquine, bafilomycin, and IFNγ was noted in A549 and H1299 cancer cells, respectively. This effect was further confirmed in CD133+ cancer stem cells. HLA-class-I, β2-microglobulin, and TAP1 mRNA levels remained stable. Prolonged exposure to chloroquine further enhanced HLA-class-I expression. Similar results were noted following exposure to a ULK1 and a PIKfyve inhibitor. Permanent silencing of the MAP1LC3A gene resulted in enhanced HLA-class-I expression. In immunohistochemistry experiments, double LC3A+/HLA-class-I expression was seldom. Pre-incubation of H1299 cancer cells with chloroquine and anti-PD-L1 MoAbs increased the mean % of apoptotic/necrotic cells from 2.5% to 18.4%; Conclusions: Autophagy blockers acting either at late or early stages of the autophagic process may restore HLA-class-I-mediated antigen presentation, eventually leading to enhanced immunotherapy efficacy. Full article

(This article belongs to the Special Issue Lung Cancer: Molecular Pathways, Current Therapies and New Targeted Treatments)

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12 pages, 1195 KiB

Open AccessArticle

Genetic Analysis of Biopsy Tissues from Colorectal Tumors in Patients with Ulcerative Colitis

by Noriko Yamamoto, Yuji Urabe, Hikaru Nakahara, Takeo Nakamura, Daisuke Shimizu, Hirona Konishi, Kazuki Ishibashi, Misa Ariyoshi, Ryo Miyamoto, Junichi Mizuno, Takeshi Takasago, Akira Ishikawa, Akiyoshi Tsuboi, Hidenori Tanaka, Ken Yamashita, Yuichi Hiyama, Yoshihiro Kishida, Hidehiko Takigawa, Toshio Kuwai, Koji Arihiro, Fumio Shimamoto and Shiro Oka Show full author list Hide full author list

Cancers 2024, 16(19), 3271; https://doi.org/10.3390/cancers16193271 - 26 Sep 2024

Abstract

Background/Objectives: Colorectal neoplasia developing from ulcerative colitis mucosa (CRNUC) can be divided into ulcerative colitis-associated neoplasia (UCAN) and non-UCAN; however, it is often difficult to distinguish UCAN from non-UCAN during a biopsy diagnosis. We investigated whether a genomic analysis could improve the diagnostic [...] Read more.

Background/Objectives: Colorectal neoplasia developing from ulcerative colitis mucosa (CRNUC) can be divided into ulcerative colitis-associated neoplasia (UCAN) and non-UCAN; however, it is often difficult to distinguish UCAN from non-UCAN during a biopsy diagnosis. We investigated whether a genomic analysis could improve the diagnostic accuracy of UCAN using biopsy specimens. Methods: In step 1, 14 CRNUCs were used to examine whether the genomic landscape of biopsy and resection specimens matched. In step 2, we investigated the relationship between the genomic landscapes and the pathological diagnosis of 26 CRNUCs. The cancer genome was analyzed by deep sequencing using a custom panel of 27 genes found to be mutated in our previous CRNUC analysis. Results: In step 1, of the 27 candidate genes, 14 were mutated. The concordance rate of the pathogenic mutations in these 14 genes between the biopsy and resection specimens was 29% (4/14), while that of the pathogenic mutations in TP53 and KRAS was 79% (11/14). In step 2, the pathological diagnosis of biopsy specimens using only hematoxylin and eosin (HE) staining had a sensitivity of 33% and an accuracy of 38% for UCAN diagnosis. On the other hand, the combination of the HE pathology and p53 immunohistochemical staining had a sensitivity of 73% and an accuracy of 85% for UCAN diagnosis, while the combination of HE staining and a TP53 mutation had a sensitivity of 87% and an accuracy of 88% for UCAN diagnosis. Conclusions: An evaluation of TP53 mutations in biopsy specimens may be useful for diagnosing UCAN. However, further studies with larger sample sizes are required before this can be applied in clinical practice. Full article

(This article belongs to the Section Methods and Technologies Development)

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12 pages, 3148 KiB

Open AccessArticle

Prioritizing Radiation and Targeted Systemic Therapies in Patients with Resected Brain Metastases from Lung Cancer Primaries with Targetable Mutations: A Report from a Multi-Site Single Institution

by Yen-Ruh Wuu, Mostafa Kokabee, Bin Gui, Simon Lee, Jacob Stone, Jessie Karten, Randy S. D’Amico, Morana Vojnic and A.Gabriella Wernicke

Cancers 2024, 16(19), 3270; https://doi.org/10.3390/cancers16193270 - 26 Sep 2024

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Abstract

Background/Objectives: Brain metastases (BrMs) are a common complication of non-small cell lung cancer (NSCLC), present in up to 50% of patients. While the treatment of BrMs requires a multidisciplinary approach with surgery, radiotherapy (RT), and systemic therapy, the advances in molecular sequencing [...] Read more.

Background/Objectives: Brain metastases (BrMs) are a common complication of non-small cell lung cancer (NSCLC), present in up to 50% of patients. While the treatment of BrMs requires a multidisciplinary approach with surgery, radiotherapy (RT), and systemic therapy, the advances in molecular sequencing have improved outcomes in patients with targetable mutations. With a push towards the molecular characterization of cancers, we evaluated the outcomes by treatment modality at our institution with respect to prioritizing RT and targeted therapies. Methods: We identified the patients with NSCLC BrMs treated with surgical resection. The primary endpoints were in-brain freedom from progression (FFP) and overall survival (OS). The secondary endpoint included index lesion recurrence. The tumor molecular profiles were reviewed. The outcomes were evaluated by treatment modality: surgery followed by adjuvant RT and/or adjuvant systemic therapy. Results: In total, 155/272 (57%) patients who received adjuvant therapy with adequate follow-up were included in this analysis. The patients treated with combination therapy vs. monotherapy had a median FFP time of 10.72 months vs. 5.38 months, respectively (p = 0.072). The patients of Hispanic/Latino vs. non-Hispanic/Latino descent had a statistically significant worse OS of 12.75 months vs. 53.15 months, respectively (p = 0.015). The patients who received multimodality therapy had a trend towards a reduction in index lesion recurrences (χ² test, p = 0.063) with a statistically significant improvement in the patients receiving immunotherapy (χ² test, p = 0.0018). Conclusions: We found that systemic therapy combined with RT may have an increasing role in delaying the time to progression; however, there was no statistically significant relationship between OS and treatment modality. Full article

(This article belongs to the Special Issue Brain Metastases: Diagnosis and Treatment)

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16 pages, 42416 KiB

Open AccessArticle

FBXO11 Mediates Ubiquitination of ZEB1 and Modulates Epithelial-to-Mesenchymal Transition in Lung Cancer Cells

by Xinyue Zhao, Zhihui Han, Ruiying Liu, Zehao Li, Ling Mei and Yue Jin

Cancers 2024, 16(19), 3269; https://doi.org/10.3390/cancers16193269 - 26 Sep 2024

Abstract

Epithelial-to-mesenchymal transition (EMT) affects the invasion and migration of cancer cells. Here, we show that FBXO11 recognizes and promotes ubiquitin-mediated degradation of ZEB1. There is a strong association between FBXO11 and ZEB1 in non-small cell lung cancer (NSLC) in a clinical database. FBXO11 [...] Read more.

Epithelial-to-mesenchymal transition (EMT) affects the invasion and migration of cancer cells. Here, we show that FBXO11 recognizes and promotes ubiquitin-mediated degradation of ZEB1. There is a strong association between FBXO11 and ZEB1 in non-small cell lung cancer (NSLC) in a clinical database. FBXO11 interacts with ZEB1, a core inducer of EMT. FBXO11 leads to increased ubiquitination and proteasomal degradation of ZEB1. Depletion of endogenous FBXO11 causes ZEB1 protein accumulation and EMT in A549 and H1299 cells, while overexpression of FBXO11 reduces ZEB1 protein abundance and cellular invasiveness. Importantly, the depletion of ZEB1 suppresses the increased migration and invasion of A549 and H1299 cells promoted by the depletion of FBXO11. The same results are shown in xenograft tumors. High FBXO11 expression is associated with a favorable prognosis in NSLC. Collectively, our study demonstrates that FBXO11 modulates EMT by mediating the stability of ZEB1 in lung cancer cells. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cancer Development and Metastasis)

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17 pages, 314 KiB

Open AccessFeature PaperReview

Novel Targeted Agents in Advanced and Recurrent Low-Grade Serous Ovarian Cancer: A Silver Lining in the Therapy of a Chemoresistant Disease?

by Arina Onoprienko, Thomas Bartl, Christoph Grimm, Nicole Concin and Stephan Polterauer

Cancers 2024, 16(19), 3268; https://doi.org/10.3390/cancers16193268 - 26 Sep 2024

Viewed by 67

Abstract

Low-grade serous ovarian carcinoma (LGSOC) is a rare subtype of epithelial ovarian cancer, characterized by a unique molecular background and specific clinical behavior. A growing body of molecular data underscores LGSOC as a distinct disease entity; however, clinical evidence on the optimal treatment [...] Read more.

Low-grade serous ovarian carcinoma (LGSOC) is a rare subtype of epithelial ovarian cancer, characterized by a unique molecular background and specific clinical behavior. A growing body of molecular data underscores LGSOC as a distinct disease entity; however, clinical evidence on the optimal treatment regimens for LGSOC remains limited due to the low incidence of the disease. Consequently, treatment recommendations for LGSOC are still often derived from findings on the more common high-grade serous ovarian carcinoma (HGSOC) and typically focus on radical cytoreductive surgery and platinum-based chemotherapy. Since LGSOCs typically exhibit only limited responsiveness to platinum-based chemotherapy, the clinical management of advanced and recurrent LGSOCs remains a significant therapeutic challenge and often results in limited treatment options and suboptimal outcomes. Recent advances in molecular profiling and the identification of new, promising targets, such as the mitogen-activated protein kinase (MAPK) pathway, offer hope for improving both the prognosis and health-related quality of life in affected patients. Given the high unmet clinical need to establish new therapeutic standards beyond cytotoxic chemotherapy, this review aims to summarize the most promising molecular targets and emerging targeted agents. Full article

(This article belongs to the Special Issue Feature Review for Cancer Therapy)

8 pages, 496 KiB

Open AccessReview

Menopausal Hormone Therapy in Breast Cancer Survivors

by Rose Culhane, Alexandra M. Zaborowski and Arnold D. K. Hill

Cancers 2024, 16(19), 3267; https://doi.org/10.3390/cancers16193267 - 26 Sep 2024

Viewed by 68

Abstract

Menopausal symptoms negatively impact quality of life in breast cancer survivors. The paucity of data on the impact of Menopausal Hormone Therapy (MHT) on oncological outcomes in these patients limits informed clinical discussion. Defining the risk of cancer recurrence with MHT is central [...] Read more.

Menopausal symptoms negatively impact quality of life in breast cancer survivors. The paucity of data on the impact of Menopausal Hormone Therapy (MHT) on oncological outcomes in these patients limits informed clinical discussion. Defining the risk of cancer recurrence with MHT is central to the appraisal of risk/benefit, particularly with low-risk disease (based on genomic profile). The aim of this review is to summarize the current data evaluating MHT in breast cancer patients. A systematic review of the literature was performed to evaluate the impact of MHT on oncological outcomes in breast cancer survivors. Three major databases (PubMed, EMBASE and Medline) were searched. The review included all prospective studies published in English. Four randomized control trials and four non-randomized prospective studies were identified. An increase in breast cancer recurrence with MHT was observed in the early randomized trials whilst no increased risk of recurrence was reported in the observational studies. There remains a need to quantify MHT-related recurrence risk in patients with molecularly favorable disease. Full article

(This article belongs to the Special Issue Breast Cancer and Hormone-Related Therapy)

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14 pages, 1053 KiB

Open AccessReview

The Multimodality Management of Malignant Peripheral Nerve Sheath Tumours

by Remus Seres, Hassan Hameed, Martin G. McCabe, David Russell and Alexander T. J. Lee

Cancers 2024, 16(19), 3266; https://doi.org/10.3390/cancers16193266 - 26 Sep 2024

Viewed by 144

Abstract

Malignant peripheral nerve sheath tumours (MPNST) are aggressive sarcomas that have nerve sheath differentiation and can present at any anatomical site. They can arise from precursor neurofibroma in the context of neurofibromatosis type 1 (NF1) or as de novo and sporadic tumours in [...] Read more.

Malignant peripheral nerve sheath tumours (MPNST) are aggressive sarcomas that have nerve sheath differentiation and can present at any anatomical site. They can arise from precursor neurofibroma in the context of neurofibromatosis type 1 (NF1) or as de novo and sporadic tumours in the absence of an underlying genetic predisposition. The primary therapeutic approach is most often radical surgery, with non-surgical modalities playing an important role, especially in locally advanced or metastatic cases. The aim of multimodality approaches is to optimize both local and systemic control while keeping to a minimum acute and late treatment morbidity. Advances in the understanding of the underlying biology of MPNSTs in both sporadic and NF-1-related contexts are essential for the management and implementation of novel therapeutic approaches. Full article

(This article belongs to the Special Issue Multimodality Management of Sarcomas)

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18 pages, 1270 KiB

Open AccessReview

Unravelling the Complexity of HNSCC Using Single-Cell Transcriptomics

by Cristina Conde-Lopez, Divyasree Marripati, Moshe Elkabets, Jochen Hess and Ina Kurth

Cancers 2024, 16(19), 3265; https://doi.org/10.3390/cancers16193265 - 25 Sep 2024

Viewed by 165

Abstract

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous and the most common form of head and neck cancer, posing significant challenges for disease management. The objective of this review is to assess the utility of single-cell RNA sequencing (scRNAseq) [...] Read more.

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous and the most common form of head and neck cancer, posing significant challenges for disease management. The objective of this review is to assess the utility of single-cell RNA sequencing (scRNAseq) in addressing these challenges by enabling a detailed characterization of the tumor microenvironment (TME) at the cellular level. Methods: This review compiles and analyzes current strategies that utilize scRNAseq and other single-cell technologies in HNSCC research. Results: For HNSCC etiology, scRNAseq allows for the construction of cellular atlases, characterization of different cell types, and investigation of genes and processes involved in cancer initiation, development, and progression within the TME. In terms of HNSCC diagnosis and prognosis, the resolution offered by scRNAseq enables the identification of cell type-specific signatures, enhancing prognostic models and disease stratifiers for patient outcome assessments. Regarding HNSCC treatment, scRNAseq provides insights into cellular responses to various treatments, including radiotherapy, chemotherapy, and immunotherapy, contributing to a better understanding of treatment efficacy and patient outcomes. Conclusions: This review highlights the contributions of scRNAseq to HNSCC research, addressing its cellular and biological complexity, and emphasizes its potential for advancing research and clinical practice in other cancer types. Full article

(This article belongs to the Special Issue Head and Neck Cancers—Novel Approaches and Future Outlook)

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16 pages, 1648 KiB

Open AccessArticle

Germline Polymorphisms Associated with Overall Survival in Lung Adenocarcinoma: Genome-Wide Analysis

by Francesca Minnai, Sara Noci, Martina Esposito, Marc A. Schneider, Sonja Kobinger, Martin Eichhorn, Hauke Winter, Hans Hoffmann, Mark Kriegsmann, Matteo A. Incarbone, Giovanni Mattioni, Davide Tosi, Thomas Muley, Tommaso A. Dragani and Francesca Colombo

Cancers 2024, 16(19), 3264; https://doi.org/10.3390/cancers16193264 - 25 Sep 2024

Viewed by 196

Abstract

Background/Objectives: Lung cancer remains a global health concern, with substantial variation in patient survival. Despite advances in detection and treatment, the genetic basis for the divergent outcomes is not understood. We investigated germline polymorphisms that modulate overall survival in 1464 surgically resected lung [...] Read more.

Background/Objectives: Lung cancer remains a global health concern, with substantial variation in patient survival. Despite advances in detection and treatment, the genetic basis for the divergent outcomes is not understood. We investigated germline polymorphisms that modulate overall survival in 1464 surgically resected lung adenocarcinoma patients. Methods: A multivariable Cox proportional hazard model was used to assess the association of more than seven million polymorphisms with overall survival at the 60-month follow-up, considering age, sex, pathological stage, decade of surgery and principal components as covariates. Genes in which variants were identified were studied in silico to investigate functional roles. Results: Six germline variants passed the genome-wide significance threshold. These single nucleotide polymorphisms were mapped to non-coding (intronic) regions on chromosomes 2, 3, and 5. The minor alleles of rs13000315, rs151212827, and rs190923216 (chr. 2, 3 and 5, respectively) were found to be independent negative prognostic factors. All six variants have been reported to regulate the expression of nine genes, seven of which are protein-coding, in different tissues. Survival-associated variants on chromosomes 2 and 3 were already reported to regulate the expression of NT5DC2 and NAGK, with high expression associated with the minor alleles. High NT5DC2 and NAGK expression in lung adenocarcinoma tissue was already shown to correlate with poor overall survival. Conclusions: This study highlights a potential regulatory role of the identified polymorphisms in influencing outcome and suggests a mechanistic link between these variants, gene expression regulation, and lung adenocarcinoma prognosis. Validation and functional studies are warranted to elucidate the mechanisms underlying these associations. Full article

(This article belongs to the Section Cancer Pathophysiology)

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24 pages, 8095 KiB

Open AccessArticle

Signature Genes Selection and Functional Analysis of Phenotypes: A Comparative Study

by Anna Drozdz, Caitriona E. McInerney, Kevin M. Prise, Veronica J. Spence and Jose Sousa

Cancers 2024, 16(19), 3263; https://doi.org/10.3390/cancers16193263 - 25 Sep 2024

Viewed by 203

Abstract

Novel cancer biomarkers discoveries are driven by the application of omics technologies. The vast quantity of highly dimensional data necessitates the implementation of feature selection. The mathematical basis of different selection methods varies considerably, which may influence subsequent inferences. In the study, feature [...] Read more.

Novel cancer biomarkers discoveries are driven by the application of omics technologies. The vast quantity of highly dimensional data necessitates the implementation of feature selection. The mathematical basis of different selection methods varies considerably, which may influence subsequent inferences. In the study, feature selection and classification methods were employed to identify six signature gene sets of grade 2 and 3 astrocytoma samples from the Rembrandt repository. Subsequently, the impact of these variables on classification and further discovery of biological patterns was analysed. Principal component analysis (PCA), uniform manifold approximation and projection (UMAP), and hierarchical clustering revealed that the data set (10,096 genes) exhibited a high degree of noise, feature redundancy, and lack of distinct patterns. The application of feature selection methods resulted in a reduction in the number of genes to between 28 and 128. Notably, no single gene was selected by all of the methods tested. Selection led to an increase in classification accuracy and noise reduction. Significant differences in the Gene Ontology terms were discovered, with only 13 terms overlapping. One selection method did not result in any enriched terms. KEGG pathway analysis revealed only one pathway in common (cell cycle), while the two methods did not yield any enriched pathways. The results demonstrated a significant difference in outcomes when classification-type algorithms were utilised in comparison to mixed types (selection and classification). This may result in the inadvertent omission of biological phenomena, while simultaneously achieving enhanced classification outcomes. Full article

(This article belongs to the Section Cancer Biomarkers)

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19 pages, 3108 KiB

Open AccessReview

Revisiting HER2 in Prostate Cancer from an Inclusive Perspective: From Biomarkers to Omics

by Nicole Mavingire, Janelle C. Moore, Jabril R. Johnson, Abdulrahman M. Dwead, Cheryl D. Cropp, Yehia Mechref, Firas Kobeissy, Soroush Rais-Bahrami and Leanne Woods-Burnham

Cancers 2024, 16(19), 3262; https://doi.org/10.3390/cancers16193262 - 25 Sep 2024

Viewed by 451

Abstract

Human epidermal growth factor receptor 2 (HER2) is a major driver of disease progression, treatment resistance, and worse survival for patients with various types of cancers, including prostate cancer. However, key bench studies and clinical trials have failed to evaluate the role of [...] Read more.

Human epidermal growth factor receptor 2 (HER2) is a major driver of disease progression, treatment resistance, and worse survival for patients with various types of cancers, including prostate cancer. However, key bench studies and clinical trials have failed to evaluate the role of HER2 in prostate cancer using racially diverse experimental designs and protocols. This lack of diversity represents what has been the status quo of cancer research in the United States for decades. In the case of prostate cancer, homogenic study designs are problematic as Black men are much more likely to be diagnosed and die from aggressive and incurable forms of the disease. Therefore, the strategic inclusion of biospecimens collected from Black patients as well as the recruitment and enrollment of Black men into prostate cancer clinical trials is necessary to comprehensively evaluate genetic and molecular factors that contribute to variable outcomes in this high-risk population. Additionally, a higher prevalence of HER2 expression in Black men was recently reported in a small cohort of prostate cancer patients and may contribute to worsened prognosis. In this review, we carefully consider the role of HER2 in prostate cancer while, for the first time, taking into account the influences of race and genetic ancestry. Full article

(This article belongs to the Special Issue Molecular Biology of Urological Cancers)

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12 pages, 4082 KiB

Open AccessArticle

Simultaneous Autophagy and Androgen Receptor Inhibition in a Prostate Cancer Xenograft Model

by Souzan Salemi, Benedikt Kranzbühler, Valentin Baumgartner, Lara Breitenmoser, Aleksandar Kuzmanov, Fabienne Lehner and Daniel Eberli

Cancers 2024, 16(19), 3261; https://doi.org/10.3390/cancers16193261 - 25 Sep 2024

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Abstract

Objective: Abi, when used in conjunction with prednisone, is an established treatment for advanced PCa. Our goal was to explore the level of autophagy induced by Abi treatment, both alone and in combination with the autophagy inhibitor Chl, in a castrated mouse xenograft [...] Read more.

Objective: Abi, when used in conjunction with prednisone, is an established treatment for advanced PCa. Our goal was to explore the level of autophagy induced by Abi treatment, both alone and in combination with the autophagy inhibitor Chl, in a castrated mouse xenograft model. Methods: LNCaP cells were injected into the left and right sides of the back of nude mice that had been previously castrated. Mice were divided into four groups and treated daily with intraperitoneal injections of vehicle (control), Abi (10 mg/kg), Abi (10 mg/kg) combined with Chl (10 mg/kg), or Chl (10 mg/kg), and were monitored for periods of 2 and 3 weeks. Results: A significant reduction in tumor weight was observed in mice treated with the combination therapy, as opposed to those receiving vehicle control, Abi, or Chl alone. Mice receiving Abi + Chl exhibited reduced expression of ATG5, Beclin 1, and LC3 punctuations, along with an increase in P62, as determined by immunofluorescence and WES analysis. AR expression decreased significantly in all treatment groups compared to the control. PSMA expression was highest in the vehicle and combined treatment groups after 3 weeks, with a significant reduction observed with Chl treatment. Conclusions: These findings demonstrate that Abi + Chl treatment lowers autophagy levels and suppresses tumors more effectively than Abi alone. Full article

(This article belongs to the Special Issue The Mouse Xenograft Model in Cancer Research)

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22 pages, 1548 KiB

Open AccessReview

Chondroitin Sulfate Proteoglycan 4 (CSPG4) as an Emerging Target for Immunotherapy to Treat Melanoma

by Xinyi Chen, Shabana Habib, Madalina Alexandru, Jitesh Chauhan, Theodore Evan, Joanna M. Troka, Avigail Rahimi, Benjamina Esapa, Thomas J. Tull, Wen Zhe Ng, Amanda Fitzpatrick, Yin Wu, Jenny L. C. Geh, Hawys Lloyd-Hughes, Lais C. G. F. Palhares, Rebecca Adams, Heather J. Bax, Sean Whittaker, Joanna Jacków-Malinowska and Sophia N. Karagiannis

Cancers 2024, 16(19), 3260; https://doi.org/10.3390/cancers16193260 - 25 Sep 2024

Viewed by 337

Abstract

Immunotherapies, including checkpoint inhibitor antibodies, have precipitated significant improvements in clinical outcomes for melanoma. However, approximately half of patients do not benefit from approved treatments. Additionally, apart from Tebentafusp, which is approved for the treatment of uveal melanoma, there is a lack of [...] Read more.

Immunotherapies, including checkpoint inhibitor antibodies, have precipitated significant improvements in clinical outcomes for melanoma. However, approximately half of patients do not benefit from approved treatments. Additionally, apart from Tebentafusp, which is approved for the treatment of uveal melanoma, there is a lack of immunotherapies directly focused on melanoma cells. This is partly due to few available targets, especially those expressed on the cancer cell surface. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface molecule overexpressed in human melanoma, with restricted distribution and low expression in non-malignant tissues and involved in several cancer-promoting and dissemination pathways. Here, we summarize the current understanding of the expression and functional significance of CSPG4 in health and melanoma, and we outline immunotherapeutic strategies. These include monoclonal antibodies, antibody–drug conjugates (ADCs), chimeric-antigen receptor (CAR) T cells, and other strategies such as anti-idiotypic and mimotope vaccines to raise immune responses against CSPG4-expressing melanomas. Several showed promising functions in preclinical models of melanoma, yet few have reached clinical testing, and none are approved for therapeutic use. Obstacles preventing that progress include limited knowledge of CSPG4 function in human cancer and a lack of in vivo models that adequately represent patient immune responses and human melanoma biology. Despite several challenges, immunotherapy directed to CSPG4-expressing melanoma harbors significant potential to transform the treatment landscape. Full article

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

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15 pages, 3971 KiB

Open AccessArticle

PLK1 Inhibitor Onvansertib Enhances the Efficacy of Alpelisib in PIK3CA-Mutated HR-Positive Breast Cancer Resistant to Palbociclib and Endocrine Therapy: Preclinical Insights

by Sreeja Sreekumar, Elodie Montaudon, Davis Klein, Migdalia E. Gonzalez, Pierre Painsec, Héloise Derrien, Laura Sourd, Tod Smeal, Elisabetta Marangoni and Maya Ridinger

Cancers 2024, 16(19), 3259; https://doi.org/10.3390/cancers16193259 - 25 Sep 2024

Viewed by 348

Abstract

Background: Endocrine therapy (ET) combined with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) is the preferred first-line treatment for hormone receptor-positive (HR+)/HER2- metastatic breast cancer. Although this is beneficial, acquired resistance leads to disease progression, and patients harboring PIK3CA mutations are treated with targeted therapies [...] Read more.

Background: Endocrine therapy (ET) combined with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) is the preferred first-line treatment for hormone receptor-positive (HR+)/HER2- metastatic breast cancer. Although this is beneficial, acquired resistance leads to disease progression, and patients harboring PIK3CA mutations are treated with targeted therapies such as the PI3Kα inhibitor, alpelisib, alongside ET. Drug-associated resistance mechanisms limit the efficacy of alpelisib, highlighting the need for better combination therapies. This study aimed to evaluate the efficacy of combining alpelisib with a highly specific PLK1 inhibitor, onvansertib, in PIK3CA-mutant HR+ breast cancer preclinical models. Methods: We assessed the effect of the alpelisib and onvansertib combination on cell viability, PI3K signaling pathway, cell cycle phase distribution and apoptosis in PI3K-activated HR+ breast cancer cell lines. The antitumor activity of the combination was evaluated in three PIK3CA-mutant HR+ breast cancer patient-derived xenograft (PDX) models, resistant to ET and CDK4/6 inhibitor palbociclib. Pharmacodynamics studies were performed using immunohistochemistry and Simple Western analyses in tumor tissues. Results: The combination synergistically inhibited cell viability, suppressed PI3K signaling, induced G2/M arrest and apoptosis in PI3K-activated cell lines. In the three PDX models, the combination demonstrated superior anti-tumor activity compared to the single agents. Pharmacodynamic studies confirmed the inhibition of both PLK1 and PI3K activity and pronounced apoptosis in the combination-treated tumors. Conclusions: Our findings support that targeting PLK1 and PI3Kα with onvansertib and alpelisib, respectively, may be a promising strategy for patients with PIK3CA-mutant HR+ breast cancer failing ET + CDK4/6i therapies and warrant clinical evaluation. Full article

(This article belongs to the Section Cancer Therapy)

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1 pages, 169 KiB

Open AccessCorrection

Correction: Russo et al. The Role of Dielectrophoresis for Cancer Diagnosis and Prognosis. Cancers 2022, 14, 198

by Giorgio Ivan Russo, Nicolò Musso, Alessandra Romano, Giuseppe Caruso, Salvatore Petralia, Luca Lanzanò, Giuseppe Broggi and Massimo Camarda

Cancers 2024, 16(19), 3258; https://doi.org/10.3390/cancers16193258 - 25 Sep 2024

Viewed by 109

Abstract

References [...] Full article

16 pages, 721 KiB

Open AccessArticle

Improved Outcomes in Myelofibrosis after Allogeneic Stem-Cell Transplantation in the Era of Ruxolitinib Pretreatment and Intensified Conditioning Regimen—Single-Center Analysis

by Sigrid Machherndl-Spandl, Sarah Hannouf, Alexander Nikoloudis, Otto Zach, Irene Strassl, Emine Kaynak, Gerald Webersinke, Christine Gruber-Rossipal, Holger Rumpold, Wolfgang Schimetta, Johannes Clausen and Veronika Buxhofer-Ausch

Cancers 2024, 16(19), 3257; https://doi.org/10.3390/cancers16193257 - 25 Sep 2024

Viewed by 311

Abstract

(1) Background: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is the only treatment with the potential for cure in patients with myelofibrosis (MF). However, the risk of graft rejection, which is particularly high in MF, and the risk of significant non-relapse mortality must be considered. [...] Read more.

(1) Background: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is the only treatment with the potential for cure in patients with myelofibrosis (MF). However, the risk of graft rejection, which is particularly high in MF, and the risk of significant non-relapse mortality must be considered. (2) Methods: In this retrospective, single-center study, we compared allo-HSCT outcomes in 36 adult patients with MF transplanted at two-time intervals (2001–2015 versus 2016–2021). (3) Results: The estimated median overall survival was 48.9 months (95%CI 0.00–98.2) in the cohort transplanted before 2016 and not reached in the more recent years (p = 0.04) due to markedly lower non-relapse mortality (p = 0.02). The 3-year relapse incidence was low in both cohorts (11.1% and 12.5%, p > 0.99). When comparing only subgroups within the more recent cohort based on the presence or absence of total body irradiation (TBI) or the use of sequential regimens, OS and PFS were comparable. (4) Conclusion: Pretreatment with ruxolitinib, intensified conditioning, and the preferential use of haploidentical related instead of mismatched unrelated donors for patients lacking an HLA-identical donor are most likely responsible for the improved outcome after allo-HCT in MF in recent years. Full article

(This article belongs to the Special Issue Blood Stem Cell and Hematological Malignancies)

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