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Novel Therapeutic Targets of Solid Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 October 2024) | Viewed by 12848

Special Issue Editor

Special Issue Information

Dear Colleagues,

We are proposing a Special Issue on “Novel Therapeutic Targets of Solid Cancer”.

Cancer is a complex genetic disease in which multiple pathways are involved in its development and progression. The identification of some key pathways of cancer pathogenesis is among the most spectacular achievements of modern biomedical science. Decades of research have helped to understand some of the underlying mechanisms, but our understanding of the disease is still incomplete. In recent years, technological advances such as various high-throughput omics methods have immensely helped unravel some of the unknown intricacies of cancer. The integration of data obtained from different omics methods has further facilitated the improvement of our knowledge. However, despite great progress, the dream of converting solid tumors into a chronic disease is still unsatisfied and long-term remission eludes us.

In recent years, the treatment of solid tumors has focused more on the personalization of treatment, progressively orienting itself towards what is called precision medicine. that is now considered a consolidated approach to cancer treatment and prevention. Indeed, for many types of cancer, molecular characterization of the tumor is the starting point for therapeutic decision-making. There are a few dozen well-validated targets in cancer cells, with a few hundred new drugs approved or in the final stages of clinical development. These therapies have revolutionized the treatment of lung, colorectal, breast, ovarian, skin and other cancers. Current advances in targeted therapy deserve in-depth discussion and are of considerable interest to a large readership. 

This Special Issue of IJMS seeks to collect a series of original research articles and updated reviews that encompass all aspects of precision medicine through the identification of new targets in solid tumor oncology. Investigations in a myriad of fields such as biomarker discovery, "omics" approaches, such as pharmacogenomics, proteomics, genomics and transcriptomics are welcome. Work that helps decipher molecular changes and identify biomarkers and predictors of prognosis and behavior, as well as advances in therapeutic options and resistance mechanisms, are also topics of particular interest as are contributions on other significant topics that further enhance our understanding of molecular immunotherapy and all targeted cancer therapies.

Dr. Valentina De Falco
Guest Editor

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Keywords

  • cancer
  • signal transduction
  • kinase inhibitors
  • targeted therapy
  • precision medicine
  • drug resistance
  • survival
  • cell cycle
  • cell reprogramming
  • stem cells
  • immunotherapy

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Published Papers (6 papers)

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Research

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15 pages, 11768 KiB  
Article
Cullin 4B Ubiquitin Ligase Is Important for Cell Survival and Regulates TGF-β1 Expression in Pleural Mesothelioma
by Jessica Kreienbühl, Sakunthip Changkhong, Vanessa Orlowski, Michaela B. Kirschner, Isabelle Opitz and Mayura Meerang
Int. J. Mol. Sci. 2023, 24(17), 13410; https://doi.org/10.3390/ijms241713410 - 29 Aug 2023
Cited by 1 | Viewed by 1467
Abstract
We previously demonstrated that cullin 4B (CUL4B) upregulation was associated with worse outcomes of pleural mesothelioma (PM) patients, while the overexpression of its paralog CUL4A was not associated with clinical outcomes. Here, we aimed to identify the distinct roles of CUL4B and CUL4A [...] Read more.
We previously demonstrated that cullin 4B (CUL4B) upregulation was associated with worse outcomes of pleural mesothelioma (PM) patients, while the overexpression of its paralog CUL4A was not associated with clinical outcomes. Here, we aimed to identify the distinct roles of CUL4B and CUL4A in PM using an siRNA approach in PM cell lines (ACC Meso-1 and Mero82) and primary culture. The knockdown of CUL4B and CUL4A resulted in significantly reduced colony formation, increased cell death, and delayed cell proliferation. Furthermore, similar to the effect of CUL4A knockdown, downregulation of CUL4B led to reduced expression of Hippo pathway genes including YAP1, CTGF, and survivin. Interestingly, CUL4B and not CUL4A knockdown reduced TGF-β1 and MMP2 expression, suggesting a unique association of CUL4B with this pathway. However, the treatment of PM cells with exogenous TGF-β1 following CUL4B knockdown did not rescue PM cell growth. We further analyzed ACC Meso-1 xenograft tumor tissues treated with the cullin inhibitor, pevonedistat, which targets protein neddylation, and observed the downregulation of human TGF-β1 and MMP2. In summary, our data suggest that CUL4B overexpression is important for tumor cell growth and survival and may drive PM aggressiveness via the regulation of TGF-β1 expression and, furthermore, reveal a new mechanism of action of pevonedistat. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets of Solid Cancer)
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21 pages, 4683 KiB  
Article
Overexpression and Role of HHLA2, a Novel Immune Checkpoint, in Colorectal Cancer
by Agnieszka Kula, Miriam Dawidowicz, Sylwia Mielcarska, Paweł Kiczmer, Hanna Skiba, Małgorzata Krygier, Magdalena Chrabańska, Jerzy Piecuch, Monika Szrot, Julia Robotycka, Błażej Ochman, Bogumiła Strzałkowska, Zenon Czuba, Elżbieta Świętochowska and Dariusz Waniczek
Int. J. Mol. Sci. 2023, 24(6), 5876; https://doi.org/10.3390/ijms24065876 - 20 Mar 2023
Cited by 10 | Viewed by 2931
Abstract
The study aimed to investigate correlations between HHLA2 levels and parameters, including microsatellite instability (MSI) status, CD8+ cells, and histopathological features: budding, tumor-infiltrating lymphocytes (TILs), TNM scale, grading, cytokines, chemokines, and cell signaling moleculesin colorectal cancer (CRC). Furthermore, the immune infiltration landscape and [...] Read more.
The study aimed to investigate correlations between HHLA2 levels and parameters, including microsatellite instability (MSI) status, CD8+ cells, and histopathological features: budding, tumor-infiltrating lymphocytes (TILs), TNM scale, grading, cytokines, chemokines, and cell signaling moleculesin colorectal cancer (CRC). Furthermore, the immune infiltration landscape and HHLA2-related pathways in colorectal cancer using available online datasets were analyzed. The study included 167 patients diagnosed with CRC. Expression of HHLA2 was detected by immunohistochemistry method (IHC) and enzyme-linked immunosorbent assay (ELISA). The IHC was used to evaluate the MSI and CD8+ status. The budding and TILs were measured using a light microscope. The concentrations of cytokines, chemokines, and cell signaling molecules were measured to analyze the data by the Bio-Plex Pro Human cytokine screening panel, 48 cytokine assay, and principal component analysis (PCA). Geneset enrichment analysis (GSEA) was conducted to identify HHLA2-related pathways. The biological function of HHLA2 was predicted by Gene Ontology (GO). Analysis of the immune infiltration landscape of HHLA2 in colorectal cancer was made by the web-based tool Camoip. High HHLA2 expression was detected in CRC tumor tissues compared to the adjacent noncancerous tissues. The percentage of HHLA2-positive tumors was 97%. GSEA and GO showed that HHLA2 upregulation correlated with cancer-related pathways and several biological functions. Tumor-infiltrating lymphocytes score correlated positively with IHC HHLA2 expression level percentage. There was a negative correlation between HHLA2, anti-tumor cytokines and pro-tumor growth factors. This study provides a valuable insight into the role of HHLA2 in CRC. We reveal the role of HHLA2 expression as well as a stimulatory and inhibitory immune checkpoint in colorectal cancer. Further research may verify the therapeutic values of the HHLA2-KIR3DL3/TMIGD2 pathway in colorectal cancer. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets of Solid Cancer)
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12 pages, 1986 KiB  
Article
Differential Plasma Metabolites between High- and Low-Grade Meningioma Cases
by Gabriel A. Kurokawa, Pedro T. Hamamoto Filho, Jeany Delafiori, Aline F. Galvani, Arthur N. de Oliveira, Flávia L. Dias-Audibert, Rodrigo R. Catharino, Maria Inês M. C. Pardini, Marco A. Zanini, Estela de O. Lima and Adriana C. Ferrasi
Int. J. Mol. Sci. 2023, 24(1), 394; https://doi.org/10.3390/ijms24010394 - 26 Dec 2022
Cited by 4 | Viewed by 2063
Abstract
Meningiomas (MGMs) are currently classified into grades I, II, and III. High-grade tumors are correlated with decreased survival rates and increased recurrence rates. The current grading classification is based on histological criteria and determined only after surgical tumor sampling. This study aimed to [...] Read more.
Meningiomas (MGMs) are currently classified into grades I, II, and III. High-grade tumors are correlated with decreased survival rates and increased recurrence rates. The current grading classification is based on histological criteria and determined only after surgical tumor sampling. This study aimed to identify plasma metabolic alterations in meningiomas of different grades, which would aid surgeons in predefining the ideal surgical strategy. Plasma samples were collected from 51 patients with meningioma and classified into low-grade (LG) (grade I; n = 43), and high-grade (HG) samples (grade II, n = 5; grade III, n = 3). An untargeted metabolomic approach was used to analyze plasma metabolites. Statistical analyses were performed to select differential biomarkers among HG and LG groups. Metabolites were identified using tandem mass spectrometry along with database verification. Five and four differential biomarkers were identified for HG and LG meningiomas, respectively. To evaluate the potential of HG MGM metabolites to differentiate between HG and LG tumors, a receiving operating characteristic curve was constructed, which revealed an area under the curve of 95.7%. This indicates that the five HG MGM metabolites represent metabolic alterations that can differentiate between LG and HG meningiomas. These metabolites may indicate tumor grade even before the appearance of histological features. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets of Solid Cancer)
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Review

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18 pages, 3089 KiB  
Review
Survival Difference of Endometrial Cancer Patients with Peritoneal Metastasis Receiving Cytoreductive Surgery (CRS) with and without Hyperthermic Intraperitoneal Chemotherapy (HIPEC): A Systematic Review and Meta-Analysis
by Ivan Panczel, Miklos Acs, Magdolna Herold, Viktor Madar-Dank, Pompiliu Piso, Hans Jürgen Schlitt, Magdolna Dank, Attila Marcell Szasz and Zoltan Herold
Int. J. Mol. Sci. 2024, 25(13), 7495; https://doi.org/10.3390/ijms25137495 - 8 Jul 2024
Viewed by 1268
Abstract
Although several studies have been completed to investigate the effect of cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) in endometrial cancer with peritoneal metastasis (ECPM), a direct comparison was not performed previously. A meta-analysis was performed to investigate the suspected [...] Read more.
Although several studies have been completed to investigate the effect of cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) in endometrial cancer with peritoneal metastasis (ECPM), a direct comparison was not performed previously. A meta-analysis was performed to investigate the suspected additional survival benefits of CRS plus HIPEC over CRS only. Twenty-one and ten studies with a total number of 1116 and 152 cases investigating CRS only and CRS plus HIPEC were identified, respectively. When all articles were analyzed, the 1-year survival rate was 17.60% higher for CRS plus HIPEC (82.28% vs. 64.68%; p = 0.0102). The same tendency was observed for the 2-year (56.07% vs. 36.95%; difference: 19.12%; p = 0.0014), but not for the 5-year (21.88% vs. 16.45%; difference: 5.43%; p = 0.3918) survival rates. The same clinical significance, but statistically less strong observations, could be made if only the studies published after 2010 were investigated (1-year survival rate: 12.08% and p = 0.0648; 2-year survival rate: 10.90% and p = 0.0988). CRS remains one of the core elements of ECPM treatment, but the addition of HIPEC to CRS can increase the positive clinical outcome, especially in the first 2 years. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets of Solid Cancer)
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22 pages, 1841 KiB  
Review
EWS/FLI1 Characterization, Activation, Repression, Target Genes and Therapeutic Opportunities in Ewing Sarcoma
by Muhammad Yasir, Jinyoung Park and Wanjoo Chun
Int. J. Mol. Sci. 2023, 24(20), 15173; https://doi.org/10.3390/ijms242015173 - 14 Oct 2023
Cited by 2 | Viewed by 2471
Abstract
Despite their clonal origins, tumors eventually develop into complex communities made up of phenotypically different cell subpopulations, according to mounting evidence. Tumor cell-intrinsic programming and signals from geographically and temporally changing microenvironments both contribute to this variability. Furthermore, the mutational load is typically [...] Read more.
Despite their clonal origins, tumors eventually develop into complex communities made up of phenotypically different cell subpopulations, according to mounting evidence. Tumor cell-intrinsic programming and signals from geographically and temporally changing microenvironments both contribute to this variability. Furthermore, the mutational load is typically lacking in childhood malignancies of adult cancers, and they still exhibit high cellular heterogeneity levels largely mediated by epigenetic mechanisms. Ewing sarcomas represent highly aggressive malignancies affecting both bone and soft tissue, primarily afflicting adolescents. Unfortunately, the outlook for patients facing relapsed or metastatic disease is grim. These tumors are primarily fueled by a distinctive fusion event involving an FET protein and an ETS family transcription factor, with the most prevalent fusion being EWS/FLI1. Despite originating from a common driver mutation, Ewing sarcoma cells display significant variations in transcriptional activity, both within and among tumors. Recent research has pinpointed distinct fusion protein activities as a principal source of this heterogeneity, resulting in markedly diverse cellular phenotypes. In this review, we aim to characterize the role of the EWS/FLI fusion protein in Ewing sarcoma by exploring its general mechanism of activation and elucidating its implications for tumor heterogeneity. Additionally, we delve into potential therapeutic opportunities to target this aberrant fusion protein in the context of Ewing sarcoma treatment. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets of Solid Cancer)
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17 pages, 954 KiB  
Review
The Enigma of Mammaglobin: Redefining the Biomarker Paradigm in Breast Carcinoma
by Bojan Milosevic, Bojan Stojanovic, Aleksandar Cvetkovic, Ivan Jovanovic, Marko Spasic, Milica Dimitrijevic Stojanovic, Vesna Stankovic, Marija Sekulic, Bojana S. Stojanovic, Natasa Zdravkovic, Minja Mitrovic, Jasmina Stojanovic, Darko Laketic, Maja Vulovic and Danijela Cvetkovic
Int. J. Mol. Sci. 2023, 24(17), 13407; https://doi.org/10.3390/ijms241713407 - 29 Aug 2023
Cited by 3 | Viewed by 1689
Abstract
The continuous evolution of cancer biology has led to the discovery of mammaglobin, a potential novel biomarker for breast carcinoma. This review aims to unravel the enigmatic aspects of mammaglobin and elucidate its potential role in redefining the paradigm of breast carcinoma biomarkers. [...] Read more.
The continuous evolution of cancer biology has led to the discovery of mammaglobin, a potential novel biomarker for breast carcinoma. This review aims to unravel the enigmatic aspects of mammaglobin and elucidate its potential role in redefining the paradigm of breast carcinoma biomarkers. We will thoroughly examine its expression in tumoral and peritumoral tissues and its circulating levels in the blood, thereby providing insights into its possible function in cancer progression and metastasis. Furthermore, the potential application of mammaglobin as a non-invasive diagnostic tool and a target for personalized treatment strategies will be discussed. Given the increasing incidence of breast carcinoma worldwide, the exploration of novel biomarkers such as mammaglobin is crucial in advancing our diagnostic capabilities and treatment modalities, ultimately contributing to improved patient outcomes. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets of Solid Cancer)
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