Cancers

19 pages, 3798 KiB

Open AccessEditor’s ChoiceArticle

An Aminosteroid Derivative Shows Higher In Vitro and In Vivo Potencies than Gold Standard Drugs in Androgen-Dependent Prostate Cancer Models

by Donald Poirier, Jenny Roy, René Maltais, Cindy Weidmann and Étienne Audet-Walsh

Cancers 2023, 15(11), 3033; https://doi.org/10.3390/cancers15113033 - 2 Jun 2023

Cited by 1 | Viewed by 5878

Abstract

The aminosteroid derivative RM-581 blocks with high potency the growth of androgen-dependent (AR⁺) prostate cancer VCaP, 22Rv1, and LAPC-4 cells. Notably, RM-581 demonstrated superior antiproliferative activity in LAPC-4 cells compared to enzalutamide and abiraterone, two drugs that exhibited a synergistic effect [...] Read more.

The aminosteroid derivative RM-581 blocks with high potency the growth of androgen-dependent (AR⁺) prostate cancer VCaP, 22Rv1, and LAPC-4 cells. Notably, RM-581 demonstrated superior antiproliferative activity in LAPC-4 cells compared to enzalutamide and abiraterone, two drugs that exhibited a synergistic effect in combination with RM-581. These findings suggest that RM-581 may have an action that is not directly associated with the hormonal pathway of androgens. Furthermore, RM-581 completely blocks tumor growth in LAPC-4 xenografts when given orally at 3, 10, and 30 mg/kg in non-castrated (intact) nude mice. During this study, an accumulation of RM-581 was observed in tumors compared to plasma (3.3–10 folds). Additionally, the level of fatty acids (FA) increased in the tumors and livers of mice treated with RM-581 but not in plasma. The increase was greater in unsaturated FA (21–28%) than in saturated FA (7–11%). The most affected FA were saturated palmitic acid (+16%), monounsaturated oleic acid (+34%), and di-unsaturated linoleic acid (+56%), i.e., the 3 most abundant FA, with a total of 55% of the 56 FA measured. For cholesterol levels, there was no significant difference in the tumor, liver, or plasma of mice treated or not with RM-581. Another important result was the innocuity of RM-581 in mice during a 28-day xenograft experiment and a 7-week dose-escalation study, suggesting a favorable safety window for this new promising drug candidate when given orally. Full article

(This article belongs to the Special Issue Novel Drugs for Prostate Cancer)

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13 pages, 1789 KiB

Open AccessEditor’s ChoiceArticle

Plasma Metabolomics Predicts Chemotherapy Response in Advanced Pancreatic Cancer

by Hayato Muranaka, Andrew Hendifar, Arsen Osipov, Natalie Moshayedi, Veronica Placencio-Hickok, Nicholas Tatonetti, Aleksandr Stotland, Sarah Parker, Jennifer Van Eyk, Stephen J. Pandol, Neil A. Bhowmick and Jun Gong

Cancers 2023, 15(11), 3020; https://doi.org/10.3390/cancers15113020 - 1 Jun 2023

Cited by 6 | Viewed by 2834

Abstract

Pancreatic cancer (PC) is one of the deadliest cancers. Developing biomarkers for chemotherapeutic response prediction is crucial for improving the dismal prognosis of advanced-PC patients (pts). To evaluate the potential of plasma metabolites as predictors of the response to chemotherapy for PC patients, [...] Read more.

Pancreatic cancer (PC) is one of the deadliest cancers. Developing biomarkers for chemotherapeutic response prediction is crucial for improving the dismal prognosis of advanced-PC patients (pts). To evaluate the potential of plasma metabolites as predictors of the response to chemotherapy for PC patients, we analyzed plasma metabolites using high-performance liquid chromatography–mass spectrometry from 31 cachectic, advanced-PC subjects enrolled into the PANCAX-1 (NCT02400398) prospective trial to receive a jejunal tube peptide-based diet for 12 weeks and who were planned for palliative chemotherapy. Overall, there were statistically significant differences in the levels of intermediates of multiple metabolic pathways in pts with a partial response (PR)/stable disease (SD) vs. progressive disease (PD) to chemotherapy. When stratified by the chemotherapy regimen, PD after 5-fluorouracil-based chemotherapy (e.g., FOLFIRINOX) was associated with decreased levels of amino acids (AAs). For gemcitabine-based chemotherapy (e.g., gemcitabine/nab-paclitaxel), PD was associated with increased levels of intermediates of glycolysis, the TCA cycle, nucleoside synthesis, and bile acid metabolism. These results demonstrate the feasibility of plasma metabolomics in a prospective cohort of advanced-PC patients for assessing the effect of enteral feeding as their primary source of nutrition. Metabolic signatures unique to FOLFIRINOX or gemcitabine/nab-paclitaxel may be predictive of a patient’s response and warrant further study. Full article

(This article belongs to the Special Issue Lipids and Small Metabolites in Cancer)

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19 pages, 1166 KiB

Open AccessEditor’s ChoiceSystematic Review

Drug Repurposing in Oncology: A Systematic Review of Randomized Controlled Clinical Trials

by Ignatios Ioakeim-Skoufa, Natalia Tobajas-Ramos, Enrica Menditto, Mercedes Aza-Pascual-Salcedo, Antonio Gimeno-Miguel, Valentina Orlando, Francisca González-Rubio, Ana Fanlo-Villacampa, Carmen Lasala-Aza, Ewelina Ostasz and Jorge Vicente-Romero

Cancers 2023, 15(11), 2972; https://doi.org/10.3390/cancers15112972 - 30 May 2023

Cited by 15 | Viewed by 6688

Abstract

Quality pharmacological treatment can improve survival in many types of cancer. Drug repurposing offers advantages in comparison with traditional drug development procedures, reducing time and risk. This systematic review identified the most recent randomized controlled clinical trials that focus on drug repurposing in [...] Read more.

Quality pharmacological treatment can improve survival in many types of cancer. Drug repurposing offers advantages in comparison with traditional drug development procedures, reducing time and risk. This systematic review identified the most recent randomized controlled clinical trials that focus on drug repurposing in oncology. We found that only a few clinical trials were placebo-controlled or standard-of-care-alone-controlled. Metformin has been studied for potential use in various types of cancer, including prostate, lung, and pancreatic cancer. Other studies assessed the possible use of the antiparasitic agent mebendazole in colorectal cancer and of propranolol in multiple myeloma or, when combined with etodolac, in breast cancer. We were able to identify trials that study the potential use of known antineoplastics in other non-oncological conditions, such as imatinib for severe coronavirus disease in 2019 or a study protocol aiming to assess the possible repurposing of leuprolide for Alzheimer’s disease. Major limitations of these clinical trials were the small sample size, the high clinical heterogeneity of the participants regarding the stage of the neoplastic disease, and the lack of accounting for multimorbidity and other baseline clinical characteristics. Drug repurposing possibilities in oncology must be carefully examined with well-designed trials, considering factors that could influence prognosis. Full article

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14 pages, 1409 KiB

Open AccessEditor’s ChoiceArticle

Efficacy of Tango Argentino for Cancer-Associated Fatigue and Quality of Life in Breast Cancer Survivors: A Randomized Controlled Trial

by Friedemann Schad, Thomas Rieser, Sarah Becker, Jessica Groß, Harald Matthes, Shiao Li Oei and Anja Thronicke

Cancers 2023, 15(11), 2920; https://doi.org/10.3390/cancers15112920 - 26 May 2023

Cited by 9 | Viewed by 4482

Abstract

Background: Persistent impairments of quality of life—in particular, cancer-associated fatigue—are a major limitation for breast cancer survivors. As physical activity and mindfulness interventions have been shown to be effective in reducing fatigue symptoms, we investigated the efficacy of a six-week Argentine tango program. [...] Read more.

Background: Persistent impairments of quality of life—in particular, cancer-associated fatigue—are a major limitation for breast cancer survivors. As physical activity and mindfulness interventions have been shown to be effective in reducing fatigue symptoms, we investigated the efficacy of a six-week Argentine tango program. Methods: A randomized controlled trial was conducted with 60 breast cancer survivors diagnosed with stage I-III tumors 12–48 months prior to study enrollment and who had increased symptoms of fatigue. The participants were randomly assigned with a 1:1 allocation to either the tango or the waiting group. The treatment consisted of six weeks of supervised weekly one-hour tango group-sessions. Self-reported fatigue and further quality of life parameters were assessed at baseline and six weeks post-baseline. Longitudinal changes, correlations, Cohen’s D (d) effect sizes, and association factors were also calculated. Results: Superiority of the tango intervention over the waiting list control was found in terms of improvement in fatigue (d = −0.64; 95%CI, −1.2 to −0.08; p = 0.03), especially cognitive fatigue. In addition, a superiority of the tango intervention over the waiting list was found in the improvement of diarrhea (d = −0.69; 95%CI, −1.25 to −0.13; p = 0.02). A pooled pre-post analysis of the 50 participants completing the six-week tango program revealed a close to 10% improvement of fatigue (p = 0.0003), insomnia (p = 0.008) and further quality of life outcomes. Adjusted multivariate linear regression analyses revealed the greatest improvements for participants who were more active in sports. In particular, survivors who received endocrine therapies, were obese, or had no prior dance experience seemed to especially benefit from the tango program. Conclusions: This randomized controlled trial demonstrated that a six-week Argentine tango program improves fatigue in breast cancer survivors. Further trials are warranted to determine whether such improvements lead to better long-term clinical outcomes. Trial registration: trial registration number DRKS00021601. Retrospectively registered on 21 August 2020. Full article

(This article belongs to the Special Issue Breast Cancer Survivors and Supportive Therapies)

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26 pages, 2938 KiB

Open AccessEditor’s ChoiceReview

PDAC, the Influencer Cancer: Cross-Talk with Tumor Microenvironment and Connected Potential Therapy Strategies

by Leonardo Mercanti, Maria Sindaco, Mariangela Mazzone, Maria Carmela Di Marcantonio, Mariagrazia Piscione, Raffaella Muraro and Gabriella Mincione

Cancers 2023, 15(11), 2923; https://doi.org/10.3390/cancers15112923 - 26 May 2023

Cited by 30 | Viewed by 6718

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is among the leading causes of death by cancer in the world. What makes this pathological condition particularly lethal is a combination of clinical and molecular heterogeneity, lack of early diagnostic indexes, and underwhelming results from current therapeutic protocols. [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is among the leading causes of death by cancer in the world. What makes this pathological condition particularly lethal is a combination of clinical and molecular heterogeneity, lack of early diagnostic indexes, and underwhelming results from current therapeutic protocols. A major cause of PDAC chemoresistance seems to lie in the ability of cancer cells to spread out and fill the pancreatic parenchyma, exchanging nutrients, substrates, and even genetic material with cells from the surrounding tumor microenvironment (TME). Several components can be found in the TME ultrastructure, including collagen fibers, cancer-associated fibroblasts, macrophages, neutrophils, mast cells, and lymphocytes. Cross-talk between PDAC and TME cells results in the latter being converted into cancer-favoring phenotypes; this behavior could be compared to an influencer guiding followers into supporting his activity. Moreover, TME could be a potential target for some of the newest therapeutic strategies; these include the use of pegvorhyaluronidase-α and CAR-T lymphocytes against HER2, FAP, CEA, MLSN, PSCA, and CD133. Other experimental therapy options are being currently studied, aiming to interfere with the KRAS pathway, DNA-repairing proteins, and apoptosis resistance in PDAC cells. Hopefully these new approaches will grant better clinical outcomes in future patients. Full article

(This article belongs to the Collection Recent Advances in Pancreatic Ductal Adenocarcinoma)

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22 pages, 1193 KiB

Open AccessEditor’s ChoiceReview

Hope and Hype around Immunotherapy in Triple-Negative Breast Cancer

by Flavia Jacobs, Elisa Agostinetto, Chiara Miggiano, Rita De Sanctis, Alberto Zambelli and Armando Santoro

Cancers 2023, 15(11), 2933; https://doi.org/10.3390/cancers15112933 - 26 May 2023

Cited by 14 | Viewed by 4571

Abstract

Triple-negative breast cancer (TNBC) holds a poor prognosis compared to other breast cancer subtypes, and the development of new effective treatment strategies is an unmet medical need. TNBC has traditionally been considered not amenable to treatment with targeted agents due to a lack [...] Read more.

Triple-negative breast cancer (TNBC) holds a poor prognosis compared to other breast cancer subtypes, and the development of new effective treatment strategies is an unmet medical need. TNBC has traditionally been considered not amenable to treatment with targeted agents due to a lack of actionable targets. Therefore, chemotherapy has remained the mainstay of systemic treatment for many decades. The advent of immunotherapy raised very hopeful expectations in TNBC, possibly due to higher levels of tumor-infiltrating lymphocytes, PD-L1 expression and tumor mutational burden compared to other breast cancer subtypes, that predict an effective anti-tumor immune-engagement. The results of clinical trials testing immunotherapy in TNBC led to the approval of the combination of immune checkpoint inhibitors and chemotherapy in both early and advanced settings. However, some open questions about the use of immunotherapy in TNBC still exist. These include a deeper understanding of the heterogeneity of the disease, identification of reliable predictive biomarkers of response, determination of the most appropriate chemotherapy backbone and appropriate management of potential long-term immune-related adverse events. In this review we aim to examine the available evidence on the use of immunotherapy strategies in both early and advanced TNBC, to critically discuss some of the limitations encountered in clinical research and to summarize data on novel promising immunotherapeutic strategies beyond PD-(L)1 blockade that have been investigated in the most recent trials. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Multidisciplinary Approaches and Predictive Biomarkers)

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25 pages, 2621 KiB

Open AccessEditor’s ChoiceReview

Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer

by Shenduo Li, Guilherme Sacchi de Camargo Correia, Jing Wang, Rami Manochakian, Yujie Zhao and Yanyan Lou

Cancers 2023, 15(11), 2899; https://doi.org/10.3390/cancers15112899 - 24 May 2023

Cited by 43 | Viewed by 6306

Abstract

Lung cancer remains the leading cause of cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC) is the most common type and is still incurable for most patients at the advanced stage. Targeted therapy is an effective treatment that has significantly improved survival in NSCLC [...] Read more.

Lung cancer remains the leading cause of cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC) is the most common type and is still incurable for most patients at the advanced stage. Targeted therapy is an effective treatment that has significantly improved survival in NSCLC patients with actionable mutations. However, therapy resistance occurs widely among patients leading to disease progression. In addition, many oncogenic driver mutations in NSCLC still lack targeted agents. New drugs are being developed and tested in clinical trials to overcome these challenges. This review aims to summarize emerging targeted therapy that have been conducted or initiated through first-in-human clinical trials in the past year. Full article

(This article belongs to the Special Issue Advances in Precision Medicine: Targeting Known and Emerging Oncogenic Targets in Lung Cancer)

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21 pages, 7124 KiB

Open AccessEditor’s ChoiceReview

Novel Targets, Novel Treatments: The Changing Landscape of Non-Small Cell Lung Cancer

by Dorine de Jong, Jeeban P. Das, Hong Ma, Jacienta Pailey Valiplackal, Conor Prendergast, Tina Roa, Brian Braumuller, Aileen Deng, Laurent Dercle, Randy Yeh, Mary M. Salvatore and Kathleen M. Capaccione

Cancers 2023, 15(10), 2855; https://doi.org/10.3390/cancers15102855 - 21 May 2023

Cited by 29 | Viewed by 6409

Abstract

Treatment of non-small cell lung cancer (NSCLC) has undergone a paradigm shift. Once a disease with limited potential therapies, treatment options for patients have exploded with the availability of molecular testing to direct management and targeted therapies to treat tumors with specific driver [...] Read more.

Treatment of non-small cell lung cancer (NSCLC) has undergone a paradigm shift. Once a disease with limited potential therapies, treatment options for patients have exploded with the availability of molecular testing to direct management and targeted therapies to treat tumors with specific driver mutations. New in vitro diagnostics allow for the early and non-invasive detection of disease, and emerging in vivo imaging techniques allow for better detection and monitoring. The development of checkpoint inhibitor immunotherapy has arguably been the biggest advance in lung cancer treatment, given that the vast majority of NSCLC tumors can be treated with these therapies. Specific targeted therapies, including those against KRAS, EGFR, RTK, and others have also improved the outcomes for those individuals bearing an actionable mutation. New and emerging therapies, such as bispecific antibodies, CAR T cell therapy, and molecular targeted radiotherapy, offer promise to patients for whom none of the existing therapies have proved effective. In this review, we provide the most up-to-date survey to our knowledge regarding emerging diagnostic and therapeutic strategies for lung cancer to provide clinicians with a comprehensive reference of the options for treatment available now and those which are soon to come. Full article

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

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32 pages, 907 KiB

Open AccessEditor’s ChoiceReview

Beyond CTLA-4 and PD-1 Inhibition: Novel Immune Checkpoint Molecules for Melanoma Treatment

by Dimitrios C. Ziogas, Charalampos Theocharopoulos, Panagiotis-Petros Lialios, Dimitra Foteinou, Ioannis-Alexios Koumprentziotis, Georgios Xynos and Helen Gogas

Cancers 2023, 15(10), 2718; https://doi.org/10.3390/cancers15102718 - 11 May 2023

Cited by 53 | Viewed by 8775

Abstract

More than ten years after the approval of ipilimumab, immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 have been established as the most effective treatment for locally advanced or metastatic melanoma, achieving durable responses either as monotherapies or in combinatorial regimens. However, a [...] Read more.

More than ten years after the approval of ipilimumab, immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 have been established as the most effective treatment for locally advanced or metastatic melanoma, achieving durable responses either as monotherapies or in combinatorial regimens. However, a considerable proportion of patients do not respond or experience early relapse, due to multiple parameters that contribute to melanoma resistance. The expression of other immune checkpoints beyond the PD-1 and CTLA-4 molecules remains a major mechanism of immune evasion. The recent approval of anti-LAG-3 ICI, relatlimab, in combination with nivolumab for metastatic disease, has capitalized on the extensive research in the field and has highlighted the potential for further improvement of melanoma prognosis by synergistically blocking additional immune targets with new ICI-doublets, antibody–drug conjugates, or other novel modalities. Herein, we provide a comprehensive overview of presently published immune checkpoint molecules, including LAG-3, TIGIT, TIM-3, VISTA, IDO1/IDO2/TDO, CD27/CD70, CD39/73, HVEM/BTLA/CD160 and B7-H3. Beginning from their immunomodulatory properties as co-inhibitory or co-stimulatory receptors, we present all therapeutic modalities targeting these molecules that have been tested in melanoma treatment either in preclinical or clinical settings. Better understanding of the checkpoint-mediated crosstalk between melanoma and immune effector cells is essential for generating more effective strategies with augmented immune response. Full article

(This article belongs to the Special Issue Immunotherapy in Melanoma: Recent Advances and Future Directions)

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27 pages, 4387 KiB

Open AccessEditor’s ChoiceArticle

Development and Validation of Blood-Based Predictive Biomarkers for Response to PD-1/PD-L1 Checkpoint Inhibitors: Evidence of a Universal Systemic Core of 3D Immunogenetic Profiling across Multiple Oncological Indications

by Ewan Hunter, Matthew Salter, Ryan Powell, Ann Dring, Tarun Naithani, Maria Eleni Chatziioannou, Abel Gebregzabhar, Mutaz Issa, Jayne Green, Serene Ng, Chun Ren Lim, Cheah Soon Keat, Ang Tick Suan, Rakesh Raman, Ho Kean Fatt, Fabian Lee Wei Luen, Heba Alshaker, Dmitri Pchejetski, Dave Blum, Thomas Guiel, Robert Heaton, Jr., Jedd Levine and Alexandre Akoulitchev Show full author list Hide full author list

Cancers 2023, 15(10), 2696; https://doi.org/10.3390/cancers15102696 - 10 May 2023

Cited by 9 | Viewed by 6416

Abstract

Background: Unprecedented advantages in cancer treatment with immune checkpoint inhibitors (ICIs) remain limited to only a subset of patients. Systemic analyses of the regulatory 3D genome architecture linked to individual epigenetic and immunogenetic controls associated with tumour immune evasion mechanisms and immune checkpoint [...] Read more.

Background: Unprecedented advantages in cancer treatment with immune checkpoint inhibitors (ICIs) remain limited to only a subset of patients. Systemic analyses of the regulatory 3D genome architecture linked to individual epigenetic and immunogenetic controls associated with tumour immune evasion mechanisms and immune checkpoint pathways reveal a highly prevalent molecular profile predictive of response to PD-1/PD-L1 ICIs. A clinical blood test based on a set of eight (8) 3D genomic biomarkers has been developed and validated on the basis of an observational trial to predict response to ICI therapy. Methods: The predictive eight biomarker set is derived from prospective observational clinical trials, representing 280 treatments with Pembrolizumab, Atezolizumab, Durvalumab, Nivolumab, and Avelumab in a broad range of indications: melanoma, lung, hepatocellular, renal, breast, bladder, colon, head and neck, bone, brain, lymphoma, prostate, vulvar, and cervical cancers. Results: The 3D genomic eight biomarker panel for response to immune checkpoint therapy achieved a high accuracy of 85%, sensitivity of 93%, and specificity of 82%. Conclusions: This study demonstrates that a 3D genomic approach can be used to develop a predictive clinical assay for response to PD-1/PD-L1 checkpoint inhibition in cancer patients. Full article

(This article belongs to the Topic Biomarker Development and Application)

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12 pages, 1034 KiB

Open AccessEditor’s ChoiceReview

HER2 Intratumoral Heterogeneity in Breast Cancer, an Evolving Concept

by Yanjun Hou, Hiroaki Nitta and Zaibo Li

Cancers 2023, 15(10), 2664; https://doi.org/10.3390/cancers15102664 - 9 May 2023

Cited by 42 | Viewed by 5779

Abstract

Amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer is associated with an adverse prognosis. The introduction of anti-HER2 targeted therapy has dramatically improved the clinical outcomes of patients with HER2-positive breast cancer. Unfortunately, a significant number of [...] Read more.

Amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer is associated with an adverse prognosis. The introduction of anti-HER2 targeted therapy has dramatically improved the clinical outcomes of patients with HER2-positive breast cancer. Unfortunately, a significant number of patients eventually relapse and develop distant metastasis. HER2 intratumoral heterogeneity (ITH) has been reported to be associated with poor prognosis in patients with anti-HER2 targeted therapies and was proposed to be a potential mechanism for anti-HER2 resistance. In this review, we described the current definition, common types of HER2 ITH in breast cancer, the challenge in interpretation of HER2 status in cases showing ITH and the clinical applications of anti-HER2 agents in breast cancer showing heterogeneous HER2 expression. Digital image analysis has emerged as an objective and reproducible scoring method and its role in the assessment of HER2 status with ITH remains to be demonstrated. Full article

(This article belongs to the Special Issue Biomarkers in Breast Cancer: Recent Advances and Challenges)

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12 pages, 272 KiB

Open AccessEditor’s ChoiceReview

The Role of HER2 Status in the Biliary Tract Cancers

by Ruveyda Ayasun, Muhammet Ozer and Ilyas Sahin

Cancers 2023, 15(9), 2628; https://doi.org/10.3390/cancers15092628 - 5 May 2023

Cited by 15 | Viewed by 4927

Abstract

Despite recent advances, biliary tract cancer (BTC) is traditionally known as being hard to treat with a poor prognosis. Recent state-of-the-art genomic technologies such as next-generation sequencing (NGS) revolutionized cancer management and shed light on the genomic landscape of BTCs. There are ongoing [...] Read more.

Despite recent advances, biliary tract cancer (BTC) is traditionally known as being hard to treat with a poor prognosis. Recent state-of-the-art genomic technologies such as next-generation sequencing (NGS) revolutionized cancer management and shed light on the genomic landscape of BTCs. There are ongoing clinical trials to assess the efficacy of HER2-blocking antibodies or drug conjugates in BTCs with HER2 amplifications. However, HER2 amplifications may not be the sole eligibility factor for these clinical trials. In this review, we aimed to comprehensively examine the role of somatic HER2 alterations and amplifications in patient stratification and provide an overview of the current state of ongoing clinical trials. Full article

(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment)

48 pages, 7853 KiB

Open AccessEditor’s ChoiceReview

Regulation of Autophagy via Carbohydrate and Lipid Metabolism in Cancer

by Javad Alizadeh, Mahboubeh Kavoosi, Navjit Singh, Shahrokh Lorzadeh, Amir Ravandi, Biniam Kidane, Naseer Ahmed, Fatima Mraiche, Michael R. Mowat and Saeid Ghavami

Cancers 2023, 15(8), 2195; https://doi.org/10.3390/cancers15082195 - 7 Apr 2023

Cited by 37 | Viewed by 6826

Abstract

Metabolic changes are an important component of tumor cell progression. Tumor cells adapt to environmental stresses via changes to carbohydrate and lipid metabolism. Autophagy, a physiological process in mammalian cells that digests damaged organelles and misfolded proteins via lysosomal degradation, is closely associated [...] Read more.

Metabolic changes are an important component of tumor cell progression. Tumor cells adapt to environmental stresses via changes to carbohydrate and lipid metabolism. Autophagy, a physiological process in mammalian cells that digests damaged organelles and misfolded proteins via lysosomal degradation, is closely associated with metabolism in mammalian cells, acting as a meter of cellular ATP levels. In this review, we discuss the changes in glycolytic and lipid biosynthetic pathways in mammalian cells and their impact on carcinogenesis via the autophagy pathway. In addition, we discuss the impact of these metabolic pathways on autophagy in lung cancer. Full article

(This article belongs to the Special Issue Autophagy–EMT Interrelations: At the Core of Tumor Transformation)

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25 pages, 1410 KiB

Open AccessEditor’s ChoiceReview

The Cell Biology of Metastatic Invasion in Pancreatic Cancer: Updates and Mechanistic Insights

by Vidhu B. Joshi, Omar L. Gutierrez Ruiz and Gina L. Razidlo

Cancers 2023, 15(7), 2169; https://doi.org/10.3390/cancers15072169 - 6 Apr 2023

Cited by 12 | Viewed by 5854

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality worldwide. This is largely due to the lack of routine screening protocols, an absence of symptoms in early-stage disease leading to late detection, and a paucity of effective treatment options. [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality worldwide. This is largely due to the lack of routine screening protocols, an absence of symptoms in early-stage disease leading to late detection, and a paucity of effective treatment options. Critically, the majority of patients either present with metastatic disease or rapidly develop metastatic disease. Thus, there is an urgent need to deepen our understanding of metastasis in PDAC. During metastasis, tumor cells escape from the primary tumor, enter the circulation, and travel to a distant site to form a secondary tumor. In order to accomplish this relatively rare event, tumor cells develop an enhanced ability to detach from the primary tumor, migrate into the surrounding matrix, and invade across the basement membrane. In addition, cancer cells interact with the various cell types and matrix proteins that comprise the tumor microenvironment, with some of these factors working to promote metastasis and others working to suppress it. In PDAC, many of these processes are not well understood. The purpose of this review is to highlight recent advances in the cell biology of the early steps of the metastatic cascade in pancreatic cancer. Specifically, we will examine the regulation of epithelial-to-mesenchymal transition (EMT) in PDAC and its requirement for metastasis, summarize our understanding of how PDAC cells invade and degrade the surrounding matrix, and discuss how migration and adhesion dynamics are regulated in PDAC to optimize cancer cell motility. In addition, the role of the tumor microenvironment in PDAC will also be discussed for each of these invasive processes. Full article

(This article belongs to the Collection Recent Advances in Pancreatic Ductal Adenocarcinoma)

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20 pages, 1020 KiB

Open AccessEditor’s ChoiceReview

Detection and Molecular Characterization of Circulating Tumour Cells: Challenges for the Clinical Setting

by Areti Strati, Athina Markou, Evgenia Kyriakopoulou and Evi Lianidou

Cancers 2023, 15(7), 2185; https://doi.org/10.3390/cancers15072185 - 6 Apr 2023

Cited by 23 | Viewed by 4827

Abstract

Over the last decade, liquid biopsy has gained much attention as a powerful tool in personalized medicine since it enables monitoring cancer evolution and follow-up of cancer patients in real time. Through minimally invasive procedures, liquid biopsy provides important information through the analysis [...] Read more.

Over the last decade, liquid biopsy has gained much attention as a powerful tool in personalized medicine since it enables monitoring cancer evolution and follow-up of cancer patients in real time. Through minimally invasive procedures, liquid biopsy provides important information through the analysis of circulating tumour cells (CTCs) and circulating tumour-derived material, such as circulating tumour DNA (ctDNA), circulating miRNAs (cfmiRNAs) and extracellular vehicles (EVs). CTC analysis has already had an important impact on the prognosis, detection of minimal residual disease (MRD), treatment selection and monitoring of cancer patients. Numerous clinical trials nowadays include a liquid biopsy arm. CTC analysis is now an exponentially expanding field in almost all types of solid cancers. Functional studies, mainly based on CTC-derived cell-lines and CTC-derived explants (CDx), provide important insights into the metastatic process. The purpose of this review is to summarize the latest findings on the clinical significance of CTCs for the management of cancer patients, covering the last four years. This review focuses on providing a comprehensive overview of CTC analysis in breast, prostate and non-small-cell lung cancer. The unique potential of CTC single-cell analysis for understanding metastasis biology, and the importance of quality control and standardization of methodologies used in this field, is also discussed. Full article

(This article belongs to the Special Issue The 5th ACTC: “Liquid Biopsy in Its Best”)

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58 pages, 2391 KiB

Open AccessEditor’s ChoiceReview

DNA-Based Nanomaterials as Drug Delivery Platforms for Increasing the Effect of Drugs in Tumors

by Anastasiya N. Shishparenok, Vitalina V. Furman and Dmitry D. Zhdanov

Cancers 2023, 15(7), 2151; https://doi.org/10.3390/cancers15072151 - 5 Apr 2023

Cited by 24 | Viewed by 6773

Abstract

DNA nanotechnology has significantly advanced and might be used in biomedical applications, drug delivery, and cancer treatment during the past few decades. DNA nanomaterials are widely used in biomedical research involving biosensing, bioimaging, and drug delivery since they are remarkably addressable and biocompatible. [...] Read more.

DNA nanotechnology has significantly advanced and might be used in biomedical applications, drug delivery, and cancer treatment during the past few decades. DNA nanomaterials are widely used in biomedical research involving biosensing, bioimaging, and drug delivery since they are remarkably addressable and biocompatible. Gradually, modified nucleic acids have begun to be employed to construct multifunctional DNA nanostructures with a variety of architectural designs. Aptamers are single-stranded nucleic acids (both DNAs and RNAs) capable of self-pairing to acquire secondary structure and of specifically binding with the target. Diagnosis and tumor therapy are prospective fields in which aptamers can be applied. Many DNA nanomaterials with three-dimensional structures have been studied as drug delivery systems for different anticancer medications or gene therapy agents. Different chemical alterations can be employed to construct a wide range of modified DNA nanostructures. Chemically altered DNA-based nanomaterials are useful for drug delivery because of their improved stability and inclusion of functional groups. In this work, the most common oligonucleotide nanomaterials were reviewed as modern drug delivery systems in tumor cells. Full article

(This article belongs to the Special Issue Nanoplatforms Based Cancers Therapy 2.0)

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37 pages, 1753 KiB

Open AccessEditor’s ChoiceReview

Mechanisms of Resistance and Current Treatment Options for Glioblastoma Multiforme (GBM)

by Satya Siva Kishan Yalamarty, Nina Filipczak, Xiang Li, Md Abdus Subhan, Farzana Parveen, Janaína Artem Ataide, Bharat Ashok Rajmalani and Vladimir P. Torchilin

Cancers 2023, 15(7), 2116; https://doi.org/10.3390/cancers15072116 - 1 Apr 2023

Cited by 130 | Viewed by 17169

Abstract

Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer that is difficult to treat due to its resistance to both radiation and chemotherapy. This resistance is largely due to the unique biology of GBM cells, which can evade the effects of [...] Read more.

Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer that is difficult to treat due to its resistance to both radiation and chemotherapy. This resistance is largely due to the unique biology of GBM cells, which can evade the effects of conventional treatments through mechanisms such as increased resistance to cell death and rapid regeneration of cancerous cells. Additionally, the blood–brain barrier makes it difficult for chemotherapy drugs to reach GBM cells, leading to reduced effectiveness. Despite these challenges, there are several treatment options available for GBM. The standard of care for newly diagnosed GBM patients involves surgical resection followed by concurrent chemoradiotherapy and adjuvant chemotherapy. Emerging treatments include immunotherapy, such as checkpoint inhibitors, and targeted therapies, such as bevacizumab, that attempt to attack specific vulnerabilities in GBM cells. Another promising approach is the use of tumor-treating fields, a type of electric field therapy that has been shown to slow the growth of GBM cells. Clinical trials are ongoing to evaluate the safety and efficacy of these and other innovative treatments for GBM, intending to improve with outcomes for patients. Full article

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14 pages, 3978 KiB

Open AccessEditor’s ChoiceArticle

Pediatric Patients with Stage IV Rhabdomyosarcoma Significantly Benefit from Long-Term Maintenance Therapy: Results of the CWS-IV 2002 and the CWS DOK IV 2004-Trials

by Lars Tramsen, Konrad Bochennek, Monika Sparber-Sauer, Emilia Salzmann-Manrique, Monika Scheer, Tobias Dantonello, Arndt Borkhardt, Uta Dirksen, Anne Thorwarth, Jeanette Greiner, Martin Ebinger, Jadwiga Weclawek-Tompol, Ruth Ladenstein, Gustaf Ljungman, Erika Hallmen, Thomas Lehrnbecher, Ewa Koscielniak and Thomas Klingebiel

Cancers 2023, 15(7), 2050; https://doi.org/10.3390/cancers15072050 - 30 Mar 2023

Cited by 13 | Viewed by 4791

Abstract

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma (STS) in childhood. Whereas more than 90% of patients with localized low-risk RMS can be cured, metastatic RMS have a dismal outcome, with survival rates of less than 30%. The HD CWS-96 trial showed [...] Read more.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma (STS) in childhood. Whereas more than 90% of patients with localized low-risk RMS can be cured, metastatic RMS have a dismal outcome, with survival rates of less than 30%. The HD CWS-96 trial showed an improved outcome for patients receiving maintenance therapy after completing intensive chemotherapy. Consequently, the international clinical trials CWS-IV 2002 and CWS DOK IV 2004 on metastatic disease of STS of the Cooperative Weichteilsarkom Studiengruppe (CWS) were designed in addition to the CWS-2002P trial for localized RMS disease. All patients received a multimodal intensive treatment regimen. To maintain remission, three options were compared: long-term maintenance therapy (LTMT) versus allogeneic hematopoietic stem cell transplantation (alloHSCT) versus high-dose chemotherapy (HDCT). A total of 176 pediatric patients with a histologically confirmed diagnosis of metastatic RMS or RMS-like tumor were included. A total of 89 patients receiving LTML showed a significantly better outcome, with an event-free survival (EFS) of 41% and an overall survival (OS) of 53%, than alloHSCT (n = 21, EFS 19%, p = 0.02, OS 24%, p = 0.002). The outcome of LTML was slightly improved compared to HDCT (n = 13, EFS 35%, OS 34%). In conclusion, our data suggest that in patients suffering from metastatic RMS, long-term maintenance therapy is a superior strategy in terms of EFS and OS compared to alloHSCT. EFS and OS of HDCT are similar in these strategies; however, the therapeutic burden of LTMT is much lower. Full article

(This article belongs to the Special Issue Rhabdomyosarcoma: Still Unresolved Questions but New Perspectives)

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30 pages, 1692 KiB

Open AccessEditor’s ChoiceReview

The Glioma Immune Landscape: A Double-Edged Sword for Treatment Regimens

by Sukrit Mahajan, Mirko H. H. Schmidt and Ulrike Schumann

Cancers 2023, 15(7), 2024; https://doi.org/10.3390/cancers15072024 - 28 Mar 2023

Cited by 16 | Viewed by 5044

Abstract

Immune cells constitute a major part of the tumor microenvironment, thereby playing an important role in regulating tumor development. They interact with tumor cells, resulting in the suppression or promotion of glioma development. Therefore, in recent years, scientists have focused on immunotherapy that [...] Read more.

Immune cells constitute a major part of the tumor microenvironment, thereby playing an important role in regulating tumor development. They interact with tumor cells, resulting in the suppression or promotion of glioma development. Therefore, in recent years, scientists have focused on immunotherapy that involves enhancing the immune response to fight the battle against cancer more effectively. While it has shown success against different cancer types, immunotherapy faces major roadblocks in glioma treatment. These involve the blood brain barrier, tumor heterogeneity and an immunosuppressive glioma microenvironment, among other factors. Additionally, the interaction of the peripheral immune system with the central nervous system provides another challenge for immunotherapeutic regimens. For modulating different immune cell populations to counter glioma cells, it is important to expand our knowledge about their role within the glioma microenvironment; therefore, herein, we review the different immune cell populations found in the glioma microenvironment and navigate through the various shortcomings of current immunotherapies for glioma. We conclude by providing an insight into ongoing pre-clinical and clinical trials for glioma therapies. Full article

(This article belongs to the Special Issue The Development of Effective Therapy Targeting the Microenvironment of Cancer)

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20 pages, 576 KiB

Open AccessEditor’s ChoiceArticle

Mathematical Model of Clonal Evolution Proposes a Personalised Multi-Modal Therapy for High-Risk Neuroblastoma

by Matteo Italia, Kenneth Y. Wertheim, Sabine Taschner-Mandl, Dawn Walker and Fabio Dercole

Cancers 2023, 15(7), 1986; https://doi.org/10.3390/cancers15071986 - 26 Mar 2023

Cited by 10 | Viewed by 3695

Abstract

Neuroblastoma is the most common extra-cranial solid tumour in children. Despite multi-modal therapy, over half of the high-risk patients will succumb. One contributing factor is the one-size-fits-all nature of multi-modal therapy. For example, during the first step (induction chemotherapy), the standard regimen (rapid [...] Read more.

Neuroblastoma is the most common extra-cranial solid tumour in children. Despite multi-modal therapy, over half of the high-risk patients will succumb. One contributing factor is the one-size-fits-all nature of multi-modal therapy. For example, during the first step (induction chemotherapy), the standard regimen (rapid COJEC) administers fixed doses of chemotherapeutic agents in eight two-week cycles. Perhaps because of differences in resistance, this standard regimen results in highly heterogeneous outcomes in different tumours. In this study, we formulated a mathematical model comprising ordinary differential equations. The equations describe the clonal evolution within a neuroblastoma tumour being treated with vincristine and cyclophosphamide, which are used in the rapid COJEC regimen, including genetically conferred and phenotypic drug resistance. The equations also describe the agents’ pharmacokinetics. We devised an optimisation algorithm to find the best chemotherapy schedules for tumours with different pre-treatment clonal compositions. The optimised chemotherapy schedules exploit the cytotoxic difference between the two drugs and intra-tumoural clonal competition to shrink the tumours as much as possible during induction chemotherapy and before surgical removal. They indicate that induction chemotherapy can be improved by finding and using personalised schedules. More broadly, we propose that the overall multi-modal therapy can be enhanced by employing targeted therapies against the mutations and oncogenic pathways enriched and activated by the chemotherapeutic agents. To translate the proposed personalised multi-modal therapy into clinical use, patient-specific model calibration and treatment optimisation are necessary. This entails a decision support system informed by emerging medical technologies such as multi-region sequencing and liquid biopsies. The results and tools presented in this paper could be the foundation of this decision support system. Full article

(This article belongs to the Special Issue Childhood Cancer in the Genomic Era: Experimental and Theoretical Approaches)

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15 pages, 2281 KiB

Open AccessEditor’s ChoiceArticle

Immune Checkpoint and EMT-Related Molecules in Circulating Tumor Cells (CTCs) from Triple Negative Breast Cancer Patients and Their Clinical Impact

by Vasileios Vardas, Anastasios Tolios, Athina Christopoulou, Vassilis Georgoulias, Anastasia Xagara, Filippos Koinis, Athanasios Kotsakis and Galatea Kallergi

Cancers 2023, 15(7), 1974; https://doi.org/10.3390/cancers15071974 - 25 Mar 2023

Cited by 14 | Viewed by 2623

Abstract

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. There are few targeted therapies for these patients, leading to an unmet need for new biomarkers. The present study aimed to investigate the expression of PD-L1, CTLA-4, GLU, and VIM in [...] Read more.

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. There are few targeted therapies for these patients, leading to an unmet need for new biomarkers. The present study aimed to investigate the expression of PD-L1, CTLA-4, GLU, and VIM in CTCs of TNBC patients. Ninety-five patients were enrolled in this study: sixty-four TNBC and thirty-one luminal. Of these patients, 60 were in the early stage, while 35 had metastatic disease. Protein expression was identified by immunofluorescence staining experiments and VyCAP analysis. All the examined proteins were upregulated in TNBC patients. The expression of the GLU⁺VIM⁺CK⁺ phenotype was higher (50%) in metastatic TNBC compared to early TNBC patients (17%) (p = 0.005). Among all the BC patients, a significant correlation was found between PD-L1⁺CD45⁻CK⁺ and CTLA-4⁺CD45⁻CK⁺ phenotypes (Spearman test, p = 0.024), implying an important role of dual inhibition in BC. Finally, the phenotypes GLU⁺VIM⁺CK⁺ and PD-L1⁺CD45⁻CK⁺ were associated with shorter OS in TNBC patients (OS: log-rank p = 0.048, HR = 2.9, OS: log-rank p < 0.001, HR = 8.7, respectively). Thus, PD-L1, CTLA-4, GLU, and VIM constitute significant biomarkers in TNBC associated with patients’ outcome, providing new therapeutic targets for this difficult breast cancer subtype. Full article

(This article belongs to the Special Issue The Analysis of Circulating Tumor Cells (CTCs): New Insights into the Biology of Cancers)

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21 pages, 5153 KiB

Open AccessEditor’s ChoiceArticle

From Head and Neck Tumour and Lymph Node Segmentation to Survival Prediction on PET/CT: An End-to-End Framework Featuring Uncertainty, Fairness, and Multi-Region Multi-Modal Radiomics

by Zohaib Salahuddin, Yi Chen, Xian Zhong, Henry C. Woodruff, Nastaran Mohammadian Rad, Shruti Atul Mali and Philippe Lambin

Cancers 2023, 15(7), 1932; https://doi.org/10.3390/cancers15071932 - 23 Mar 2023

Cited by 13 | Viewed by 4112

Abstract

Automatic delineation and detection of the primary tumour (GTVp) and lymph nodes (GTVn) using PET and CT in head and neck cancer and recurrence-free survival prediction can be useful for diagnosis and patient risk stratification. We used data from nine different centres, with [...] Read more.

Automatic delineation and detection of the primary tumour (GTVp) and lymph nodes (GTVn) using PET and CT in head and neck cancer and recurrence-free survival prediction can be useful for diagnosis and patient risk stratification. We used data from nine different centres, with 524 and 359 cases used for training and testing, respectively. We utilised posterior sampling of the weight space in the proposed segmentation model to estimate the uncertainty for false positive reduction. We explored the prognostic potential of radiomics features extracted from the predicted GTVp and GTVn in PET and CT for recurrence-free survival prediction and used SHAP analysis for explainability. We evaluated the bias of models with respect to age, gender, chemotherapy, HPV status, and lesion size. We achieved an aggregate Dice score of 0.774 and 0.760 on the test set for GTVp and GTVn, respectively. We observed a per image false positive reduction of 19.5% and 7.14% using the uncertainty threshold for GTVp and GTVn, respectively. Radiomics features extracted from GTVn in PET and from both GTVp and GTVn in CT are the most prognostic, and our model achieves a C-index of 0.672 on the test set. Our framework incorporates uncertainty estimation, fairness, and explainability, demonstrating the potential for accurate detection and risk stratification. Full article

(This article belongs to the Special Issue Diagnostic, Prognostic, Predictive Biomarkers and New Targets for Treatment in Head and Neck Cancers)

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14 pages, 1976 KiB

Open AccessEditor’s ChoiceArticle

Exact Probability Distribution for the ROC Area under Curve

by Joakim Ekström, Jim Åkerrén Ögren and Tobias Sjöblom

Cancers 2023, 15(6), 1788; https://doi.org/10.3390/cancers15061788 - 15 Mar 2023

Cited by 15 | Viewed by 2509

Abstract

The Receiver Operating Characteristic (ROC) is a de facto standard for determining the accuracy of in vitro diagnostic (IVD) medical devices, and thus the exactness in its probability distribution is crucial toward accurate statistical inference. We show the exact probability distribution of the [...] Read more.

The Receiver Operating Characteristic (ROC) is a de facto standard for determining the accuracy of in vitro diagnostic (IVD) medical devices, and thus the exactness in its probability distribution is crucial toward accurate statistical inference. We show the exact probability distribution of the ROC AUC-value, hence exact critical values and p-values are readily obtained. Because the exact calculations are computationally intense, we demonstrate a method of geometric interpolation, which is exact in a special case but generally an approximation, vastly increasing computational speeds. The method is illustrated through open access data, demonstrating superiority of 26 composite biomarkers relative to a predicate device. Especially under correction for testing of multiple hypotheses, traditional asymptotic approximations are encumbered by considerable imprecision, adversely affecting IVD device development. The ability to obtain exact p-values will allow more efficient IVD device development. Full article

(This article belongs to the Section Cancer Informatics and Big Data)

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85 pages, 4243 KiB

Open AccessEditor’s ChoiceReview

The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy

by Katarzyna Starska-Kowarska

Cancers 2023, 15(6), 1642; https://doi.org/10.3390/cancers15061642 - 7 Mar 2023

Cited by 25 | Viewed by 10350

Abstract

Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive and heterogeneous groups of human neoplasms. HNSCC is characterized by high morbidity, accounting for 3% of all cancers, and high mortality with ~1.5% of all cancer deaths. It was the [...] Read more.

Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive and heterogeneous groups of human neoplasms. HNSCC is characterized by high morbidity, accounting for 3% of all cancers, and high mortality with ~1.5% of all cancer deaths. It was the most common cancer worldwide in 2020, according to the latest GLOBOCAN data, representing the seventh most prevalent human malignancy. Despite great advances in surgical techniques and the application of modern combinations and cytotoxic therapies, HNSCC remains a leading cause of death worldwide with a low overall survival rate not exceeding 40–60% of the patient population. The most common causes of death in patients are its frequent nodal metastases and local neoplastic recurrences, as well as the relatively low response to treatment and severe drug resistance. Much evidence suggests that the tumour microenvironment (TME), tumour infiltrating lymphocytes (TILs) and circulating various subpopulations of immunocompetent cells, such regulatory T cells (CD4⁺CD25⁺Foxp3⁺T_regs), cytotoxic CD3⁺CD8⁺ T cells (CTLs) and CD3⁺CD4⁺ T helper type 1/2/9/17 (Th₁/Th₂/Th₉/Th₁₇) lymphocytes, T follicular helper cells (T_fh) and CD56^dim/CD16^bright activated natural killer cells (NK), carcinoma-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), tumour-associated neutrophils (N1/N2 TANs), as well as tumour-associated macrophages (M1/M2 phenotype TAMs) can affect initiation, progression and spread of HNSCC and determine the response to immunotherapy. Rapid advances in the field of immuno-oncology and the constantly growing knowledge of the immunosuppressive mechanisms and effects of tumour cancer have allowed for the use of effective and personalized immunotherapy as a first-line therapeutic procedure or an essential component of a combination therapy for primary, relapsed and metastatic HNSCC. This review presents the latest reports and molecular studies regarding the anti-tumour role of selected subpopulations of immunocompetent cells in the pathogenesis of HNSCC, including HPV^+ve (HPV⁺) and HPV^−ve (HPV⁻) tumours. The article focuses on the crucial regulatory mechanisms of pro- and anti-tumour activity, key genetic or epigenetic changes that favour tumour immune escape, and the strategies that the tumour employs to avoid recognition by immunocompetent cells, as well as resistance mechanisms to T and NK cell-based immunotherapy in HNSCC. The present review also provides an overview of the pre- and clinical early trials (I/II phase) and phase-III clinical trials published in this arena, which highlight the unprecedented effectiveness and limitations of immunotherapy in HNSCC, and the emerging issues facing the field of HNSCC immuno-oncology. Full article

(This article belongs to the Special Issue Molecular Signatures in Head and Neck Cancer)

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18 pages, 3732 KiB

Open AccessEditor’s ChoiceReview

Treatment Strategies for KRAS-Mutated Non-Small-Cell Lung Cancer

by Éabha O’Sullivan, Anna Keogh, Brian Henderson, Stephen P. Finn, Steven G. Gray and Kathy Gately

Cancers 2023, 15(6), 1635; https://doi.org/10.3390/cancers15061635 - 7 Mar 2023

Cited by 51 | Viewed by 14410

Abstract

Activating mutations in KRAS are highly prevalent in solid tumours and are frequently found in 35% of lung, 45% of colorectal, and up to 90% of pancreatic cancers. Mutated KRAS is a prognostic factor for disease-free survival (DFS) and overall survival (OS) in [...] Read more.

Activating mutations in KRAS are highly prevalent in solid tumours and are frequently found in 35% of lung, 45% of colorectal, and up to 90% of pancreatic cancers. Mutated KRAS is a prognostic factor for disease-free survival (DFS) and overall survival (OS) in NSCLC and is associated with a more aggressive clinical phenotype, highlighting the need for KRAS-targeted therapy. Once considered undruggable due to its smooth shallow surface, a breakthrough showed that the activated G12C-mutated KRAS isozyme can be directly inhibited via a newly identified switch II pocket. This discovery led to the development of a new class of selective small-molecule inhibitors against the KRAS G12C isoform. Sotorasib and adagrasib are approved in locally advanced or metastatic NSCLC patients who have received at least one prior systemic therapy. Currently, there are at least twelve KRAS G12C inhibitors being tested in clinical trials, either as a single agent or in combination. In this study, KRAS mutation prevalence, subtypes, rates of occurrence in treatment-resistant invasive mucinous adenocarcinomas (IMAs), and novel drug delivery options are reviewed. Additionally, the current status of KRAS inhibitors, multiple resistance mechanisms that limit efficacy, and their use in combination treatment strategies and novel multitargeted approaches in NSCLC are discussed. Full article

(This article belongs to the Special Issue Update in Lung Cancer Molecular Pathology: Technological Advances and Clinical Practice)

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35 pages, 1829 KiB

Open AccessEditor’s ChoiceReview

Immunotargeting of Cancer Stem Cells

by Ayse Sedef Köseer, Simona Di Gaetano, Claudia Arndt, Michael Bachmann and Anna Dubrovska

Cancers 2023, 15(5), 1608; https://doi.org/10.3390/cancers15051608 - 5 Mar 2023

Cited by 16 | Viewed by 5079

Abstract

The generally accepted view is that CSCs hijack the signaling pathways attributed to normal stem cells that regulate the self-renewal and differentiation processes. Therefore, the development of selective targeting strategies for CSC, although clinically meaningful, is associated with significant challenges because CSC and [...] Read more.

The generally accepted view is that CSCs hijack the signaling pathways attributed to normal stem cells that regulate the self-renewal and differentiation processes. Therefore, the development of selective targeting strategies for CSC, although clinically meaningful, is associated with significant challenges because CSC and normal stem cells share many important signaling mechanisms for their maintenance and survival. Furthermore, the efficacy of this therapy is opposed by tumor heterogeneity and CSC plasticity. While there have been considerable efforts to target CSC populations by the chemical inhibition of the developmental pathways such as Notch, Hedgehog (Hh), and Wnt/β-catenin, noticeably fewer attempts were focused on the stimulation of the immune response by CSC-specific antigens, including cell-surface targets. Cancer immunotherapies are based on triggering the anti-tumor immune response by specific activation and targeted redirecting of immune cells toward tumor cells. This review is focused on CSC-directed immunotherapeutic approaches such as bispecific antibodies and antibody-drug candidates, CSC-targeted cellular immunotherapies, and immune-based vaccines. We discuss the strategies to improve the safety and efficacy of the different immunotherapeutic approaches and describe the current state of their clinical development. Full article

(This article belongs to the Special Issue Cancer Stem Cells and Targeted Therapy)

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20 pages, 4420 KiB

Open AccessEditor’s ChoiceSystematic Review

A Systematic Review of High-Dose Methotrexate for Adults with Primary Central Nervous System Lymphoma

by Gabriela Villanueva, Martin Guscott, Paula Schaiquevich, Claudia Sampor, Ryan Combs, Nicolás Tentoni, Miriam Hwang, Jennifer Lowe and Scott Howard

Cancers 2023, 15(5), 1459; https://doi.org/10.3390/cancers15051459 - 25 Feb 2023

Cited by 16 | Viewed by 4560

Abstract

Primary central nervous system lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma that is confined within the CNS. Due to its ability to cross the blood–brain barrier, high-dose methotrexate (HDMTX) is the backbone for induction chemotherapy. This systematic review was conducted to observe [...] Read more.

Primary central nervous system lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma that is confined within the CNS. Due to its ability to cross the blood–brain barrier, high-dose methotrexate (HDMTX) is the backbone for induction chemotherapy. This systematic review was conducted to observe outcomes among different HDMTX doses (low, <3 g/m²; intermediate, 3–4.9 g/m²; high, ≥5 g/m²) and regimens used in the treatment of PCNSL. A PubMed search resulted in 26 articles reporting clinical trials using HDMTX for PCNSL, from which 35 treatment cohorts were identified for analysis. The median dose of HDMTX used for induction was 3.5 g/m² (interquartile range IQR, 3–3.5); the intermediate dose was most frequently used in the studies examined (24 cohorts, 69%). Five cohorts used HDMTX monotherapy, 19 cohorts used HDMTX + polychemotherapy, and 11 cohorts used HDMTX + rituximab ± polychemotherapy. Pooled overall response rate (ORR) estimates for low, intermediate, and high dose HDMTX cohorts were 71%, 76%, and 76%, respectively. Pooled 2-year progression-free survival (PFS) estimates for low, intermediate, and high HDMTX dose cohorts were 50%, 51%, and 55%, respectively. Regimens that included rituximab showed a tendency to have higher ORR and 2-year PFS than those that did not include rituximab. These findings indicate that current protocols utilizing 3–4 g/m² of HDMTX in combination with rituximab provide therapeutic efficacy in PCNSL. Full article

(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)

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23 pages, 370 KiB

Open AccessEditor’s ChoiceReview

Bispecific T-Cell Engagers Therapies in Solid Tumors: Focusing on Prostate Cancer

by Diana C. Simão, Kevin K. Zarrabi, José L. Mendes, Ricardo Luz, Jorge A. Garcia, William K. Kelly and Pedro C. Barata

Cancers 2023, 15(5), 1412; https://doi.org/10.3390/cancers15051412 - 23 Feb 2023

Cited by 31 | Viewed by 8479

Abstract

Over the past decade, immunotherapy has demonstrated an impressive improvement in treatment outcomes for multiple cancers. Following the landmark approvals for use of immune checkpoint inhibitors, new challenges emerged in various clinical settings. Not all tumor types harbor immunogenic characteristics capable of triggering [...] Read more.

Over the past decade, immunotherapy has demonstrated an impressive improvement in treatment outcomes for multiple cancers. Following the landmark approvals for use of immune checkpoint inhibitors, new challenges emerged in various clinical settings. Not all tumor types harbor immunogenic characteristics capable of triggering responses. Similarly, many tumors’ immune microenvironment allows them to become evasive, leading to resistance and, thus, limiting the durability of responses. To overcome this limitation, new T-cell redirecting strategies such as bispecific T-cell engager (BiTE) have become attractive and promising immunotherapies. Our review provides a comprehensive perspective of the current evidence of BiTE therapies in solid tumors. Considering that immunotherapy has shown modest results in advanced prostate cancer to date, we review the biologic rationale and promising results of BiTE therapy in this clinical setting and discuss potential tumor-associated antigens that may be integrated into BiTE construct designs. Our review also aims to evaluate the advances of BiTE therapies in prostate cancer, illustrate the major obstacles and underlying limitations, and discuss directions for future research. Full article

(This article belongs to the Collection Urological Cancer 2023-2025)

16 pages, 1929 KiB

Open AccessEditor’s ChoiceReview

Unlocking the Resistance to Anti-HER2 Treatments in Breast Cancer: The Issue of HER2 Spatial Distribution

by Federica Giugliano, Ambra Carnevale Schianca, Chiara Corti, Mariia Ivanova, Nadia Bianco, Silvia Dellapasqua, Carmen Criscitiello, Nicola Fusco, Giuseppe Curigliano and Elisabetta Munzone

Cancers 2023, 15(5), 1385; https://doi.org/10.3390/cancers15051385 - 22 Feb 2023

Cited by 16 | Viewed by 5699

Abstract

Approximately 15% of breast cancers are classified as HER2-positive, with an amplification of the ERBB2 gene and/or an overexpression of the HER2 protein. Up to 30% of HER2-positive breast cancers shows heterogeneity in HER2 expression and different patterns of spatial distribution, i.e., the [...] Read more.

Approximately 15% of breast cancers are classified as HER2-positive, with an amplification of the ERBB2 gene and/or an overexpression of the HER2 protein. Up to 30% of HER2-positive breast cancers shows heterogeneity in HER2 expression and different patterns of spatial distribution, i.e., the variability in the distribution and expression of the HER2 protein within a single tumour. Spatial heterogeneity may potentially affect treatment, response, assessment of HER2 status and consequently, may impact on the best treatment strategy. Understanding this feature can help clinicians to predict response to HER2-targeted therapies and patient outcomes, and to fine tune treatment decisions. This review summarizes the available evidence on HER2 heterogeneity and spatial distribution and how this may affect current available treatment choices, exploring possible opportunities for overcoming this issue, such as novel pharmacological agents, belonging to the group of antibody–drug conjugates. Full article

(This article belongs to the Special Issue Anti-HER2 Therapy Resistance in Breast Cancer)

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14 pages, 1198 KiB

Open AccessEditor’s ChoiceReview

The Gut-Prostate Axis: A New Perspective of Prostate Cancer Biology through the Gut Microbiome

by Kazutoshi Fujita, Makoto Matsushita, Marco A. De Velasco, Koji Hatano, Takafumi Minami, Norio Nonomura and Hirotsugu Uemura

Cancers 2023, 15(5), 1375; https://doi.org/10.3390/cancers15051375 - 21 Feb 2023

Cited by 32 | Viewed by 6838

Abstract

Obesity and a high-fat diet are risk factors associated with prostate cancer, and lifestyle, especially diet, impacts the gut microbiome. The gut microbiome plays important roles in the development of several diseases, such as Alzheimer’s disease, rheumatoid arthritis, and colon cancer. The analysis [...] Read more.

Obesity and a high-fat diet are risk factors associated with prostate cancer, and lifestyle, especially diet, impacts the gut microbiome. The gut microbiome plays important roles in the development of several diseases, such as Alzheimer’s disease, rheumatoid arthritis, and colon cancer. The analysis of feces from patients with prostate cancer by 16S rRNA sequencing has uncovered various associations between altered gut microbiomes and prostate cancer. Gut dysbiosis caused by the leakage of gut bacterial metabolites, such as short-chain fatty acids and lipopolysaccharide results in prostate cancer growth. Gut microbiota also play a role in the metabolism of androgen which could affect castration-resistant prostate cancer. Moreover, men with high-risk prostate cancer share a specific gut microbiome and treatments such as androgen-deprivation therapy alter the gut microbiome in a manner that favors prostate cancer growth. Thus, implementing interventions aiming to modify lifestyle or altering the gut microbiome with prebiotics or probiotics may curtail the development of prostate cancer. From this perspective, the “Gut–Prostate Axis” plays a fundamental bidirectional role in prostate cancer biology and should be considered when screening and treating prostate cancer patients. Full article

(This article belongs to the Special Issue Metastatic Prostate Cancer: Interaction with Tumors and Their Microenvironments)

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23 pages, 1809 KiB

Open AccessEditor’s ChoiceReview

Downstream Targets of VHL/HIF-α Signaling in Renal Clear Cell Carcinoma Progression: Mechanisms and Therapeutic Relevance

by Sonia Mazumder, Paul J. Higgins and Rohan Samarakoon

Cancers 2023, 15(4), 1316; https://doi.org/10.3390/cancers15041316 - 19 Feb 2023

Cited by 46 | Viewed by 9556

Abstract

The clear cell variant of renal cell carcinoma (ccRCC) is the most common renal epithelial malignancy and responsible for most of the deaths from kidney cancer. Patients carrying inactivating mutations in the Von Hippel-Lindau (VHL) gene have an increased proclivity to develop several [...] Read more.

The clear cell variant of renal cell carcinoma (ccRCC) is the most common renal epithelial malignancy and responsible for most of the deaths from kidney cancer. Patients carrying inactivating mutations in the Von Hippel-Lindau (VHL) gene have an increased proclivity to develop several types of tumors including ccRCC. Normally, the Hypoxia Inducible Factor alpha (HIF-α) subunits of the HIF heterodimeric transcription factor complex are regulated by oxygen-dependent prolyl-hydroxylation, VHL-mediated ubiquitination and proteasomal degradation. Loss of pVHL function results in elevated levels of HIF-α due to increased stability, leading to RCC progression. While HIF-1α acts as a tumor suppressor, HIF-2α promotes oncogenic potential by driving tumor progression and metastasis through activation of hypoxia-sensitive signaling pathways and overexpression of HIF-2α target genes. One strategy to suppress ccRCC aggressiveness is directed at inhibition of HIF-2α and the associated molecular pathways leading to cell proliferation, angiogenesis, and metastasis. Indeed, clinical and pre-clinical data demonstrated the effectiveness of HIF-2α targeted therapy in attenuating ccRCC progression. This review focuses on the signaling pathways and the involved genes (cyclin D, c-Myc, VEGF-a, EGFR, TGF-α, GLUT-1) that confer oncogenic potential downstream of the VHL-HIF-2α signaling axis in ccRCC. Discussed as well are current treatment options (including receptor tyrosine kinase inhibitors such as sunitinib), the medical challenges (high prevalence of metastasis at the time of diagnosis, refractory nature of advanced disease to current treatment options), scientific challenges and future directions. Full article

(This article belongs to the Special Issue Cancers Driven by HIF)

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12 pages, 1341 KiB

Open AccessEditor’s ChoiceReview

Mechanisms of Resistance to Antibody–Drug Conjugates

by Rachel Occhiogrosso Abelman, Bogang Wu, Laura M. Spring, Leif W. Ellisen and Aditya Bardia

Cancers 2023, 15(4), 1278; https://doi.org/10.3390/cancers15041278 - 17 Feb 2023

Cited by 69 | Viewed by 9063

Abstract

Antibody–drug conjugates (ADCs), with antibodies targeted against specific antigens linked to cytotoxic payloads, offer the opportunity for a more specific delivery of chemotherapy and other bioactive payloads to minimize side effects. First approved in the setting of HER2+ breast cancer, more recent ADCs [...] Read more.

Antibody–drug conjugates (ADCs), with antibodies targeted against specific antigens linked to cytotoxic payloads, offer the opportunity for a more specific delivery of chemotherapy and other bioactive payloads to minimize side effects. First approved in the setting of HER2+ breast cancer, more recent ADCs have been developed for triple-negative breast cancer (TNBC) and, most recently, hormone receptor-positive (HR+) breast cancer. While antibody–drug conjugates have compared favorably against traditional chemotherapy in some settings, patients eventually progress on these therapies and require a change in treatment. Mechanisms to explain the resistance to ADCs are highly sought after, in hopes of developing next-line treatment options and expanding the therapeutic windows of existing therapies. These resistance mechanisms are categorized as follows: change in antigen expression, change in ADC processing and resistance, and efflux of the ADC payload. This paper reviews the recently published literature on these mechanisms as well as potential options to overcome these barriers. Full article

(This article belongs to the Special Issue Resistance in Breast Cancer)

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12 pages, 293 KiB

Open AccessEditor’s ChoiceReview

Evolving Treatment Landscape of HER2-mutant Non-Small Cell Lung Cancer: Trastuzumab Deruxtecan and Beyond

by Ioannis A. Vathiotis, Dimitrios Bafaloukos, Konstantinos N. Syrigos and George Samonis

Cancers 2023, 15(4), 1286; https://doi.org/10.3390/cancers15041286 - 17 Feb 2023

Cited by 15 | Viewed by 4577

Abstract

Successful targeting of HER2-activating mutations in DESTINY-Lung02 phase II study has led to the approval of the antibody–drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) as second-line treatment in patients with non-small cell lung cancer (NSCLC). Despite the impressive results, several matters need to [...] Read more.

Successful targeting of HER2-activating mutations in DESTINY-Lung02 phase II study has led to the approval of the antibody–drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) as second-line treatment in patients with non-small cell lung cancer (NSCLC). Despite the impressive results, several matters need to be addressed, including the clinical activity of T-DXd in patients with disease in the central nervous system as well as the role of T-DXd in the context of HER2 overexpression. Additionally, data regarding novel agents used to target HER2 continue to accumulate. This review highlights the challenges and unanswered questions that have emerged after the approval of T-DXd in patients with HER2-mutant NSCLC. Full article

(This article belongs to the Special Issue World Lung Cancer Awareness Month)

8 pages, 2264 KiB

Open AccessEditor’s ChoiceArticle

Radical Prostatectomy without Prior Biopsy in Patients with High Suspicion of Prostate Cancer Based on Multiparametric Magnetic Resonance Imaging and Prostate-Specific Membrane Antigen Positron Emission Tomography: A Prospective Cohort Study

by Michael Chaloupka, Maria Apfelbeck, Nikolaos Pyrgidis, Julian Marcon, Philipp Weinhold and Christian G. Stief

Cancers 2023, 15(4), 1266; https://doi.org/10.3390/cancers15041266 - 16 Feb 2023

Cited by 16 | Viewed by 2683

Abstract

Modern risk stratification of prostate cancer (PCa) allows for prediction of advanced disease with a high level of certainty. We aimed to evaluate a prospective series of patients undergoing radical prostatectomy without prior biopsy based solely on clinical criteria and imaging results. The [...] Read more.

Modern risk stratification of prostate cancer (PCa) allows for prediction of advanced disease with a high level of certainty. We aimed to evaluate a prospective series of patients undergoing radical prostatectomy without prior biopsy based solely on clinical criteria and imaging results. The patients were divided into three groups. Group 1 included 27 patients with: (i) suspicious digital rectal examination, (ii) PSA ≥ 10 ng/mL, (iii) PI-RADS 4/5 on mpMRI, and (iv) high suspicion of PCa on PSMA-PET. Group 2 included six patients who fulfilled criteria i, ii, and iii but did not undergo PSMA-PET imaging. Group 3 included 17 patients with at least one clinical (i or ii) and one imaging (iii or iv) criterion. All of the patients were diagnosed with PCa. Comparison of Group 1 and 2 versus Group 3 showed a significantly higher ratio of locally advanced PCa for Groups 1 and 2 compared to Group 3 (60.6% versus 11.8%, p = 0.005, respectively). Similarly, these patients displayed a significantly higher ratio of aggressive PCa (ISUP grade > 2: 66.7% versus 23.5%, p = 0.027, respectively) and tumor infiltration (median tumor infiltration: 32.5% vs. 15%, p = 0.001, respectively) in the final specimen compared to Group 3. In conclusion, we have shown that radical prostatectomy without prior biopsy is safe in terms of the diagnosis of clinically significant PCa when proper preoperative risk stratification involving mpMRI and PSMA-PET imaging is applied. Full article

(This article belongs to the Section Cancer Therapy)

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21 pages, 2645 KiB

Open AccessEditor’s ChoiceReview

NKG2A Immune Checkpoint in Vδ2 T Cells: Emerging Application in Cancer Immunotherapy

by Valentina Cazzetta, Delphine Depierreux, Francesco Colucci, Joanna Mikulak and Domenico Mavilio

Cancers 2023, 15(4), 1264; https://doi.org/10.3390/cancers15041264 - 16 Feb 2023

Cited by 9 | Viewed by 5150

Abstract

Immune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). This successful immunotherapy has led to a more complete view of cancer that now considers not only the cancer cells to be targeted and destroyed but also the [...] Read more.

Immune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). This successful immunotherapy has led to a more complete view of cancer that now considers not only the cancer cells to be targeted and destroyed but also the immune environment of the cancer cells. Current challenges associated with the enhancement of ICI effects are increasing the fraction of responding patients through personalized combinations of multiple ICIs and overcoming acquired resistance. This requires a complete overview of the anti-tumor immune response, which depends on a complex interplay between innate and adaptive immune cells with the tumor microenvironment. The NKG2A was revealed to be a key immune checkpoint for both Natural Killer (NK) cells and T cells. Monalizumab, a humanized anti-NKG2A antibody, enhances NK cell activity against various tumor cells and rescues CD8 αβ T cell function in combination with PD-1/PD-L1 blockade. In this review, we discuss the potential for targeting NKG2A expressed on tumor-sensing human γδ T cells, mostly on the specific Vδ2 T cell subset, in order to emphasize its importance and potential in the development of new ICI-based therapeutic approaches. Full article

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

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12 pages, 862 KiB

Open AccessEditor’s ChoiceReview

CAR-T Therapy in GBM: Current Challenges and Avenues for Improvement

by Ayush Pant and Michael Lim

Cancers 2023, 15(4), 1249; https://doi.org/10.3390/cancers15041249 - 16 Feb 2023

Cited by 20 | Viewed by 5007

Abstract

Completed clinical trials of CAR-T cells in glioblastoma (GBM) have revealed key challenges that limit their efficacy. These include incomplete antigen coverage, downregulation of target antigen in response to therapy, exposure to immunosuppressive cells and cytokines in the tumor microenvironment and exhaustion of [...] Read more.

Completed clinical trials of CAR-T cells in glioblastoma (GBM) have revealed key challenges that limit their efficacy. These include incomplete antigen coverage, downregulation of target antigen in response to therapy, exposure to immunosuppressive cells and cytokines in the tumor microenvironment and exhaustion of CAR-T cells. To overcome these challenges, CAR-T cells have been modified to maximize effector function and resist immunosuppression in the tumor while limiting toxicities to the host. Adoption of these novel CAR-T strategies in GBM can overcome the “cold tumor” phenotype of GBM and trigger an inflammatory cascade that maximizes tumor clearance and minimizes CAR-T dysfunction. To achieve this, understanding and harnessing the antigenic, metabolic and immunological composition of GBM is crucial. Here we review the findings from completed clinical trials of CAR-T cells in GBM as well as novel strategies that could improve CAR-T survival and function in the tumor. Full article

(This article belongs to the Collection Treatment of Glioma)

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28 pages, 1165 KiB

Open AccessEditor’s ChoiceReview

Hypoxia, a Targetable Culprit to Counter Pancreatic Cancer Resistance to Therapy

by Raefa Abou Khouzam, Jean-Marie Lehn, Hemma Mayr, Pierre-Alain Clavien, Michael Bradley Wallace, Michel Ducreux, Perparim Limani and Salem Chouaib

Cancers 2023, 15(4), 1235; https://doi.org/10.3390/cancers15041235 - 15 Feb 2023

Cited by 15 | Viewed by 4802

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and it is a disease of dismal prognosis. While immunotherapy has revolutionized the treatment of various solid tumors, it has achieved little success in PDAC. Hypoxia within the stroma-rich tumor microenvironment [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and it is a disease of dismal prognosis. While immunotherapy has revolutionized the treatment of various solid tumors, it has achieved little success in PDAC. Hypoxia within the stroma-rich tumor microenvironment is associated with resistance to therapies and promotes angiogenesis, giving rise to a chaotic and leaky vasculature that is inefficient at shuttling oxygen and nutrients. Hypoxia and its downstream effectors have been implicated in immune resistance and could be contributing to the lack of response to immunotherapy experienced by patients with PDAC. Paradoxically, increasing evidence has shown hypoxia to augment genomic instability and mutagenesis in cancer, suggesting that hypoxic tumor cells could have increased production of neoantigens that can potentially enable their clearance by cytotoxic immune cells. Strategies aimed at relieving this condition have been on the rise, and one such approach opts for normalizing the tumor vasculature to reverse hypoxia and its downstream support of tumor pathogenesis. An important consideration for the successful implementation of such strategies in the clinic is that not all PDACs are equally hypoxic, therefore hypoxia-detection approaches should be integrated to enable optimal patient selection for achieving improved patient outcomes. Full article

(This article belongs to the Collection Recent Advances in Pancreatic Ductal Adenocarcinoma)

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25 pages, 775 KiB

Open AccessEditor’s ChoiceReview

Radiomics Applications in Head and Neck Tumor Imaging: A Narrative Review

by Mario Tortora, Laura Gemini, Alessandra Scaravilli, Lorenzo Ugga, Andrea Ponsiglione, Arnaldo Stanzione, Felice D’Arco, Gennaro D’Anna and Renato Cuocolo

Cancers 2023, 15(4), 1174; https://doi.org/10.3390/cancers15041174 - 12 Feb 2023

Cited by 29 | Viewed by 4471

Abstract

Recent advances in machine learning and artificial intelligence technology have ensured automated evaluation of medical images. As a result, quantifiable diagnostic and prognostic biomarkers have been created. We discuss radiomics applications for the head and neck region in this paper. Molecular characterization, categorization, [...] Read more.

Recent advances in machine learning and artificial intelligence technology have ensured automated evaluation of medical images. As a result, quantifiable diagnostic and prognostic biomarkers have been created. We discuss radiomics applications for the head and neck region in this paper. Molecular characterization, categorization, prognosis and therapy recommendation are given special consideration. In a narrative manner, we outline the fundamental technological principles, the overall idea and usual workflow of radiomic analysis and what seem to be the present and potential challenges in normal clinical practice. Clinical oncology intends for all of this to ensure informed decision support for personalized and useful cancer treatment. Head and neck cancers present a unique set of diagnostic and therapeutic challenges. These challenges are brought on by the complicated anatomy and heterogeneity of the area under investigation. Radiomics has the potential to address these barriers. Future research must be interdisciplinary and focus on the study of certain oncologic functions and outcomes, with external validation and multi-institutional cooperation in order to achieve this. Full article

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27 pages, 471 KiB

Open AccessEditor’s ChoiceReview

CAR-Based Immunotherapy of Solid Tumours—A Survey of the Emerging Targets

by John Maher and David M. Davies

Cancers 2023, 15(4), 1171; https://doi.org/10.3390/cancers15041171 - 11 Feb 2023

Cited by 19 | Viewed by 7278

Abstract

Immunotherapy with CAR T-cells has revolutionised the treatment of B-cell and plasma cell-derived cancers. However, solid tumours present a much greater challenge for treatment using CAR-engineered immune cells. In a partner review, we have surveyed data generated in clinical trials in which patients [...] Read more.

Immunotherapy with CAR T-cells has revolutionised the treatment of B-cell and plasma cell-derived cancers. However, solid tumours present a much greater challenge for treatment using CAR-engineered immune cells. In a partner review, we have surveyed data generated in clinical trials in which patients with solid tumours that expressed any of 30 discrete targets were treated with CAR-based immunotherapy. That exercise confirms that efficacy of this approach falls well behind that seen in haematological malignancies, while significant toxic events have also been reported. Here, we consider approximately 60 additional candidates for which such clinical data are not available yet, but where pre-clinical data have provided support for their advancement to clinical evaluation as CAR target antigens. Full article

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31 pages, 1969 KiB

Open AccessEditor’s ChoiceReview

Mitochondrial Metabolism in Pancreatic Ductal Adenocarcinoma: From Mechanism-Based Perspectives to Therapy

by Hafiza Padinharayil, Vikrant Rai and Alex George

Cancers 2023, 15(4), 1070; https://doi.org/10.3390/cancers15041070 - 8 Feb 2023

Cited by 11 | Viewed by 4316

Abstract

Pancreatic ductal adenocarcinoma (PDAC), the fourteenth most common malignancy, is a major contributor to cancer-related death with the utmost case fatality rate among all malignancies. Functional mitochondria, regardless of their complex ecosystem relative to normal cells, are essential in PDAC progression. Tumor cells’ [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC), the fourteenth most common malignancy, is a major contributor to cancer-related death with the utmost case fatality rate among all malignancies. Functional mitochondria, regardless of their complex ecosystem relative to normal cells, are essential in PDAC progression. Tumor cells’ potential to produce ATP as energy, despite retaining the redox potential optimum, and allocating materials for biosynthetic activities that are crucial for cell growth, survival, and proliferation, are assisted by mitochondria. The polyclonal tumor cells with different metabolic profiles may add to carcinogenesis through inter-metabolic coupling. Cancer cells frequently possess alterations in the mitochondrial genome, although they do not hinder metabolism; alternatively, they change bioenergetics. This can further impart retrograde signaling, educate cell signaling, epigenetic modifications, chromatin structures, and transcription machinery, and ultimately satisfy cancer cellular and nuclear demands. To maximize the tumor microenvironment (TME), tumor cells remodel nearby stromal cells and extracellular matrix. These changes initiate polyclonality, which is crucial for growth, stress response, and metastasis. Here, we evaluate all the intrinsic and extrinsic pathways drawn by mitochondria in carcinogenesis, emphasizing the perspectives of mitochondrial metabolism in PDAC progression and treatment. Full article

(This article belongs to the Special Issue Mitochondria and Metabolism of Pancreatic Adenocarcinoma Cells)

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23 pages, 3095 KiB

Open AccessEditor’s ChoiceReview

Aquaporins and Ion Channels as Dual Targets in the Design of Novel Glioblastoma Therapeutics to Limit Invasiveness

by Alanah Varricchio and Andrea J. Yool

Cancers 2023, 15(3), 849; https://doi.org/10.3390/cancers15030849 - 30 Jan 2023

Cited by 5 | Viewed by 4392

Abstract

Current therapies for Glioblastoma multiforme (GBM) focus on eradicating primary tumors using radiotherapy, chemotherapy and surgical resection, but have limited success in controlling the invasive spread of glioma cells into a healthy brain, the major factor driving short survival times for patients post-diagnosis. [...] Read more.

Current therapies for Glioblastoma multiforme (GBM) focus on eradicating primary tumors using radiotherapy, chemotherapy and surgical resection, but have limited success in controlling the invasive spread of glioma cells into a healthy brain, the major factor driving short survival times for patients post-diagnosis. Transcriptomic analyses of GBM biopsies reveal clusters of membrane signaling proteins that in combination serve as robust prognostic indicators, including aquaporins and ion channels, which are upregulated in GBM and implicated in enhanced glioblastoma motility. Accumulating evidence supports our proposal that the concurrent pharmacological targeting of selected subclasses of aquaporins and ion channels could impede glioblastoma invasiveness by impairing key cellular motility pathways. Optimal sets of channels to be selected as targets for combined therapies could be tailored to the GBM cancer subtype, taking advantage of differences in patterns of expression between channels that are characteristic of GBM subtypes, as well as distinguishing them from non-cancerous brain cells such as neurons and glia. Focusing agents on a unique channel fingerprint in GBM would further allow combined agents to be administered at near threshold doses, potentially reducing off-target toxicity. Adjunct therapies which confine GBM tumors to their primary sites during clinical treatments would offer profound advantages for treatment efficacy. Full article

(This article belongs to the Special Issue The Emerging Role of Ion Channels in Brain Cancer: Mechanisms of Action and Therapeutic Targets)

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44 pages, 1995 KiB

Open AccessEditor’s ChoiceReview

Gut Microbiota in Colorectal Cancer: Biological Role and Therapeutic Opportunities

by Himani Pandey, Daryl W. T. Tang, Sunny H. Wong and Devi Lal

Cancers 2023, 15(3), 866; https://doi.org/10.3390/cancers15030866 - 30 Jan 2023

Cited by 81 | Viewed by 11640

Abstract

Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths worldwide. While CRC is thought to be an interplay between genetic and environmental factors, several lines of evidence suggest the involvement of gut microbiota in promoting inflammation and tumor progression. Gut microbiota refer [...] Read more.

Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths worldwide. While CRC is thought to be an interplay between genetic and environmental factors, several lines of evidence suggest the involvement of gut microbiota in promoting inflammation and tumor progression. Gut microbiota refer to the ~40 trillion microorganisms that inhabit the human gut. Advances in next-generation sequencing technologies and metagenomics have provided new insights into the gut microbial ecology and have helped in linking gut microbiota to CRC. Many studies carried out in humans and animal models have emphasized the role of certain gut bacteria, such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and colibactin-producing Escherichia coli, in the onset and progression of CRC. Metagenomic studies have opened up new avenues for the application of gut microbiota in the diagnosis, prevention, and treatment of CRC. This review article summarizes the role of gut microbiota in CRC development and its use as a biomarker to predict the disease and its potential therapeutic applications. Full article

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13 pages, 1717 KiB

Open AccessEditor’s ChoiceArticle

Circulating Chromosome Conformation Signatures Significantly Enhance PSA Positive Predicting Value and Overall Accuracy for Prostate Cancer Detection

by Dmitri Pchejetski, Ewan Hunter, Mehrnoush Dezfouli, Matthew Salter, Ryan Powell, Jayne Green, Tarun Naithani, Christina Koutsothanasi, Heba Alshaker, Jiten Jaipuria, Martin J. Connor, David Eldred-Evans, Francesca Fiorentino, Hashim Ahmed, Alexandre Akoulitchev and Mathias Winkler

Cancers 2023, 15(3), 821; https://doi.org/10.3390/cancers15030821 - 29 Jan 2023

Cited by 9 | Viewed by 23446

Abstract

Background: Prostate cancer (PCa) has a high lifetime prevalence (one out of six men), but currently there is no widely accepted screening programme. Widely used prostate specific antigen (PSA) test at cut-off of 3.0 ng/mL does not have sufficient accuracy for detection of [...] Read more.

Background: Prostate cancer (PCa) has a high lifetime prevalence (one out of six men), but currently there is no widely accepted screening programme. Widely used prostate specific antigen (PSA) test at cut-off of 3.0 ng/mL does not have sufficient accuracy for detection of any prostate cancer, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance in some men with PCa. We have recently identified circulating chromosome conformation signatures (CCSs, Episwitch^® PCa test) allowing PCa detection and risk stratification in line with standards of clinical PCa staging. The purpose of this study was to determine whether combining the Episwitch PCa test with the PSA test will increase its diagnostic accuracy. Methods: n = 109 whole blood samples of men enrolled in the PROSTAGRAM screening pilot study and n = 38 samples of patients with established PCa diagnosis and cancer-negative controls from Imperial College NHS Trust were used. Samples were tested for PSA, and the presence of CCSs in the loci encoding for of DAPK1, HSD3B2, SRD5A3, MMP1, and miRNA98 associated with high-risk PCa identified in our previous work. Results: PSA > 3 ng/mL alone showed a low positive predicted value (PPV) of 0.14 and a high negative predicted value (NPV) of 0.93. EpiSwitch alone showed a PPV of 0.91 and a NPV of 0.32. Combining PSA and Episwitch tests has significantly increased the PPV to 0.81 although reducing the NPV to 0.78. Furthermore, integrating PSA, as a continuous variable (rather than a dichotomised 3 ng/mL cut-off), with EpiSwitch in a new multivariant stratification model, Prostate Screening EpiSwitch (PSE) test, has yielded a remarkable combined PPV of 0.93 and NPV of 0.95 when tested on the independent combined cohort. Conclusions: Our results demonstrate that combining the standard PSA readout with circulating chromosome conformations (PSE test) allows for significantly enhanced PSA PPV and overall accuracy for PCa detection. The PSE test is accurate, rapid, minimally invasive, and inexpensive, suggesting significant screening diagnostic potential to minimise unnecessary referrals for expensive and invasive MRI and/or biopsy testing. Further extended prospective blinded validation of the new combined signature in a screening cohort with low cancer prevalence would be the recommended step for PSE adoption in PCa screening. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

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13 pages, 1181 KiB

Open AccessEditor’s ChoiceReview

CAR-T Cell Therapy and the Gut Microbiota

by Sahana Asokan, Nyssa Cullin, Christoph K. Stein-Thoeringer and Eran Elinav

Cancers 2023, 15(3), 794; https://doi.org/10.3390/cancers15030794 - 28 Jan 2023

Cited by 21 | Viewed by 7830

Abstract

Chimeric antigen receptor (CAR) - T cell cancer therapy has yielded promising results in treating hematologic malignancies in clinical studies, and a growing number of CAR-T regimens are approved for clinical usage. While the therapy is considered of great potential in expanding the [...] Read more.

Chimeric antigen receptor (CAR) - T cell cancer therapy has yielded promising results in treating hematologic malignancies in clinical studies, and a growing number of CAR-T regimens are approved for clinical usage. While the therapy is considered of great potential in expanding the cancer immunotherapy arsenal, more than half of patients receiving CAR-T infusions do not respond, while others develop significant adverse effects, collectively indicating a need for optimization of CAR-T treatment to the individual. The microbiota is increasingly suggested as a major modulator of immunotherapy responsiveness. Studying causal microbiota roles possibly contributing to CAR-T therapy efficacy, adverse effects reduction, and prediction of patient responsiveness constitutes an exciting area of active research. Herein, we discuss the latest developments implicating human microbiota involvement in CAR-T therapy, while highlighting challenges and promises in harnessing the microbiota as a predictor and modifier of CAR-T treatment towards optimized efficacy and minimization of treatment-related adverse effects. Full article

(This article belongs to the Special Issue CAR T-cell Therapy for Lymphoma Research)

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15 pages, 787 KiB

Open AccessEditor’s ChoiceReview

Tumor Infiltrating Lymphocytes across Breast Cancer Subtypes: Current Issues for Biomarker Assessment

by Carmine Valenza, Beatrice Taurelli Salimbeni, Celeste Santoro, Dario Trapani, Gabriele Antonarelli and Giuseppe Curigliano

Cancers 2023, 15(3), 767; https://doi.org/10.3390/cancers15030767 - 26 Jan 2023

Cited by 44 | Viewed by 5349

Abstract

Tumor-infiltrating lymphocytes (TILs) represent a surrogate biomarker of anti-tumor, lymphocyte-mediated immunity. In early, triple-negative breast cancer, TILs have level 1B of evidence to predict clinical outcomes. TILs represent a promising biomarker to select patients who can experience a better prognosis with de-intensified cancer [...] Read more.

Tumor-infiltrating lymphocytes (TILs) represent a surrogate biomarker of anti-tumor, lymphocyte-mediated immunity. In early, triple-negative breast cancer, TILs have level 1B of evidence to predict clinical outcomes. TILs represent a promising biomarker to select patients who can experience a better prognosis with de-intensified cancer treatments and derive larger benefits from immune checkpoint inhibitors. However, the assessment and the validation of TILs as a biomarker require a prospective and rigorous demonstration of its clinical validity and utility, provided reproducible analytical performance. With pending data about the prospective validation of TILs’ clinical validity to modulate treatments in early breast cancer, this review summarizes the most important current issues and future challenges related to the implementation of TILs assessments across all breast cancer subtypes and their potential integration into clinical practice. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Multidisciplinary Approaches and Predictive Biomarkers)

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29 pages, 1727 KiB

Open AccessEditor’s ChoiceReview

Current Status and Future Prospects for Esophageal Cancer

by Mahdi Sheikh, Gholamreza Roshandel, Valerie McCormack and Reza Malekzadeh

Cancers 2023, 15(3), 765; https://doi.org/10.3390/cancers15030765 - 26 Jan 2023

Cited by 146 | Viewed by 15456

Abstract

Esophageal cancer (EC) is the ninth most common cancer and the sixth leading cause of cancer deaths worldwide. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two main histological subtypes with distinct epidemiological and clinical features. While the global incidence [...] Read more.

Esophageal cancer (EC) is the ninth most common cancer and the sixth leading cause of cancer deaths worldwide. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two main histological subtypes with distinct epidemiological and clinical features. While the global incidence of ESCC is declining, the incidence of EAC is increasing in many countries. Decades of epidemiologic research have identified distinct environmental exposures for ESCC and EAC subtypes. Recent advances in understanding the genomic aspects of EC have advanced our understanding of EC causes and led to using specific genomic alterations in EC tumors as biomarkers for early diagnosis, treatment, and prognosis of this cancer. Nevertheless, the prognosis of EC is still poor, with a five-year survival rate of less than 20%. Currently, there are significant challenges for early detection and secondary prevention for both ESCC and EAC subtypes, but Cytosponge™ is shifting this position for EAC. Primary prevention remains the preferred strategy for reducing the global burden of EC. In this review, we will summarize recent advances, current status, and future prospects of the studies related to epidemiology, time trends, environmental risk factors, prevention, early diagnosis, and treatment for both EC subtypes. Full article

(This article belongs to the Special Issue Current Status and Future Prospects for Oesophageal Cancer)

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31 pages, 974 KiB

Open AccessEditor’s ChoiceReview

Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy

by Marianna Sirico, Alberto D’Angelo, Caterina Gianni, Chiara Casadei, Filippo Merloni and Ugo De Giorgi

Cancers 2023, 15(3), 703; https://doi.org/10.3390/cancers15030703 - 23 Jan 2023

Cited by 61 | Viewed by 6937

Abstract

The phosphoinositide 3 kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of the rapamycin (mTOR) axis is a key signal transduction system that links oncogenes and multiple receptor classes which are involved in many essential cellular functions. Aberrant PI3K signalling is one of the most [...] Read more.

The phosphoinositide 3 kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of the rapamycin (mTOR) axis is a key signal transduction system that links oncogenes and multiple receptor classes which are involved in many essential cellular functions. Aberrant PI3K signalling is one of the most commonly mutated pathways in cancer. Consequently, more than 40 compounds targeting key components of this signalling network have been tested in clinical trials among various types of cancer. As the oncogenic activation of the PI3K/AKT/mTOR pathway often occurs alongside mutations in other signalling networks, combination therapy should be considered. In this review, we highlight recent advances in the knowledge of the PI3K pathway and discuss the current state and future challenges of targeting this pathway in clinical practice. Full article

(This article belongs to the Special Issue PI3K Pathway in Cancer)

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17 pages, 920 KiB

Open AccessEditor’s ChoiceArticle

Safety and Feasibility of Radiation Therapy Combined with CDK 4/6 Inhibitors in the Management of Advanced Breast Cancer

by Marcin Kubeczko, Dorota Gabryś, Marzena Gawkowska, Anna Polakiewicz-Gilowska, Alexander J. Cortez, Aleksandra Krzywon, Grzegorz Woźniak, Tomasz Latusek, Aleksandra Leśniak, Katarzyna Świderska, Marta Mianowska-Malec, Barbara Łanoszka, Konstanty Chomik, Mateusz Gajek, Anna Michalik, Elżbieta Nowicka, Rafał Tarnawski, Tomasz Rutkowski and Michał Jarząb

Cancers 2023, 15(3), 690; https://doi.org/10.3390/cancers15030690 - 22 Jan 2023

Cited by 15 | Viewed by 5787

Abstract

The addition of CDK4/6 inhibitors to endocrine therapy in advanced hormone receptor-positive HER2-negative breast cancer has led to practice-changing improvements in overall survival. However, data concerning the safety of CDK4/6i combination with radiotherapy (RT) are conflicting. A retrospective evaluation of 288 advanced breast [...] Read more.

The addition of CDK4/6 inhibitors to endocrine therapy in advanced hormone receptor-positive HER2-negative breast cancer has led to practice-changing improvements in overall survival. However, data concerning the safety of CDK4/6i combination with radiotherapy (RT) are conflicting. A retrospective evaluation of 288 advanced breast cancer patients (pts) treated with CDK4/6i was performed, and 100 pts also received RT. Forty-six pts received 63 RT courses concurrently and fifty-four sequentially before CDK4/6i initiation (76 RT courses). Neutropenia was common (79%) and more frequent during and after concurrent RT than sequential RT (86% vs. 76%); however, CDK4/6i dose reduction rates were similar. In patients treated with CDK4/6i alone, the dose reduction rate was 42% (79 pts) versus 38% with combined therapy, and 5% discontinued treatment due to toxicity in the combined group. The risk of CDK4/6i dose reduction was correlated with neutropenia grade, RT performed within the first two CDK4/6i cycles, and more than one concurrent RT; a tendency was observed in concurrent bone irradiation. However, on multivariate regression analysis, only ECOG 1 performance status and severe neutropenia at the beginning of the second cycle were found to be associated with a higher risk of CDK4/6i dose reduction. This largest single-center experience published to date confirmed the acceptable safety profile of the CDK4/6i and RT combination without a significantly increased toxicity compared with CDK4/6i alone. However, one might delay RT for the first two CDK4/6i cycles, when myelotoxic AE are most common. Full article

(This article belongs to the Special Issue Radiation Therapy for Breast Cancer: Recent Advances and Challenges)

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25 pages, 1287 KiB

Open AccessEditor’s ChoiceReview

Treatment Strategies for Non-Small Cell Lung Cancer with Common EGFR Mutations: A Review of the History of EGFR TKIs Approval and Emerging Data

by Julian A. Marin-Acevedo, Bruna Pellini, ErinMarie O. Kimbrough, J. Kevin Hicks and Alberto Chiappori

Cancers 2023, 15(3), 629; https://doi.org/10.3390/cancers15030629 - 19 Jan 2023

Cited by 25 | Viewed by 9398

Abstract

The development of targeted therapies over the past two decades has led to a dramatic change in the management of EGFR-mutant non-small cell lung cancer (NSCLC). While there are currently five approved EGFR tyrosine kinase inhibitors (TKIs) for treating EGFR-mutant NSCLC [...] Read more.

The development of targeted therapies over the past two decades has led to a dramatic change in the management of EGFR-mutant non-small cell lung cancer (NSCLC). While there are currently five approved EGFR tyrosine kinase inhibitors (TKIs) for treating EGFR-mutant NSCLC in the first-line setting, therapy selection after progression on EGFR TKIs remains complex. Multiple groups are investigating novel therapies and drug combinations to determine the optimal therapy and treatment sequence for these patients. In this review, we summarize the landmark trials and history of the approval of EGFR TKIs, their efficacy and tolerability, and the role of these therapies in patients with central nervous system metastasis. We also briefly discuss the mechanisms of resistance to EGFR TKIs, ongoing attempts to overcome resistance and improve outcomes, and finalize by offering treatment sequencing recommendations. Full article

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

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22 pages, 2233 KiB

Open AccessEditor’s ChoiceReview

MicroRNAs in the Pathogenesis, Prognostication and Prediction of Treatment Resistance in Soft Tissue Sarcomas

by Andrea York Tiang Teo, Vivian Yujing Lim and Valerie Shiwen Yang

Cancers 2023, 15(3), 577; https://doi.org/10.3390/cancers15030577 - 18 Jan 2023

Cited by 8 | Viewed by 6277

Abstract

Soft tissue sarcomas are highly aggressive malignant neoplasms of mesenchymal origin, accounting for less than 1% of adult cancers, but comprising over 20% of paediatric solid tumours. In locally advanced, unresectable, or metastatic disease, outcomes from even the first line of systemic treatment [...] Read more.

Soft tissue sarcomas are highly aggressive malignant neoplasms of mesenchymal origin, accounting for less than 1% of adult cancers, but comprising over 20% of paediatric solid tumours. In locally advanced, unresectable, or metastatic disease, outcomes from even the first line of systemic treatment are invariably poor. MicroRNAs (miRNAs), which are short non-coding RNA molecules, target and modulate multiple dysregulated target genes and/or signalling pathways within cancer cells. Accordingly, miRNAs demonstrate great promise for their utility in diagnosing, prognosticating and improving treatment for soft tissue sarcomas. This review aims to provide an updated discussion on the known roles of specific miRNAs in the pathogenesis of sarcomas, and their potential use in prognosticating outcomes and prediction of therapeutic resistance. Full article

(This article belongs to the Topic Soft Tissue Sarcomas: Treatment and Management)

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