Pub Date : 2025-06-18DOI: 10.1016/j.seminoncol.2025.152372
Ehab Yassen Theab , Ali G. Alkhathami , Inas Ridha Ali , Hussein Riyadh Abdul Kareem Al-Hetty , Suhas Ballal , Rishiv Kalia , Sami G. Almalki , Renu Arya , Deepak Nathiya
Glioblastoma (GBM) continues to be 1 of the most malignant tumors with limited success in therapy, primarily owing to the emergence of resistance towards temozolomide TMZ. Resistance to TMZ is a multifactorial phenomenon in GBM, depending on the interactions between genetic, epigenetic, and microenvironmental factors. Noncoding RNAs, most significantly circRNAs, have recently been highlighted as playing important roles in the pathogenesis of GBM and drug resistance against TMZ. These stable, circular RNA molecules can act as microRNA sponges or encode functional peptides; hence, they modulate functions relating to different aspects of tumor development. Furthermore, circRNAs can be carried within exosomes, promoting intercellular communication and propagation of drug resistance. Exosomes serve as sophisticated delivery vehicles that harbor varying bioactive molecules like proteins, lipids, mRNAs, miRNAs, lncRNAs, and many others, including circular RNAs. This review elucidates the specific functions held by exosomal circRNAs, such as circASAP1 and circ-HIPK3, in the modulation of TMZ resistance through different molecular pathways. It also reflects the biomarker potential of exosomal circRNAs as diagnostics and prognostics, allowing their dynamic application in liquid biopsies to monitor the progression of GBM over time. This review tries to develop an understanding of the complex nature of mechanisms conferring resistance to TMZ, with a particular focus on new insights regarding the potential roles of exosomal circular RNAs.
{"title":"Exosomal circular RNAs as drivers of temozolomide resistance in glioblastoma: Mechanisms and implications","authors":"Ehab Yassen Theab , Ali G. Alkhathami , Inas Ridha Ali , Hussein Riyadh Abdul Kareem Al-Hetty , Suhas Ballal , Rishiv Kalia , Sami G. Almalki , Renu Arya , Deepak Nathiya","doi":"10.1016/j.seminoncol.2025.152372","DOIUrl":"10.1016/j.seminoncol.2025.152372","url":null,"abstract":"<div><div>Glioblastoma (GBM) continues to be 1 of the most malignant tumors with limited success in therapy, primarily owing to the emergence of resistance towards temozolomide TMZ. Resistance to TMZ is a multifactorial phenomenon in GBM, depending on the interactions between genetic, epigenetic, and microenvironmental factors. Noncoding RNAs, most significantly circRNAs, have recently been highlighted as playing important roles in the pathogenesis of GBM and drug resistance against TMZ. These stable, circular RNA molecules can act as microRNA sponges or encode functional peptides; hence, they modulate functions relating to different aspects of tumor development. Furthermore, circRNAs can be carried within exosomes, promoting intercellular communication and propagation of drug resistance. Exosomes serve as sophisticated delivery vehicles that harbor varying bioactive molecules like proteins, lipids, mRNAs, miRNAs, lncRNAs, and many others, including circular RNAs. This review elucidates the specific functions held by exosomal circRNAs, such as circASAP1 and circ-HIPK3, in the modulation of TMZ resistance through different molecular pathways. It also reflects the biomarker potential of exosomal circRNAs as diagnostics and prognostics, allowing their dynamic application in liquid biopsies to monitor the progression of GBM over time. This review tries to develop an understanding of the complex nature of mechanisms conferring resistance to TMZ, with a particular focus on new insights regarding the potential roles of exosomal circular RNAs.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152372"},"PeriodicalIF":3.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144313673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
As a key component of epigenetics, microRNAs (miRNAs) have provided promising insights into several aspects of Breast Cancer (BC). We have analyzed 2 BC tissue microarray datasets (GSE26659 and GSE40525), as well as 2 serum datasets (GSE106817 and GSE113486). The results were then intersected to identify commonly dysregulated miRNAs in the tissue and serum of BC patients. RNA-seq analysis was then applied to The Cancer Genome Atlas (TCGA) data. Briefly, 79 dysregulated miRNAs were identified in the tissue and serum of patients with BC of which 3 significantly dysregulated and previously unstudied miRNAs, let-7e-5p, miR-151a-5p and miR-887-3p, were chosen for quantification in the serum of cancer patients by RT-PCR followed by evaluation of their diagnostic and prognostic features. RT-PCR analysis revealed overexpression of let-7e-5p (logFC = 2.01, P < .05) and miR-151a-5p (logFC = 1.48, P < .05) whereas miR-887-3p was downregulated (logFC = 0.62, P < .05) similar to microarray and RNA-seq data analysis. Based on regression analysis, a 3 miRNA-signature biomarker was proposed which had better diagnostic ability (AUC = 84.17%) compared to the ability of these miRNAs when assessed individually. Moreover, enrichment analysis revealed these miRNAs mediate vital cellular processes and biological functions that influence the development of cancer. Similarly, significant prognostic clinical characteristics were observed for these miRNAs. Overall, we have identified and validated a novel and proficient signature biomarker in serum of BC patients consisting of 3 miRNAs.
{"title":"A 3-miRNA signature for noninvasive breast cancer detection","authors":"Amir Ebrahimi , Davood Ghavi , Zohreh Mirzaei , Tahereh Barati , Mahmood Shekari-Khaniani , Hossein Gahramani-almangadim , Sima Mansoori-Derakhshan","doi":"10.1016/j.seminoncol.2025.152363","DOIUrl":"10.1016/j.seminoncol.2025.152363","url":null,"abstract":"<div><div>As a key component of epigenetics, microRNAs (miRNAs) have provided promising insights into several aspects of Breast Cancer (BC). We have analyzed 2 BC tissue microarray datasets (GSE26659 and GSE40525), as well as 2 serum datasets (GSE106817 and GSE113486). The results were then intersected to identify commonly dysregulated miRNAs in the tissue and serum of BC patients. RNA-seq analysis was then applied to The Cancer Genome Atlas (TCGA) data. Briefly, 79 dysregulated miRNAs were identified in the tissue and serum of patients with BC of which 3 significantly dysregulated and previously unstudied miRNAs, let-7e-5p, miR-151a-5p and miR-887-3p, were chosen for quantification in the serum of cancer patients by RT-PCR followed by evaluation of their diagnostic and prognostic features. RT-PCR analysis revealed overexpression of let-7e-5p (logFC = 2.01, <em>P</em> < .05) and miR-151a-5p (logFC = 1.48, <em>P</em> < .05) whereas miR-887-3p was downregulated (logFC = 0.62, <em>P</em> < .05) similar to microarray and RNA-seq data analysis. Based on regression analysis, a 3 miRNA-signature biomarker was proposed which had better diagnostic ability (AUC = 84.17%) compared to the ability of these miRNAs when assessed individually. Moreover, enrichment analysis revealed these miRNAs mediate vital cellular processes and biological functions that influence the development of cancer. Similarly, significant prognostic clinical characteristics were observed for these miRNAs. Overall, we have identified and validated a novel and proficient signature biomarker in serum of BC patients consisting of 3 miRNAs.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152363"},"PeriodicalIF":3.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144263216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-11DOI: 10.1016/j.seminoncol.2025.152362
Sabrina R Comess BA , Justin K Joseph BA , Michelle Yoon BA , Salmaan Sayeed BS , Pranati Borkhetaria BA , Luke Stanisce MD , Margaret Brandwein-Weber MD , Michael Karasick PhD , Mark L Urken MD
Contemporary cancer management relies on the precise transfer of information regarding disease and treatment details between a range of providers and facilities. The time of surgery is uniquely responsible for many ambiguities in this oncological information flow, as intraoperative communication and documentation are often unregimented and imprecise. Downstream providers such as radiation oncologists, medical oncologists, and radiologists rely on surgical pathology reports for planning postoperative treatment and surveillance. However, traditional pathology reports lack critical details about the actions taken during surgery and do not make the oncologic clearance status explicit. We identified agents of change to improve information transfer and designed an improved surgical workflow and pathology report that make use of a novel pathologic reporting software to address gaps in the oncologic care timeline. Our updated workflow results in a dynamic final pathology report that integrates annotated 3D scans of the surgical specimen and extirpative defect, unequivocal reconciliation of at-risk and supplemental margins, highlighted preoperative radiographs, and brief narrative summaries by the surgeon and pathologist. These tangible changes aim to improve clarity and continuity in oncologic care.
{"title":"Identifying and closing information gaps in head and neck cancer surgery","authors":"Sabrina R Comess BA , Justin K Joseph BA , Michelle Yoon BA , Salmaan Sayeed BS , Pranati Borkhetaria BA , Luke Stanisce MD , Margaret Brandwein-Weber MD , Michael Karasick PhD , Mark L Urken MD","doi":"10.1016/j.seminoncol.2025.152362","DOIUrl":"10.1016/j.seminoncol.2025.152362","url":null,"abstract":"<div><div>Contemporary cancer management relies on the precise transfer of information regarding disease and treatment details between a range of providers and facilities. The time of surgery is uniquely responsible for many ambiguities in this oncological information flow, as intraoperative communication and documentation are often unregimented and imprecise. Downstream providers such as radiation oncologists, medical oncologists, and radiologists rely on surgical pathology reports for planning postoperative treatment and surveillance. However, traditional pathology reports lack critical details about the actions taken during surgery and do not make the oncologic clearance status explicit. We identified agents of change to improve information transfer and designed an improved surgical workflow and pathology report that make use of a novel pathologic reporting software to address gaps in the oncologic care timeline. Our updated workflow results in a dynamic final pathology report that integrates annotated 3D scans of the surgical specimen and extirpative defect, unequivocal reconciliation of at-risk and supplemental margins, highlighted preoperative radiographs, and brief narrative summaries by the surgeon and pathologist. These tangible changes aim to improve clarity and continuity in oncologic care.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152362"},"PeriodicalIF":3.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144254034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-11DOI: 10.1016/j.seminoncol.2025.152352
Carla Eksteen , Johann Riedemann , Frederick H. van der Merwe , Matthys H. Botha , Anna-Mart Engelbrecht
The World Health Organization reports that cervical cancer ranks as the eighth most common cancer worldwide and is the ninth leading cause of cancer-related deaths. It is also the most prevalent cancer among women in 25 countries, primarily in Sub-Saharan Africa. Consequently, cervical cancer continues to pose a significant global health challenge, particularly due to the limited treatment options available for advanced stages of the disease. Evidently, immunotherapy is a promising strategy, but its efficacy is variable among patients. As such, predictive indicators are essential for identifying patients who are most likely to benefit from immunotherapy and for guiding treatment decisions. This review provides an overview of the current landscape of predictive biomarkers in cervical cancer immunotherapy, including immune checkpoint molecules, tumor mutational burden and immune cell infiltration. We further discuss additional factors such as cytokines, tumor infiltrating lymphocytes and previous exposure to platinum-based chemotherapy. As the field continues to evolve, ongoing research efforts are needed to refine predictive biomarkers and optimize patient selection in LMICs for immunotherapy in cervical cancer.
{"title":"Advancing personalized medicine in LMICs: Predictive indicators for cervical cancer immunotherapy response","authors":"Carla Eksteen , Johann Riedemann , Frederick H. van der Merwe , Matthys H. Botha , Anna-Mart Engelbrecht","doi":"10.1016/j.seminoncol.2025.152352","DOIUrl":"10.1016/j.seminoncol.2025.152352","url":null,"abstract":"<div><div>The World Health Organization reports that cervical cancer ranks as the eighth most common cancer worldwide and is the ninth leading cause of cancer-related deaths. It is also the most prevalent cancer among women in 25 countries, primarily in Sub-Saharan Africa. Consequently, cervical cancer continues to pose a significant global health challenge, particularly due to the limited treatment options available for advanced stages of the disease. Evidently, immunotherapy is a promising strategy, but its efficacy is variable among patients. As such, predictive indicators are essential for identifying patients who are most likely to benefit from immunotherapy and for guiding treatment decisions. This review provides an overview of the current landscape of predictive biomarkers in cervical cancer immunotherapy, including immune checkpoint molecules, tumor mutational burden and immune cell infiltration. We further discuss additional factors such as cytokines, tumor infiltrating lymphocytes and previous exposure to platinum-based chemotherapy. As the field continues to evolve, ongoing research efforts are needed to refine predictive biomarkers and optimize patient selection in LMICs for immunotherapy in cervical cancer.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152352"},"PeriodicalIF":3.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144254699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-09DOI: 10.1016/j.seminoncol.2025.152348
Francesco Vitiello , Toshifumi Tada , Goki Suda , Shigeo Shimose , Masatoshi Kudo , Jaekyung Cheon , Fabian Finkelmeier , Ho Yeong Lim , José Presa , Gianluca Masi , Changhoon Yoo , Sara Lonardi , Francesco Tovoli , Takashi Kumada , Mario Scartozzi , Emiliano Tamburini , Francesco Giuseppe Foschi , Mara Persano , Federico Rossari , Silvia Foti , Margherita Rimini
Background
The aim of the present study was to perform a real-world analysis on a large patient cohort with Barcelona Clinic Liver Cancer stage B (BCLC-B) hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (A + B) or with Lenvatinib.
Methods
The study population included patients affected with Barcelona Clinic Liver Cancer stage B (BCLC-B) hepatocellular carcinoma not suitable for locoregional therapies (LRTs) from eastern and western populations, who received atezolizumab plus bevacizumab (A + B) or Lenvatinib as first-line treatment. Univariate and multivariate analyses were used to evaluate predictive factors for overall survival (OS) and time to progression (TTP) while prognostic factors were analyzed by univariate and multivariate analysis using Cox regression model.
Results
919 patients with BCLC-B HCC were analyzed in the study. Lenvatinib was administered to 561 (61%) patients while 358 (39%) received A + B. The median overall survival (mOS) for patients receiving Lenvatinib was 21.3 months compared to 15.8 months for patients receiving A + B as first-line treatment (Lenvatinib v A + B), hazard ratio (HRs) 0.84 P = 0.22. The median time to progression (mTTP) for patients receiving Lenvatinib was 7.3 months compared to 8.7 months for patients receiving A + B as first-line treatment (Lenvatinib v A + B): HR 1.15 P = 0.10. Multivariate analysis confirmed no different in terms of mOS and mTTP between the two treatments. Objective response rate (ORR) was 47.1% for patients receiving Lenvatinib and 27.1% for patients receiving A + B P < 0.000001. Patients receiving Lenvatinib experienced a significantly higher incidence of hand-foot skin reaction (HFSR), hypertension, diarrhea, fatigue, decrease appetite, hypothyroidism, and other toxicity compared to patients receiving A + B. Favorable prognostic factors for OS in Lenvatinib group were platelets (PLT) >100.000 (HR 0.68 P = 0.02), HCC nonalcoholic steatohepatitis/nonalcoholic fatty liver disease (NASH/NAFLD) related (HR 0.53, P = 0.03). No favorable prognostic factors were found for A + B group. Favorable prognostic factors for TTP in the A + B group were in TACE refractory patients (HR 0.76, P = 0.02), PLT <100.000 (HR 0.62, P = 0.0067), and neutrophil-to-lymphocyte ratio (NLR) < 3 (HR 0.78, P = 0.04).
Conclusion
Although Lenvatinib had a higher response rate, the study showed no statistically significant differences between Lenvatinib and A + B in terms of efficacy, in patients with BCLC-B HCC.
本研究的目的是对巴塞罗那临床肝癌B期（BCLC-B）肝细胞癌（HCC）的大型患者队列进行现实世界的分析，这些患者接受atezolizumab加贝伐单抗（a + B）或Lenvatinib治疗。方法研究人群包括来自东西方人群的不适合局部治疗（LRTs）的巴塞罗那临床肝癌B期（BCLC-B）肝细胞癌患者，他们接受atezolizumab联合贝伐单抗（A + B）或Lenvatinib作为一线治疗。采用单因素和多因素分析评估总生存期（OS）和进展时间（TTP）的预测因素，采用Cox回归模型对预后因素进行单因素和多因素分析。结果本研究共纳入919例BCLC-B型HCC患者。561例（61%）患者服用Lenvatinib， 358例（39%）患者服用A + B。接受Lenvatinib的患者的中位总生存期（mOS）为21.3个月，而一线治疗A + B （Lenvatinib vs A + B）的患者为15.8个月，风险比（hr） 0.84 P = 0.22。接受Lenvatinib的患者的中位进展时间（mTTP）为7.3个月，而一线治疗接受A + B （Lenvatinib vs A + B）的患者为8.7个月：HR 1.15 P = 0.10。多变量分析证实两种治疗在mOS和mTTP方面没有差异。Lenvatinib组患者的客观缓解率（ORR）为47.1%,A + B P <； 0.000001组患者为27.1%。与接受a + B的患者相比，接受Lenvatinib的患者发生手足皮肤反应（HFSR）、高血压、腹泻、疲劳、食欲下降、甲状腺功能减退和其他毒性反应的发生率明显更高。Lenvatinib组OS的有利预后因素为血小板（PLT） > 100,000 (HR 0.68 P = 0.02)，HCC非酒精性脂肪性肝炎/非酒精性脂肪性肝病（NASH/NAFLD）相关（HR 0.53, P = 0.03）。A组 + B组未发现预后有利因素。A + B组TTP的有利预后因素为TACE难治性患者（HR 0.76, P = 0.02），PLT <；10万（HR 0.62, P = 0.0067），中性粒细胞与淋巴细胞比值（NLR） <；3 （hr 0.78, p = 0.04）。结论虽然Lenvatinib的有效率更高，但研究显示Lenvatinib与a + B在BCLC-B HCC患者的疗效方面无统计学差异。
{"title":"Atezolizumab plus bevacizumab versus Lenvatinib for patients with Barcelona clinic liver cancer stage B (BCLC-B) hepatocellular carcinoma (HCC): A real-world population","authors":"Francesco Vitiello , Toshifumi Tada , Goki Suda , Shigeo Shimose , Masatoshi Kudo , Jaekyung Cheon , Fabian Finkelmeier , Ho Yeong Lim , José Presa , Gianluca Masi , Changhoon Yoo , Sara Lonardi , Francesco Tovoli , Takashi Kumada , Mario Scartozzi , Emiliano Tamburini , Francesco Giuseppe Foschi , Mara Persano , Federico Rossari , Silvia Foti , Margherita Rimini","doi":"10.1016/j.seminoncol.2025.152348","DOIUrl":"10.1016/j.seminoncol.2025.152348","url":null,"abstract":"<div><h3>Background</h3><div>The aim of the present study was to perform a real-world analysis on a large patient cohort with Barcelona Clinic Liver Cancer stage B (BCLC-B) hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (<em>A</em> + <em>B</em>) or with Lenvatinib.</div></div><div><h3>Methods</h3><div>The study population included patients affected with Barcelona Clinic Liver Cancer stage B (BCLC-B) hepatocellular carcinoma not suitable for locoregional therapies (LRTs) from eastern and western populations, who received atezolizumab plus bevacizumab (<em>A</em> + <em>B</em>) or Lenvatinib as first-line treatment. Univariate and multivariate analyses were used to evaluate predictive factors for overall survival (OS) and time to progression (TTP) while prognostic factors were analyzed by univariate and multivariate analysis using Cox regression model.</div></div><div><h3>Results</h3><div>919 patients with BCLC-B HCC were analyzed in the study. Lenvatinib was administered to 561 (61%) patients while 358 (39%) received <em>A</em> + <em>B</em>. The median overall survival (mOS) for patients receiving Lenvatinib was 21.3 months compared to 15.8 months for patients receiving <em>A</em> + <em>B</em> as first-line treatment (Lenvatinib <em>v A</em> + <em>B</em>), hazard ratio (HRs) 0.84 <em>P</em> = 0.22. The median time to progression (mTTP) for patients receiving Lenvatinib was 7.3 months compared to 8.7 months for patients receiving <em>A</em> + <em>B</em> as first-line treatment (Lenvatinib <em>v A</em> + <em>B</em>): HR 1.15 <em>P</em> = 0.10. Multivariate analysis confirmed no different in terms of mOS and mTTP between the two treatments. Objective response rate (ORR) was 47.1% for patients receiving Lenvatinib and 27.1% for patients receiving <em>A</em> + <em>B P</em> < 0.000001. Patients receiving Lenvatinib experienced a significantly higher incidence of hand-foot skin reaction (HFSR), hypertension, diarrhea, fatigue, decrease appetite, hypothyroidism, and other toxicity compared to patients receiving <em>A</em> + <em>B</em>. Favorable prognostic factors for OS in Lenvatinib group were platelets (PLT) >100.000 (HR 0.68 <em>P</em> = 0.02), HCC nonalcoholic steatohepatitis/nonalcoholic fatty liver disease (NASH/NAFLD) related (HR 0.53, <em>P</em> = 0.03). No favorable prognostic factors were found for <em>A</em> + <em>B</em> group. Favorable prognostic factors for TTP in the <em>A</em> + <em>B</em> group were in TACE refractory patients (HR 0.76, <em>P</em> = 0.02), PLT <100.000 (HR 0.62, <em>P</em> = 0.0067), and neutrophil-to-lymphocyte ratio (NLR) < 3 (HR 0.78, <em>P</em> = 0.04).</div></div><div><h3>Conclusion</h3><div>Although Lenvatinib had a higher response rate, the study showed no statistically significant differences between Lenvatinib and <em>A</em> + <em>B</em> in terms of efficacy, in patients with BCLC-B HCC.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152348"},"PeriodicalIF":3.0,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144240330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-06DOI: 10.1016/j.seminoncol.2025.152370
Chou-Yi Hsu , Thikra Majid Muhammed , Subasini Uthirapathy , Irfan Ahmad , Suhas Ballal , Rishiv Kalia , Premkumar J , Subhashree Ray , Riyadh Mohammed Mohsin , Abid ALi A. Abiess
Although studies have demonstrated that ovarian cancer cells can express immune checkpoint proteins like CTLA-4 and that higher levels of tumor-infiltrating lymphocytes are linked to better patient survival, clinical trials utilizing immune checkpoint inhibitors in ovarian cancer have not yielded encouraging results. Tumor heterogeneity and innate or acquired resistance associated with the tumor microenvironment (TME) may account for the inadequate response to ICIs. Understanding tumor immunobiology, identifying biomarkers for patient selection, and formulating suitable treatment regimens remain challenging, yet these are the aspirations for the future use of immunotherapy in ovarian cancer. Induced T cells express CD80 and CD86, providing a positive costimulatory signal via CD28. CTLA-4 antagonizes CD28, diminishing T cell activation and modulating the immunological response. Conversely, the negative regulation of CTLA-4 using monoclonal antibodies (mAbs), particularly ipilimumab, may stimulate T-cell responses against ovarian cancer antigens. We elucidate the mechanisms responsible for immunological suppression: T cell exhaustion and senescence in ovarian cancer. We also provide a synopsis of using CTLA-4 monoclonal antibodies in ovarian cancer alone or conjunction with other modalities (eg, chemotherapy). We finally delineate the challenges associated with responding to immunotherapy in ovarian cancer.
{"title":"CTLA-4 blockade in ovarian cancer immunotherapy: Mechanisms and clinical strategies","authors":"Chou-Yi Hsu , Thikra Majid Muhammed , Subasini Uthirapathy , Irfan Ahmad , Suhas Ballal , Rishiv Kalia , Premkumar J , Subhashree Ray , Riyadh Mohammed Mohsin , Abid ALi A. Abiess","doi":"10.1016/j.seminoncol.2025.152370","DOIUrl":"10.1016/j.seminoncol.2025.152370","url":null,"abstract":"<div><div>Although studies have demonstrated that ovarian cancer cells can express immune checkpoint proteins like CTLA-4 and that higher levels of tumor-infiltrating lymphocytes are linked to better patient survival, clinical trials utilizing immune checkpoint inhibitors in ovarian cancer have not yielded encouraging results. Tumor heterogeneity and innate or acquired resistance associated with the tumor microenvironment (TME) may account for the inadequate response to ICIs. Understanding tumor immunobiology, identifying biomarkers for patient selection, and formulating suitable treatment regimens remain challenging, yet these are the aspirations for the future use of immunotherapy in ovarian cancer. Induced T cells express CD80 and CD86, providing a positive costimulatory signal via CD28. CTLA-4 antagonizes CD28, diminishing T cell activation and modulating the immunological response. Conversely, the negative regulation of CTLA-4 using monoclonal antibodies (mAbs), particularly ipilimumab, may stimulate T-cell responses against ovarian cancer antigens. We elucidate the mechanisms responsible for immunological suppression: T cell exhaustion and senescence in ovarian cancer. We also provide a synopsis of using CTLA-4 monoclonal antibodies in ovarian cancer alone or conjunction with other modalities (eg, chemotherapy). We finally delineate the challenges associated with responding to immunotherapy in ovarian cancer.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152370"},"PeriodicalIF":3.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144221495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-04DOI: 10.1016/j.seminoncol.2025.152351
Guodong Liang , Yuehan Ma , Ping Deng , Shufeng Li , Chunyan He , Haihang He , Hairui Liu , Yunda Fan , Ze Li
Hexokinases (HKs) catalyze the first step in glycolysis by transferring a phosphate group to glucose to produce glucose-6-phosphate (G6P); dysregulation of HKs is a feature that leads to altered metabolism within gastrointestinal (GI) cancers—namely, gastric, colorectal, esophageal, and pancreatic cancer. Of note, HKs have been found to exert non-canonical roles beyond metabolism, particularly in regulating cell death pathways such as autophagy and apoptosis in these cancers. In this sense, HK2 promotes hepatocellular carcinoma (HCC) from apoptosis inhibition through the suppression of mitochondrial permeability transition pore formation by interaction with voltage-dependent anion channel (VDAC). Moreover, HK2 expression in HCC tumors decreases immune responsiveness and sensitivity to natural killer (NK) cytotoxicity, thus favoring immune escape. HK2 and co-expressed genes participate in esophageal cancer (ESCA) microenvironment immune response, especially in B cells, CD4 T cells, and macrophages. Most importantly, 3-BP, an HK-2 inhibitor, induces endoplasmic reticulum (ER) stress and disruption of the ER function by the accumulation of free radicals or reactive oxygen species (ROS) and the protein misfolding, thereby causing apoptosis in human HCC. Of note, it has been found that interaction of HK domain containing protein-1 (HKDC1) with ACTA2 (actin alpha 2) is required for the association of signal transducer and activator of transcription 1 (STAT1) with interferon-gamma receptor (IFNG-R) on the plasma membrane, STAT1-phosphorylation, and thus programmed cell death ligand 1 (PD-L1) expression upon stimulation with IFNγ in HCC. This review summarizes the mechanistic involvement of HKs in glycolytic reprogramming, apoptotic resistance, autophagy, immune evasion, metastasis, and drug resistance in GI cancers and the potential of HKs as diagnostic and therapeutic targets.
{"title":"Hexokinases in gastrointestinal cancers: From molecular insights to therapeutic opportunities","authors":"Guodong Liang , Yuehan Ma , Ping Deng , Shufeng Li , Chunyan He , Haihang He , Hairui Liu , Yunda Fan , Ze Li","doi":"10.1016/j.seminoncol.2025.152351","DOIUrl":"10.1016/j.seminoncol.2025.152351","url":null,"abstract":"<div><div>Hexokinases (HKs) catalyze the first step in glycolysis by transferring a phosphate group to glucose to produce glucose-6-phosphate (G6P); dysregulation of HKs is a feature that leads to altered metabolism within gastrointestinal (GI) cancers—namely, gastric, colorectal, esophageal, and pancreatic cancer. Of note, HKs have been found to exert non-canonical roles beyond metabolism, particularly in regulating cell death pathways such as autophagy and apoptosis in these cancers. In this sense, HK2 promotes hepatocellular carcinoma (HCC) from apoptosis inhibition through the suppression of mitochondrial permeability transition pore formation by interaction with voltage-dependent anion channel (VDAC). Moreover, HK2 expression in HCC tumors decreases immune responsiveness and sensitivity to natural killer (NK) cytotoxicity, thus favoring immune escape. HK2 and co-expressed genes participate in esophageal cancer (ESCA) microenvironment immune response, especially in B cells, CD4 T cells, and macrophages. Most importantly, 3-BP, an HK-2 inhibitor, induces endoplasmic reticulum (ER) stress and disruption of the ER function by the accumulation of free radicals or reactive oxygen species (ROS) and the protein misfolding, thereby causing apoptosis in human HCC. Of note, it has been found that interaction of HK domain containing protein-1 (HKDC1) with ACTA2 (actin alpha 2) is required for the association of signal transducer and activator of transcription 1 (STAT1) with interferon-gamma receptor (IFNG-R) on the plasma membrane, STAT1-phosphorylation, and thus programmed cell death ligand 1 (PD-L1) expression upon stimulation with IFNγ in HCC. This review summarizes the mechanistic involvement of HKs in glycolytic reprogramming, apoptotic resistance, autophagy, immune evasion, metastasis, and drug resistance in GI cancers and the potential of HKs as diagnostic and therapeutic targets.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152351"},"PeriodicalIF":3.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-29DOI: 10.1016/j.seminoncol.2025.152368
Sarah Qutayba Badraldin , Karar H. Alfarttoosi , Hayder Naji Sameer , Ashok Kumar Bishoyi , Subbulakshmi Ganesan , Aman Shankhyan , Subhashree Ray , Deepak Nathiya , Ahmed Yaseen , Zainab H. Athab , Mohaned Adil
Fat mass and obesity-associated protein (FTO), an N6-methyladenosine (m6A) RNA demethylase, plays a key role in cancer biology by regulating mRNA modifications. Its deregulation affects tumor cell proliferation, metastasis, immune evasion, and therapeutic resistance. By removing m6A methylation marks, FTO can alter the stability and translation of key oncogenes and tumor suppressor genes. These modifications directly influence essential cellular pathways involved in cancer progression, such as the phosphatidylinositol 3-kinases/ protein kinase B (PI3K/AKT), Wnt/β-catenin, and mammalian target of rapamycin (mTOR) signaling pathways. This review explores the mechanistic roles of FTO in cancer pathogenesis, focusing on its dual impact on immune regulation and chemotherapy response. In terms of immunity, FTO has been shown to promote immune evasion by modulating the expression of immune checkpoints and influencing the tumor microenvironment. Additionally, FTO’s influence on autophagy, glycolysis, and apoptosis resistance further complicates the effectiveness of chemotherapy treatments. By discussing the molecular details of how FTO regulates these processes, we provide insights into how FTO could serve as a promising therapeutic target to overcome cancer-related challenges, including immune resistance and chemotherapy failure. Finally, we evaluate current and emerging strategies for targeting FTO in cancer therapy, highlighting its potential to enhance immunotherapy and chemotherapy outcomes.
{"title":"Mechanistic role of FTO in cancer pathogenesis, immune evasion, chemotherapy resistance, and immunotherapy response","authors":"Sarah Qutayba Badraldin , Karar H. Alfarttoosi , Hayder Naji Sameer , Ashok Kumar Bishoyi , Subbulakshmi Ganesan , Aman Shankhyan , Subhashree Ray , Deepak Nathiya , Ahmed Yaseen , Zainab H. Athab , Mohaned Adil","doi":"10.1016/j.seminoncol.2025.152368","DOIUrl":"10.1016/j.seminoncol.2025.152368","url":null,"abstract":"<div><div>Fat mass and obesity-associated protein (FTO), an N6-methyladenosine (m6A) RNA demethylase, plays a key role in cancer biology by regulating mRNA modifications. Its deregulation affects tumor cell proliferation, metastasis, immune evasion, and therapeutic resistance. By removing m6A methylation marks, FTO can alter the stability and translation of key oncogenes and tumor suppressor genes. These modifications directly influence essential cellular pathways involved in cancer progression, such as the phosphatidylinositol 3-kinases/ protein kinase B (PI3K/AKT), Wnt/β-catenin, and mammalian target of rapamycin (mTOR) signaling pathways. This review explores the mechanistic roles of FTO in cancer pathogenesis, focusing on its dual impact on immune regulation and chemotherapy response. In terms of immunity, FTO has been shown to promote immune evasion by modulating the expression of immune checkpoints and influencing the tumor microenvironment. Additionally, FTO’s influence on autophagy, glycolysis, and apoptosis resistance further complicates the effectiveness of chemotherapy treatments. By discussing the molecular details of how FTO regulates these processes, we provide insights into how FTO could serve as a promising therapeutic target to overcome cancer-related challenges, including immune resistance and chemotherapy failure. Finally, we evaluate current and emerging strategies for targeting FTO in cancer therapy, highlighting its potential to enhance immunotherapy and chemotherapy outcomes.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 3","pages":"Article 152368"},"PeriodicalIF":3.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144169730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The complex interplay between collagen and cancer cells within the tumor microenvironment (TME) highlights the pivotal role of collagens in cancer progression, prognosis and therapy resistance. As a critical structural protein of the extracellular matrix (ECM), collagen not only maintains tissue architecture but also regulates key physiological functions through complex biosynthetic pathways. Deregulation in collagen biosynthesis, characterized by abnormal transcription, post-translational modifications, and deposition, contributes to ECM remodeling and tumor progression. This review explores the involvement of diverse collagen family members in cancer progression across multiple cancer types. Several collagen isoforms have emerged as key players in cancer progression, influencing tumor behavior and act as potential biomarkers for prognosis. Furthermore, circulating collagen fragments in blood present promising avenues for non-invasive cancer diagnosis and disease monitoring. Tumor collagen remodeling alters ECM architecture, impacting tumor-stromal interactions and fostering a microenvironment conducive to favour invasion and metastasis. Mechanistic insights reveal that collagen-induced signalling pathways are the major drivers of stemness, drug resistance, EMT, metastasis, angiogenesis and immune evasion, which collectively shape tumor cell behavior and immune infiltration dynamics. Further, targeting tumor collagen appear to be a viable and robust strategy to treat aggressive desmoplastic and metastatic cancers.
{"title":"The Crucial Nexus: Unveiling the Role of Collagen in Cancer Progression","authors":"Hazel Reeva , Godson Mahesh , Uma Manjunath, Nagarajan Selvamurugan, Durairaj MohanKumar","doi":"10.1016/j.seminoncol.2025.152346","DOIUrl":"10.1016/j.seminoncol.2025.152346","url":null,"abstract":"<div><div>The complex interplay between collagen and cancer cells within the tumor microenvironment (TME) highlights the pivotal role of collagens in cancer progression, prognosis and therapy resistance. As a critical structural protein of the extracellular matrix (ECM), collagen not only maintains tissue architecture but also regulates key physiological functions through complex biosynthetic pathways. Deregulation in collagen biosynthesis, characterized by abnormal transcription, post-translational modifications, and deposition, contributes to ECM remodeling and tumor progression. This review explores the involvement of diverse collagen family members in cancer progression across multiple cancer types. Several collagen isoforms have emerged as key players in cancer progression, influencing tumor behavior and act as potential biomarkers for prognosis. Furthermore, circulating collagen fragments in blood present promising avenues for non-invasive cancer diagnosis and disease monitoring. Tumor collagen remodeling alters ECM architecture, impacting tumor-stromal interactions and fostering a microenvironment conducive to favour invasion and metastasis. Mechanistic insights reveal that collagen-induced signalling pathways are the major drivers of stemness, drug resistance, EMT, metastasis, angiogenesis and immune evasion, which collectively shape tumor cell behavior and immune infiltration dynamics. Further, targeting tumor collagen appear to be a viable and robust strategy to treat aggressive desmoplastic and metastatic cancers.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 3","pages":"Article 152346"},"PeriodicalIF":3.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144169729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-24DOI: 10.1016/j.seminoncol.2025.152364
Eyachew Misganew Tegaw , Betelhem Bizuneh Asfaw
The treatment outcomes of lung cancer are highly variable, and machine learning (ML) models provide valuable insights into how clinical and biochemical factors influence survival across different treatments. This study will investigate the survival of patients after four major treatments for lung cancer by interpreting the impact of biomarkers on survival using SHapley Additive exPlanations (SHAP). We analyzed 23,658 lung cancer patient records derived from a Kaggle dataset. Using the most relevant clinical and biochemical variables, ML models were employed to study survival outcomes for different treatments. SHAP analysis revealed major survival predictors in each treatment. Survival outcomes are visualized as f(x) (predicted survival) and E[f(x)] (baseline expectation) in SHAP waterfall plots. The most performed model is Gradient Boosting with an accuracy of 88.99%, precision of 89.06%, recall of 88.99%, F1-score of 88.91%, and Receiver Operating Characteristic Curve (AUC-ROC) score of 0.9332. Chemotherapy treatment was positive for survival, the key for survival was phosphorus levels (+0.05), low Alanine Aminotransferase levels (+0.04) and low glucose levels (+0.04). Targeted therapy and radiation had worse survival, while surgery was favorable, especially in cases with high white blood cell and Lactate Dehydrogenase (LDH) levels. SHAP-based ML analysis aptly underlines how clinical and biochemical factors influence the survival rate. It indicates that ML-driven interpretability might drive personalized treatment approaches in lung cancer.
{"title":"Explainable machine learning and feature interpretation to predict survival outcomes in the treatment of lung cancer","authors":"Eyachew Misganew Tegaw , Betelhem Bizuneh Asfaw","doi":"10.1016/j.seminoncol.2025.152364","DOIUrl":"10.1016/j.seminoncol.2025.152364","url":null,"abstract":"<div><div>The treatment outcomes of lung cancer are highly variable, and machine learning (ML) models provide valuable insights into how clinical and biochemical factors influence survival across different treatments. This study will investigate the survival of patients after four major treatments for lung cancer by interpreting the impact of biomarkers on survival using SHapley Additive exPlanations (SHAP). We analyzed 23,658 lung cancer patient records derived from a Kaggle dataset. Using the most relevant clinical and biochemical variables, ML models were employed to study survival outcomes for different treatments. SHAP analysis revealed major survival predictors in each treatment. Survival outcomes are visualized as f(x) (predicted survival) and E[f(x)] (baseline expectation) in SHAP waterfall plots. The most performed model is Gradient Boosting with an accuracy of 88.99%, precision of 89.06%, recall of 88.99%, F1-score of 88.91%, and Receiver Operating Characteristic Curve (AUC-ROC) score of 0.9332. Chemotherapy treatment was positive for survival, the key for survival was phosphorus levels (+0.05), low Alanine Aminotransferase levels (+0.04) and low glucose levels (+0.04). Targeted therapy and radiation had worse survival, while surgery was favorable, especially in cases with high white blood cell and Lactate Dehydrogenase (LDH) levels. SHAP-based ML analysis aptly underlines how clinical and biochemical factors influence the survival rate. It indicates that ML-driven interpretability might drive personalized treatment approaches in lung cancer.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 3","pages":"Article 152364"},"PeriodicalIF":3.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144125323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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