Seminars in oncology最新文献_第5页

Baicalein and baicalin in cancer therapy: Multifaceted mechanisms, preclinical evidence, and translational challenges 黄芩素和黄芩苷在癌症治疗中的作用：多方面的机制、临床前证据和转化挑战

IF 3 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-10-01 Epub Date: 2025-07-03 DOI: 10.1016/j.seminoncol.2025.152377

Xavier Capó , Rajesh Kumar , Abhay Prakash Mishra , Manisha Nigam , Neti Waranuch , Miquel Martorell , Farukh Sharopov , Daniela Calina , Dragoș Popa , William N. Setzer , Javad Sharifi-Rad , Raffaele Pezzani

Natural compounds with multitargeted actions are gaining prominence in oncology for their potential to complement and transcend the limitations of conventional therapies. Among them, baicalein and baicalin, two flavonoids primarily isolated from Scutellaria baicalensis, have attracted attention for their broad-spectrum anticancer properties. This review synthesizes current evidence from cellular systems, animal models, and early-phase clinical studies, exploring their pharmacological potential and translational relevance. Both molecules interfere with key hallmarks of cancer, including proliferation, survival, angiogenesis, metastasis, and immune evasion. Mechanistically, they modulate interconnected signaling cascades governing apoptosis, inflammation, and cell cycle control, and they enhance tumor sensitivity to chemotherapy and radiotherapy. In-vivo models consistently demonstrate tumor growth inhibition, while clinical data suggest a favorable safety profile, even at relatively high oral doses. However, their clinical translation remains hampered by limited solubility, poor oral bioavailability, and rapid metabolism, factors that continue to constrain their therapeutic window. Efforts to overcome these barriers through structural modification, encapsulation strategies, and advanced delivery systems are underway, yet few have advanced beyond preclinical validation. Despite these pharmacokinetic limitations, baicalein and baicalin remain compelling candidates for integrative oncological approaches. Their pleiotropic mechanisms, combined with low toxicity and synergistic behavior with standard therapies, position them as prototypes for a new generation of phytochemical-based anticancer agents. Continued work is needed to resolve formulation challenges and define precise molecular targets, but their trajectory reflects the growing scientific and clinical momentum around rationally designed natural compound therapeutics.

具有多靶点作用的天然化合物在肿瘤学中越来越突出，因为它们具有补充和超越传统治疗局限性的潜力。其中黄芩苷（baicalein）和黄芩苷（baicalin）是主要从黄芩中分离得到的两种黄酮类化合物，因其广谱抗癌特性而备受关注。这篇综述综合了目前来自细胞系统、动物模型和早期临床研究的证据，探索了它们的药理潜力和翻译相关性。这两种分子都会干扰癌症的关键特征，包括增殖、存活、血管生成、转移和免疫逃逸。在机制上，它们调节相互关联的信号级联，控制细胞凋亡、炎症和细胞周期控制，并增强肿瘤对化疗和放疗的敏感性。体内模型一致显示肿瘤生长抑制，而临床数据显示良好的安全性，即使在相对较高的口服剂量。然而，它们的临床转化仍然受到溶解度有限、口服生物利用度差和快速代谢等因素的阻碍，这些因素继续限制它们的治疗窗口期。通过结构修改、封装策略和先进的给药系统来克服这些障碍的努力正在进行中，但很少有超过临床前验证的进展。尽管存在这些药代动力学的局限性，黄芩苷和黄芩苷仍然是综合肿瘤学方法的有力候选者。它们的多效性机制，加上低毒性和与标准疗法的协同作用，使它们成为新一代基于植物化学的抗癌药物的原型。需要继续开展工作来解决配方挑战和确定精确的分子靶点，但它们的发展轨迹反映了围绕合理设计天然化合物疗法的科学和临床势头的增长。

{"title":"Baicalein and baicalin in cancer therapy: Multifaceted mechanisms, preclinical evidence, and translational challenges","authors":"Xavier Capó , Rajesh Kumar , Abhay Prakash Mishra , Manisha Nigam , Neti Waranuch , Miquel Martorell , Farukh Sharopov , Daniela Calina , Dragoș Popa , William N. Setzer , Javad Sharifi-Rad , Raffaele Pezzani","doi":"10.1016/j.seminoncol.2025.152377","DOIUrl":"10.1016/j.seminoncol.2025.152377","url":null,"abstract":"<div><div>Natural compounds with multitargeted actions are gaining prominence in oncology for their potential to complement and transcend the limitations of conventional therapies. Among them, baicalein and baicalin, two flavonoids primarily isolated from <em>Scutellaria baicalensis</em>, have attracted attention for their broad-spectrum anticancer properties. This review synthesizes current evidence from cellular systems, animal models, and early-phase clinical studies, exploring their pharmacological potential and translational relevance. Both molecules interfere with key hallmarks of cancer, including proliferation, survival, angiogenesis, metastasis, and immune evasion. Mechanistically, they modulate interconnected signaling cascades governing apoptosis, inflammation, and cell cycle control, and they enhance tumor sensitivity to chemotherapy and radiotherapy. <em>In-vivo</em> models consistently demonstrate tumor growth inhibition, while clinical data suggest a favorable safety profile, even at relatively high oral doses. However, their clinical translation remains hampered by limited solubility, poor oral bioavailability, and rapid metabolism, factors that continue to constrain their therapeutic window. Efforts to overcome these barriers through structural modification, encapsulation strategies, and advanced delivery systems are underway, yet few have advanced beyond preclinical validation. Despite these pharmacokinetic limitations, baicalein and baicalin remain compelling candidates for integrative oncological approaches. Their pleiotropic mechanisms, combined with low toxicity and synergistic behavior with standard therapies, position them as prototypes for a new generation of phytochemical-based anticancer agents. Continued work is needed to resolve formulation challenges and define precise molecular targets, but their trajectory reflects the growing scientific and clinical momentum around rationally designed natural compound therapeutics.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 5","pages":"Article 152377"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144549944","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}

引用次数: 0

Lactylation in radiosensitivity regulation: Mechanistic insights and recent advances 放射敏感性调节中的乳酸化：机制见解和最新进展

IF 3 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-10-01 Epub Date: 2025-07-26 DOI: 10.1016/j.seminoncol.2025.152394

Caiqiang Zhu , Meng Tian , Xiaoke Di , Jin Liu , Huanhuan Chen , Lu Xu , Ying Liu , Xinchen Sun , Zhaoyue Zhang

Lactylation, as a novel post-translational modification, has gained a lot of attention in the biomedical field in recent years. Lactylation is not only related to cellular metabolism but also increasingly prominent in the tumor microenvironment, particularly in regulating radiation sensitivity. This review aims to explore the potential connection between lactylation modification and the regulation of radiation sensitivity. Current research shows that lactylation might be crucial in how tumor cells respond to radiotherapy by influencing energy metabolism, gene expression, and cell signaling. However, despite preliminary studies revealing the association between lactylation and radiation sensitivity, the understanding of its specific mechanisms remains insufficient, necessitating more systematic research to elucidate this process. Therefore, by analyzing the biological basis of lactylation modification, its role in tumor metabolism, and its relationship with radiotherapy, we summarize the importance and application prospects of lactylation in tumor treatment, providing direction for future research.

乳酸化修饰作为一种新型的翻译后修饰，近年来在生物医学领域受到了广泛的关注。乳酸化不仅与细胞代谢有关，而且在肿瘤微环境中也越来越突出，特别是在调节辐射敏感性方面。本文旨在探讨乳酸化修饰与辐射敏感性调节之间的潜在联系。目前的研究表明，乳酸化可能在肿瘤细胞如何通过影响能量代谢、基因表达和细胞信号传导来对放疗做出反应中起着至关重要的作用。然而，尽管初步研究揭示了乳酸化与辐射敏感性之间的联系，但对其具体机制的了解仍然不足，需要更系统的研究来阐明这一过程。因此，我们通过分析乳酸化修饰的生物学基础、其在肿瘤代谢中的作用以及与放疗的关系，总结了乳酸化修饰在肿瘤治疗中的重要性及应用前景，为今后的研究提供方向。

{"title":"Lactylation in radiosensitivity regulation: Mechanistic insights and recent advances","authors":"Caiqiang Zhu , Meng Tian , Xiaoke Di , Jin Liu , Huanhuan Chen , Lu Xu , Ying Liu , Xinchen Sun , Zhaoyue Zhang","doi":"10.1016/j.seminoncol.2025.152394","DOIUrl":"10.1016/j.seminoncol.2025.152394","url":null,"abstract":"<div><div>Lactylation, as a novel post-translational modification, has gained a lot of attention in the biomedical field in recent years. Lactylation is not only related to cellular metabolism but also increasingly prominent in the tumor microenvironment, particularly in regulating radiation sensitivity. This review aims to explore the potential connection between lactylation modification and the regulation of radiation sensitivity. Current research shows that lactylation might be crucial in how tumor cells respond to radiotherapy by influencing energy metabolism, gene expression, and cell signaling. However, despite preliminary studies revealing the association between lactylation and radiation sensitivity, the understanding of its specific mechanisms remains insufficient, necessitating more systematic research to elucidate this process. Therefore, by analyzing the biological basis of lactylation modification, its role in tumor metabolism, and its relationship with radiotherapy, we summarize the importance and application prospects of lactylation in tumor treatment, providing direction for future research.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 5","pages":"Article 152394"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144712849","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}

引用次数: 0

Germline mutations in B-cell non-Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis (LA-HLH) and patient outcomes b细胞非霍奇金淋巴瘤相关噬血细胞淋巴组织细胞增多症（LA-HLH）的种系突变和患者预后

IF 3 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-10-01 Epub Date: 2025-07-22 DOI: 10.1016/j.seminoncol.2025.152388

Xing Zhong , Xinyu Zhu , Xiaoxia Ma , Lili Zhou , Xiu Luo , Ping Li , Yi Ding , Jianfei Fu , Jiaqi Bo , Muye Yang , Aibin Liang , Yu Zeng , Bing Xiu

Lymphoma-associated hemophagocytic lymphohistiocytosis/syndrome (LA-HLH/LAHS) represents the most prevalent form of malignancy-associated HLH and is associated with an exceptionally poor prognosis. Emerging evidence implicates germline mutations as potential contributors to hematologic abnormalities, suggesting a genetic predisposition in affected individuals.

We conducted whole-exome sequencing (WES) on a cohort of 12 LA-HLH patients, with detailed analysis of 3 representative cases exhibiting coexisting genetic disorders. These cases were comprehensively evaluated for their clinical management strategies and therapeutic outcomes.

Our study revealed that gene mutations were detected in 6 patients (6/12), including 2 had somatic mutations, 3 had germline mutations, and 1 had both somatic and germline mutations. Among the 4 patients harbored germline mutations, 3 were diagnosed with concurrent genetic disease. Most patients (11/12) responded to immunochemotherapy for a short time and then progressed or relapsed, even after autologous hematopoietic stem cell transplantation (ASCT). Interestingly, two patients received CAR-T-cell therapy and achieved extremely good responses. One patient received CD19 CAR-T-cell infusion and had a PFS of 26 months. The other patient received double CAR-T infusions and has remained in complete remission for more than 2 years (until now).

This study proposes that LA-HLH may constitute a novel genetic subtype of lymphoma. Systematic genetic sequencing should be prioritized to guide precision treatment approaches in selected cases, including immunotherapies such as CAR-T-cell therapy. These insights redefine our understanding of LA-HLH pathogenesis and clinical intervention strategies.

淋巴瘤相关的噬血细胞淋巴组织细胞增多症/综合征（LA-HLH/LAHS）是恶性肿瘤相关的HLH最常见的形式，并伴有异常差的预后。新出现的证据暗示种系突变是血液学异常的潜在贡献者，表明受影响个体的遗传易感性。我们对12例LA-HLH患者进行了全外显子组测序（WES），并详细分析了3例具有代表性的共存遗传疾病病例。对这些病例的临床管理策略和治疗结果进行综合评估。我们的研究发现6例（6/12）患者检测到基因突变，其中2例为体细胞突变，3例为种系突变，1例为体细胞和种系突变。在4例种系突变患者中，3例诊断为并发遗传病。大多数患者（11/12）对免疫化疗有短期反应，然后进展或复发，即使在自体造血干细胞移植（ASCT）后也是如此。有趣的是，两名患者接受了car - t细胞治疗，并取得了非常好的疗效。一名患者接受了CD19 car - t细胞输注，PFS为26个月。另一位患者接受了两次CAR-T输注，并保持完全缓解超过2年（至今）。本研究提示LA-HLH可能构成一种新的遗传淋巴瘤亚型。应该优先考虑系统的基因测序，以指导特定病例的精确治疗方法，包括免疫疗法，如car - t细胞疗法。这些见解重新定义了我们对LA-HLH发病机制和临床干预策略的理解。

{"title":"Germline mutations in B-cell non-Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis (LA-HLH) and patient outcomes","authors":"Xing Zhong , Xinyu Zhu , Xiaoxia Ma , Lili Zhou , Xiu Luo , Ping Li , Yi Ding , Jianfei Fu , Jiaqi Bo , Muye Yang , Aibin Liang , Yu Zeng , Bing Xiu","doi":"10.1016/j.seminoncol.2025.152388","DOIUrl":"10.1016/j.seminoncol.2025.152388","url":null,"abstract":"<div><div>Lymphoma-associated hemophagocytic lymphohistiocytosis/syndrome (LA-HLH/LAHS) represents the most prevalent form of malignancy-associated HLH and is associated with an exceptionally poor prognosis. Emerging evidence implicates germline mutations as potential contributors to hematologic abnormalities, suggesting a genetic predisposition in affected individuals.</div><div>We conducted whole-exome sequencing (WES) on a cohort of 12 LA-HLH patients, with detailed analysis of 3 representative cases exhibiting coexisting genetic disorders. These cases were comprehensively evaluated for their clinical management strategies and therapeutic outcomes.</div><div>Our study revealed that gene mutations were detected in 6 patients (6/12), including 2 had somatic mutations, 3 had germline mutations, and 1 had both somatic and germline mutations. Among the 4 patients harbored germline mutations, 3 were diagnosed with concurrent genetic disease. Most patients (11/12) responded to immunochemotherapy for a short time and then progressed or relapsed, even after autologous hematopoietic stem cell transplantation (ASCT). Interestingly, two patients received CAR-T-cell therapy and achieved extremely good responses. One patient received CD19 CAR-T-cell infusion and had a PFS of 26 months. The other patient received double CAR-T infusions and has remained in complete remission for more than 2 years (until now).</div><div>This study proposes that LA-HLH may constitute a novel genetic subtype of lymphoma. Systematic genetic sequencing should be prioritized to guide precision treatment approaches in selected cases, including immunotherapies such as CAR-T-cell therapy. These insights redefine our understanding of LA-HLH pathogenesis and clinical intervention strategies.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 5","pages":"Article 152388"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144679765","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}

引用次数: 0

Antibody treatments for digestive cancers: Past, present, and future 消化系统癌症的抗体治疗：过去，现在和未来

IF 2.5 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-10-01 Epub Date: 2025-08-06 DOI: 10.1016/j.seminoncol.2025.152369

Ikrame Dadi , Thibault Mazard , Lena-Marie Schmitt , Tommy Chastel , Andrei Turtoi , Marie-Alix Poul , Sophie Pattingre

Gastrointestinal (GI) malignancies accounted for more than one in four cancer cases (4.8 million cases) in 2020. Among these, around 37% were colorectal followed by gastric (21%) and liver cancers (18%). Notably, GI cancers are responsible for nearly one-third of cancer-related mortality (3.4 million deaths worldwide). For decades, treatment relied primarily on conventional cytotoxic chemotherapies, which target rapidly dividing malignant cells but also cause significant harm to healthy tissue. Recent biotechnological advances enhanced our understanding of cancer biology, leading to the identification of specific molecular alterations and the development of new drugs, known as "targeted therapies." These therapies include two major categories: small molecule kinase inhibitors (SMKIs), which inhibit dysregulated intracellular kinases, and monoclonal antibodies (mAbs), able to interfere with extracellular ligands, membrane receptors, or membrane-bound proteins.

This review aims to summarize recent advancements in the treatment of GI cancers using mAbs. We provide an overview of clinically approved mAbs in GI cancers, detailing their targets, mechanisms of action, and limitations. We differentiate between mAbs that directly target cancer cells and those that act on the tumor microenvironment (TME). Additionally, we discuss developments and technological optimizations used to improve the efficacy and specificity of these therapies.

2020年，胃肠道（GI）恶性肿瘤占癌症病例的四分之一以上（480万例）。其中，约37%为结直肠癌，其次是胃癌（21%）和肝癌（18%）。值得注意的是，胃肠道癌症造成了近三分之一的癌症相关死亡（全世界340万人死亡）。几十年来，治疗主要依赖于传统的细胞毒性化疗，这种疗法针对快速分裂的恶性细胞，但也会对健康组织造成重大伤害。最近的生物技术进步增强了我们对癌症生物学的理解，导致了特定分子变化的识别和新药的开发，被称为“靶向治疗”。这些疗法包括两大类：抑制细胞内失调激酶的小分子激酶抑制剂（SMKIs）和能够干扰细胞外配体、膜受体或膜结合蛋白的单克隆抗体（mab）。本文综述了利用单克隆抗体治疗胃肠道肿瘤的最新进展。我们提供临床批准的单克隆抗体在胃肠道癌症的概述，详细说明他们的目标，作用机制和局限性。我们区分直接靶向癌细胞的单克隆抗体和作用于肿瘤微环境（TME）的单克隆抗体。此外，我们还讨论了用于提高这些疗法的疗效和特异性的发展和技术优化。

{"title":"Antibody treatments for digestive cancers: Past, present, and future","authors":"Ikrame Dadi , Thibault Mazard , Lena-Marie Schmitt , Tommy Chastel , Andrei Turtoi , Marie-Alix Poul , Sophie Pattingre","doi":"10.1016/j.seminoncol.2025.152369","DOIUrl":"10.1016/j.seminoncol.2025.152369","url":null,"abstract":"<div><div>Gastrointestinal (GI) malignancies accounted for more than one in four cancer cases (4.8 million cases) in 2020. Among these, around 37% were colorectal followed by gastric (21%) and liver cancers (18%). Notably, GI cancers are responsible for nearly one-third of cancer-related mortality (3.4 million deaths worldwide). For decades, treatment relied primarily on conventional cytotoxic chemotherapies, which target rapidly dividing malignant cells but also cause significant harm to healthy tissue. Recent biotechnological advances enhanced our understanding of cancer biology, leading to the identification of specific molecular alterations and the development of new drugs, known as \"targeted therapies.\" These therapies include two major categories: small molecule kinase inhibitors (SMKIs), which inhibit dysregulated intracellular kinases, and monoclonal antibodies (mAbs), able to interfere with extracellular ligands, membrane receptors, or membrane-bound proteins.</div><div>This review aims to summarize recent advancements in the treatment of GI cancers using mAbs. We provide an overview of clinically approved mAbs in GI cancers, detailing their targets, mechanisms of action, and limitations. We differentiate between mAbs that directly target cancer cells and those that act on the tumor microenvironment (TME). Additionally, we discuss developments and technological optimizations used to improve the efficacy and specificity of these therapies.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 5","pages":"Article 152369"},"PeriodicalIF":2.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144780000","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}

引用次数: 0

CTLA-4 blockade in ovarian cancer immunotherapy: Mechanisms and clinical strategies CTLA-4阻断在卵巢癌免疫治疗中的作用：机制和临床策略

IF 3 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-08-01 Epub Date: 2025-06-06 DOI: 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.

尽管研究表明卵巢癌细胞可以表达免疫检查点蛋白，如CTLA-4，并且更高水平的肿瘤浸润淋巴细胞与更好的患者生存有关，但在卵巢癌中使用免疫检查点抑制剂的临床试验并没有产生令人鼓舞的结果。肿瘤异质性和与肿瘤微环境（TME）相关的先天或获得性耐药可能是对ICIs反应不足的原因。了解肿瘤免疫生物学，确定患者选择的生物标志物，制定合适的治疗方案仍然具有挑战性，但这些都是未来卵巢癌免疫治疗的愿望。诱导T细胞表达CD80和CD86，通过CD28提供正向共刺激信号。CTLA-4可拮抗CD28，减少T细胞活化并调节免疫反应。相反，使用单克隆抗体（mab），特别是ipilimumab对CTLA-4进行负调控，可能会刺激t细胞对卵巢癌抗原的反应。我们阐明了卵巢癌免疫抑制的机制：T细胞衰竭和衰老。我们还提供了使用CTLA-4单克隆抗体在卵巢癌单独或联合其他方式（如化疗）的摘要。我们最后描述了与卵巢癌免疫治疗反应相关的挑战。

{"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":"2025-08-01","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}

引用次数: 0

LncRNA THUMPD3-AS1 promotes the proliferation and migration of esophageal cancer cells through the miR-29a-3p/ELK1/PRDX4 signaling pathway LncRNA THUMPD3-AS1通过miR-29a-3p/ELK1/PRDX4信号通路促进食管癌细胞的增殖和迁移

IF 3 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-08-01 Epub Date: 2025-07-09 DOI: 10.1016/j.seminoncol.2025.152350

Mingming Tang , Jianjun Sun , Zhigang Cai

Esophageal cancer (ESCA) is a significant contributor to cancer-related deaths worldwide due to its aggressive nature and poor prognosis. Recent research indicates that non-coding RNAs are critical in tumor progression. This study intends to explore the interaction between LncRNA THUMPD3-AS1 and miR-29a-3p in ESCA advancement. By conducting bioinformatic analyses and validating differentially expressed genes in ESCA clinical samples, the regulatory relationship between THUMPD3-AS1, miR-29a-3p, ETS transcription factor (ELK1), and Peroxiredoxin 4 (PRDX4) was investigated using various functional assays. In vitro and in vivo experiments were also carried out to assess the impact of this interaction on tumor growth and ESCA progression. Results indicated elevated levels of THUMPD3-AS1 in ESCA tissues, acting as a sponge for miR-29a-3p, a microRNA known for its tumor-suppressive properties. This interaction relieved miR-29a-3p's inhibition of ELK1, resulting in increased PRDX4 expression. Functional tests confirmed that the THUMPD3-AS1/miR-29a-3p/ELK1/PRDX4 axis supports tumor proliferation, migration, and invasion in ESCA. Further validation of these findings was done through in vivo experiments. In conclusion, this study underscores the significance of the THUMPD3-AS1/miR-29a-3p/ELK1/PRDX4 axis as a crucial regulatory pathway in ESCA, unveiling its oncogenic role in enhancing tumor aggressiveness.

食管癌（ESCA）由于其侵袭性和预后差，是全球癌症相关死亡的重要原因。最近的研究表明，非编码rna在肿瘤进展中起着至关重要的作用。本研究旨在探讨LncRNA THUMPD3-AS1与miR-29a-3p在ESCA进展中的相互作用。通过对ESCA临床样本进行生物信息学分析和差异表达基因验证，利用各种功能分析研究了THUMPD3-AS1、miR-29a-3p、ETS转录因子（ELK1）和过氧化物还氧蛋白4 （PRDX4）之间的调控关系。体外和体内实验也进行了评估这种相互作用对肿瘤生长和ESCA进展的影响。结果表明，ESCA组织中THUMPD3-AS1水平升高，充当miR-29a-3p的海绵，miR-29a-3p是一种以其肿瘤抑制特性而闻名的microRNA。这种相互作用减轻了miR-29a-3p对ELK1的抑制，导致PRDX4表达增加。功能测试证实，THUMPD3-AS1/miR-29a-3p/ELK1/PRDX4轴支持ESCA中肿瘤的增殖、迁移和侵袭。通过体内实验进一步验证了这些发现。总之，本研究强调了THUMPD3-AS1/miR-29a-3p/ELK1/PRDX4轴在ESCA中作为一个重要的调控通路的重要性，揭示了其在增强肿瘤侵袭性中的致癌作用。

{"title":"LncRNA THUMPD3-AS1 promotes the proliferation and migration of esophageal cancer cells through the miR-29a-3p/ELK1/PRDX4 signaling pathway","authors":"Mingming Tang , Jianjun Sun , Zhigang Cai","doi":"10.1016/j.seminoncol.2025.152350","DOIUrl":"10.1016/j.seminoncol.2025.152350","url":null,"abstract":"<div><div>Esophageal cancer (ESCA) is a significant contributor to cancer-related deaths worldwide due to its aggressive nature and poor prognosis. Recent research indicates that non-coding RNAs are critical in tumor progression. This study intends to explore the interaction between LncRNA THUMPD3-AS1 and miR-29a-3p in ESCA advancement. By conducting bioinformatic analyses and validating differentially expressed genes in ESCA clinical samples, the regulatory relationship between THUMPD3-AS1, miR-29a-3p, ETS transcription factor (ELK1), and Peroxiredoxin 4 (PRDX4) was investigated using various functional assays. In vitro and in vivo experiments were also carried out to assess the impact of this interaction on tumor growth and ESCA progression. Results indicated elevated levels of THUMPD3-AS1 in ESCA tissues, acting as a sponge for miR-29a-3p, a microRNA known for its tumor-suppressive properties. This interaction relieved miR-29a-3p's inhibition of ELK1, resulting in increased PRDX4 expression. Functional tests confirmed that the THUMPD3-AS1/miR-29a-3p/ELK1/PRDX4 axis supports tumor proliferation, migration, and invasion in ESCA. Further validation of these findings was done through in vivo experiments. In conclusion, this study underscores the significance of the THUMPD3-AS1/miR-29a-3p/ELK1/PRDX4 axis as a crucial regulatory pathway in ESCA, unveiling its oncogenic role in enhancing tumor aggressiveness.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152350"},"PeriodicalIF":3.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144579729","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}

引用次数: 0

Unlocking the therapeutic potential of polyphenols: Promising advances and future directions in pancreatic cancer treatment 释放多酚的治疗潜力：胰腺癌治疗的前景进展和未来方向

IF 3 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-08-01 Epub Date: 2025-06-18 DOI: 10.1016/j.seminoncol.2025.152353

Mohd Suhail , Shams Tabrez , Mohammad Tarique , Naoshad Muhammad , Mohd Rehan , Torki A. Zughaibi , Mohammad Hassan Alhashmi

Pancreatic cancer is one of the most lethal malignancies of the digestive tract, with a poor prognosis and a 5-year survival rate of less than 10%. The highly aggressive nature of pancreatic cancer results in a mortality rate of approximately 50% within the 6-month period of diagnosis. The absence of disease-specific symptoms significantly impedes early detection and timely intervention, contributing to its high mortality rate. Current treatment options such as radiotherapy, chemotherapy, and surgery are often inadequate for complete disease eradication and are associated with severe side effects that compromise patients' overall health. As a result, there is an urgent need for novel therapeutic strategies to address the rapidly increasing incidence of pancreatic cancer while ensuring safer, cost and more effective treatment alternatives. Plant-derived polyphenols have emerged as promising candidates due to their potent anticancer properties and minimal side effects compared to conventional therapies. In this review, we explore the biological significance and anticancer mechanisms of key polyphenols, including quercetin, resveratrol, apigenin, luteolin, EGCG, and curcumin, with a particular focus on their role in combating pancreatic cancer. Additionally, we provide a comprehensive summary of various pancreatic cancer studies, including ongoing clinical trials from the past decade.

胰腺癌是消化道最致命的恶性肿瘤之一，预后差，5年生存率不到10%。胰腺癌具有高度侵袭性，在诊断后6个月内死亡率约为50%。缺乏疾病特有症状严重阻碍了早期发现和及时干预，造成其高死亡率。目前的治疗方案，如放疗、化疗和手术，往往不足以完全根除疾病，并伴有严重的副作用，危及患者的整体健康。因此，迫切需要新的治疗策略来解决快速增加的胰腺癌发病率，同时确保更安全，成本和更有效的治疗方案。与传统疗法相比，植物源性多酚因其强大的抗癌特性和最小的副作用而成为有希望的候选者。本文综述了槲皮素、白藜芦醇、芹菜素、木犀草素、EGCG和姜黄素等主要多酚类化合物的生物学意义和抗癌机制，并重点介绍了它们在胰腺癌中的作用。此外，我们还提供了各种胰腺癌研究的综合总结，包括过去十年来正在进行的临床试验。

{"title":"Unlocking the therapeutic potential of polyphenols: Promising advances and future directions in pancreatic cancer treatment","authors":"Mohd Suhail , Shams Tabrez , Mohammad Tarique , Naoshad Muhammad , Mohd Rehan , Torki A. Zughaibi , Mohammad Hassan Alhashmi","doi":"10.1016/j.seminoncol.2025.152353","DOIUrl":"10.1016/j.seminoncol.2025.152353","url":null,"abstract":"<div><div>Pancreatic cancer is one of the most lethal malignancies of the digestive tract, with a poor prognosis and a 5-year survival rate of less than 10%. The highly aggressive nature of pancreatic cancer results in a mortality rate of approximately 50% within the 6-month period of diagnosis. The absence of disease-specific symptoms significantly impedes early detection and timely intervention, contributing to its high mortality rate. Current treatment options such as radiotherapy, chemotherapy, and surgery are often inadequate for complete disease eradication and are associated with severe side effects that compromise patients' overall health. As a result, there is an urgent need for novel therapeutic strategies to address the rapidly increasing incidence of pancreatic cancer while ensuring safer, cost and more effective treatment alternatives. Plant-derived polyphenols have emerged as promising candidates due to their potent anticancer properties and minimal side effects compared to conventional therapies. In this review, we explore the biological significance and anticancer mechanisms of key polyphenols, including quercetin, resveratrol, apigenin, luteolin, EGCG, and curcumin, with a particular focus on their role in combating pancreatic cancer. Additionally, we provide a comprehensive summary of various pancreatic cancer studies, including ongoing clinical trials from the past decade.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152353"},"PeriodicalIF":3.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144313674","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}

引用次数: 0

Peripheral blood CD4+CD25+ T lymphocytes and TGF-β predict the prognosis in relapsed/refractory multiple myeloma treated with daratumumab 外周血CD4+CD25+ T淋巴细胞和TGF-β预测达拉单抗治疗复发/难治性多发性骨髓瘤的预后

IF 3 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-08-01 Epub Date: 2025-06-25 DOI: 10.1016/j.seminoncol.2025.152373

Hanyue Xue , Fang Wei , Ruiyang Li

For patients with relapsed/refractory multiple myeloma (R/RMM), it is indispensable to choose a combination regimen based on Daratumumab, a kind of CD38-targeting monoclonal antibody (mAb), which has prominent therapeutic advantages. However, a few patients still experienced rapid progression, and the predictors of prognosis are little known. Thus, we analyzed peripheral blood (PB) CD4⁺CD25⁺ T lymphocytes and transforming growth factor-β (TGF-β) of R/RMM patients before Daratumumab treatment, to clarify their correlation with survival. Flow cytometry (FCM) was employed to detect, analyze, and compare CD4⁺CD25⁺T lymphocytes. Enzyme-linked immunosorbent assay (ELISA) was utilized to quantify serum TGF-β. Clinical indicators were gathered and classified into quartiles. In R/RMM patients’ PB, we compared these markers between the upper and lower three quartiles. We found that CD4⁺CD25⁺ T lymphocytes (pcs/µL) and TGF-β in the PB of the R/RMM patients were higher than those of the newly diagnosed MM (NDMM) patients. Additionally, serum TGF-β of R/RMM patients was positively correlated to serum creatinine (Scr) (P < 0.05). Finally, high CD4⁺CD25⁺ T lymphocytes (pcs/µL, 95% confidence interval [CI], 4.312–7.028, P = 0.001), CD4⁺CD25⁺ T lymphocytes (%, median PFS: 5.67 months, P = 0.043), and Scr (µmol/l, 95% CI, 5.378–7.422, P = 0.005) of R/RMM patients were significantly associated with inferior progression-free survival (PFS). These results suggest that patients with R/RMM are rich in CD4⁺CD25⁺ T lymphocytes and TGF-β. Additionally, R/RMM patients with elevated CD4⁺CD25⁺ T lymphocytes, TGF-β, and Scr before the treatment of daratumumab are more likely to have a poor prognosis.

对于复发/难治性多发性骨髓瘤（R/RMM）患者，选择以靶向cd38的单克隆抗体（mAb） Daratumumab为基础的联合治疗方案是必不可少的，其治疗优势突出。然而，少数患者仍经历快速进展，预后的预测因素知之甚少。因此，我们分析了达拉单抗治疗前R/RMM患者外周血（PB） CD4+CD25+ T淋巴细胞和转化生长因子-β (TGF-β)，以阐明其与生存率的相关性。流式细胞术（FCM）检测、分析和比较CD4+CD25+T淋巴细胞。采用酶联免疫吸附法（ELISA）定量血清TGF-β。收集临床指标并按四分位数进行分类。在R/RMM患者的PB中，我们比较了上下三个四分位数之间的这些标记。我们发现R/RMM患者外周血CD4+CD25+ T淋巴细胞（pcs/µL）和TGF-β高于新诊断MM （NDMM）患者。R/RMM患者血清TGF-β与血清肌酐（Scr）呈正相关（P <； 0.05）。最后，R/RMM患者的高CD4+CD25+ T淋巴细胞（pcs/µL， 95%可信区间[CI]， 4.312-7.028, P = 0.001）、CD4+CD25+ T淋巴细胞（%，中位PFS: 5.67个月，P = 0.043）和Scr（µmol/ L, 95% CI, 5.378-7.422, P = 0.005）与较差的无进展生存期（PFS）显著相关。这些结果提示R/RMM患者CD4+CD25+ T淋巴细胞和TGF-β丰富。此外，治疗前CD4+CD25+ T淋巴细胞、TGF-β、Scr升高的R/RMM患者预后更差。

{"title":"Peripheral blood CD4+CD25+ T lymphocytes and TGF-β predict the prognosis in relapsed/refractory multiple myeloma treated with daratumumab","authors":"Hanyue Xue , Fang Wei , Ruiyang Li","doi":"10.1016/j.seminoncol.2025.152373","DOIUrl":"10.1016/j.seminoncol.2025.152373","url":null,"abstract":"<div><div>For patients with relapsed/refractory multiple myeloma (R/RMM), it is indispensable to choose a combination regimen based on Daratumumab, a kind of CD38-targeting monoclonal antibody (mAb), which has prominent therapeutic advantages. However, a few patients still experienced rapid progression, and the predictors of prognosis are little known. Thus, we analyzed peripheral blood (PB) CD4<sup>+</sup>CD25<sup>+</sup> T lymphocytes and transforming growth factor-β (TGF-β) of R/RMM patients before Daratumumab treatment, to clarify their correlation with survival. Flow cytometry (FCM) was employed to detect, analyze, and compare CD4<sup>+</sup>CD25<sup>+</sup>T lymphocytes. Enzyme-linked immunosorbent assay (ELISA) was utilized to quantify serum TGF-β. Clinical indicators were gathered and classified into quartiles. In R/RMM patients’ PB, we compared these markers between the upper and lower three quartiles. We found that CD4<sup>+</sup>CD25<sup>+</sup> T lymphocytes (pcs/µL) and TGF-β in the PB of the R/RMM patients were higher than those of the newly diagnosed MM (NDMM) patients. Additionally, serum TGF-β of R/RMM patients was positively correlated to serum creatinine (Scr) (<em>P</em> < 0.05). Finally, high CD4<sup>+</sup>CD25<sup>+</sup> T lymphocytes (pcs/µL, 95% confidence interval [CI], 4.312–7.028, <em>P</em> = 0.001), CD4<sup>+</sup>CD25<sup>+</sup> T lymphocytes (%, median PFS: 5.67 months, <em>P</em> = 0.043), and Scr (µmol/l, 95% CI, 5.378–7.422, <em>P</em> = 0.005) of R/RMM patients were significantly associated with inferior progression-free survival (PFS). These results suggest that patients with R/RMM are rich in CD4<sup>+</sup>CD25<sup>+</sup> T lymphocytes and TGF-β. Additionally, R/RMM patients with elevated CD4<sup>+</sup>CD25<sup>+</sup> T lymphocytes, TGF-β, and Scr before the treatment of daratumumab are more likely to have a poor prognosis.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152373"},"PeriodicalIF":3.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144480909","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}

引用次数: 0

Breaking barriers: Deciphering the mechanisms of Olaparib resistance in prostate cancer 突破障碍：解读前列腺癌奥拉帕尼耐药机制

IF 3 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-08-01 Epub Date: 2025-06-26 DOI: 10.1016/j.seminoncol.2025.152375

Amr Ali Mohammed Abdelgawwad Wl-Sehrawy , Mahmood Yaseen Mukhlif , Aysar Ashour Khalaf , Subasini Uthirapathy , Suhas Ballal , Abhayveer Singh , V. Kavitha , Laxmidhar Maharana , Hayder Ridha-Salman , Ahmed Remthan Hussein Al-Altememe

A poly (ADP-ribose) polymerase (PARP) inhibitor, Olaparib has shown notable clinical effectiveness in treating metastatic castration-resistant prostate cancer (mCRPC) with DNA damage repair gene mutations. Though initial reactions were encouraging, the emergence of resistance poses a major clinical problem that reduces the long-term therapeutic value for patients. This paper thoroughly investigates the molecular processes behind acquired and intrinsic resistance to Olaparib in prostate cancer (PCa). Among the several resistance routes discovered are restoration of homologous recombination (HR) repair capacity via secondary BRCA2 mutations, loss of 53BP1/REV7/Shieldin complex activity, and activation of alternative DNA repair pathways. Recent studies further imply that changes in cell cycle checkpoints and epigenetic changes could help to increase therapy resistance even more. Knowing these several resistance mechanisms helps one to create reasonable combination strategies and biomarker-driven initiatives to defeat Olaparib resistance. Among the new treatment options are combination therapies aimed at compensatory DNA repair mechanisms, cell cycle checkpoint inhibitors, epigenetic modulators, and methods tackling tumor microenvironment elements. Predictive biomarker discovery of resistance will help to guide individual treatment choice and sequential therapy optimization, hence changing clinical results for advanced PCa patients in the precision medicine age.

奥拉帕尼是一种聚adp核糖聚合酶（PARP）抑制剂，在治疗DNA损伤修复基因突变的转移性去势抵抗性前列腺癌（mCRPC）中显示出显著的临床疗效。虽然最初的反应是令人鼓舞的，但耐药性的出现构成了一个主要的临床问题，降低了患者的长期治疗价值。本文深入研究了前列腺癌（PCa）获得性和内在奥拉帕尼耐药背后的分子过程。发现的几种抗性途径包括通过继发性BRCA2突变恢复同源重组（HR）修复能力，53BP1/REV7/ shield复合物活性的丧失，以及其他DNA修复途径的激活。最近的研究进一步表明，细胞周期检查点的变化和表观遗传变化可能有助于进一步增加治疗耐药性。了解这几种耐药机制有助于制定合理的组合策略和生物标志物驱动的举措，以击败奥拉帕尼耐药。新的治疗选择包括针对补偿性DNA修复机制的联合治疗、细胞周期检查点抑制剂、表观遗传调节剂和处理肿瘤微环境因素的方法。预测耐药生物标志物的发现将有助于指导个体化治疗选择和序贯治疗优化，从而改变精准医学时代晚期PCa患者的临床结果。

{"title":"Breaking barriers: Deciphering the mechanisms of Olaparib resistance in prostate cancer","authors":"Amr Ali Mohammed Abdelgawwad Wl-Sehrawy , Mahmood Yaseen Mukhlif , Aysar Ashour Khalaf , Subasini Uthirapathy , Suhas Ballal , Abhayveer Singh , V. Kavitha , Laxmidhar Maharana , Hayder Ridha-Salman , Ahmed Remthan Hussein Al-Altememe","doi":"10.1016/j.seminoncol.2025.152375","DOIUrl":"10.1016/j.seminoncol.2025.152375","url":null,"abstract":"<div><div>A poly (ADP-ribose) polymerase (PARP) inhibitor, Olaparib has shown notable clinical effectiveness in treating metastatic castration-resistant prostate cancer (mCRPC) with DNA damage repair gene mutations. Though initial reactions were encouraging, the emergence of resistance poses a major clinical problem that reduces the long-term therapeutic value for patients. This paper thoroughly investigates the molecular processes behind acquired and intrinsic resistance to Olaparib in prostate cancer (PCa). Among the several resistance routes discovered are restoration of homologous recombination (HR) repair capacity via secondary BRCA2 mutations, loss of 53BP1/REV7/Shieldin complex activity, and activation of alternative DNA repair pathways. Recent studies further imply that changes in cell cycle checkpoints and epigenetic changes could help to increase therapy resistance even more. Knowing these several resistance mechanisms helps one to create reasonable combination strategies and biomarker-driven initiatives to defeat Olaparib resistance. Among the new treatment options are combination therapies aimed at compensatory DNA repair mechanisms, cell cycle checkpoint inhibitors, epigenetic modulators, and methods tackling tumor microenvironment elements. Predictive biomarker discovery of resistance will help to guide individual treatment choice and sequential therapy optimization, hence changing clinical results for advanced PCa patients in the precision medicine age.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152375"},"PeriodicalIF":3.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144480907","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}

引用次数: 0

A 3-miRNA signature for noninvasive breast cancer detection 无创乳腺癌检测的3-miRNA特征

IF 3 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-08-01 Epub Date: 2025-06-11 DOI: 10.1016/j.seminoncol.2025.152363

Amir Ebrahimi , Davood Ghavi , Zohreh Mirzaei , Tahereh Barati , Mahmood Shekari-Khaniani , Hossein Gahramani-almangadim , Sima Mansoori-Derakhshan

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.

作为表观遗传学的关键组成部分，microRNAs （miRNAs）为乳腺癌（BC）的几个方面提供了有希望的见解。我们分析了2个BC组织芯片数据集（GSE26659和GSE40525），以及2个血清数据集（GSE106817和GSE113486）。然后将结果交叉以鉴定BC患者组织和血清中常见的失调mirna。然后将RNA-seq分析应用于癌症基因组图谱（TCGA）数据。简而言之，我们在BC患者的组织和血清中发现了79个失调的mirna，其中3个显著失调且以前未研究的mirna， let-7e-5p， miR-151a-5p和miR-887-3p，通过RT-PCR在癌症患者的血清中进行量化，然后评估其诊断和预后特征。rt - pcr分析显示过度let-7e-5p (logFC = 2.01,P & lt; . 05)和mir - 151 - 5 - P (logFC = 1.48,P & lt; . 05)而mir - 887 - 3 - P是表达下调(logFC = 0.62,P & lt; . 05)类似于微阵列和RNA-seq数据分析。基于回归分析，提出了一个3 mirna标记生物标志物，与单独评估这些mirna相比，该标志物具有更好的诊断能力（AUC = 84.17%）。此外，富集分析显示这些mirna介导影响癌症发展的重要细胞过程和生物学功能。同样，观察到这些mirna具有显著的预后临床特征。总的来说，我们已经在BC患者的血清中鉴定并验证了一种由3个mirna组成的新型且熟练的标志性生物标志物。

{"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":"2025-08-01","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}

引用次数: 0