Potential of integrin receptors to serve as therapeutic targets for metastasized prostate cancer resistant to taxanes and androgen receptor signaling inhibitors

整合素受体作为对紫杉烷和雄激素受体信号抑制剂耐药的转移性前列腺癌的治疗靶点的潜力

• 批准号: 405693502
• 负责人: Professor Dr. Roman A. Blaheta, Ph.D.
• 金额: --
• 依托单位: Klinik für Urologie und Kinderurologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/405693502?language=en
• 关键词: Potential; integrin; receptors; serve; therapeutic

Prostate cancer is the most prevalent solid malignancy in German males, which treatment, if metastasis was present, has been solely symptom-oriented till the beginning of the 21st century. During the last decade, therapeutic armamentarium for systemically disseminated tumor has been considerably expanded. Most recently, both taxane docetaxel and androgen receptor signaling inhibitor abiraterone have demonstrated an advantage in overall survival when used early in treatment course concomitantly with the beginning of androgen deprivation, i.e. in hormone-sensitive metastatic disease. For castration-resistant metastatic cancer, a number of immunologic and cytotoxic agents as well as radionucleids and androgen receptor signaling inhibitors have been approved providing a survival benefit of less than 5 months. Unfortunately, metastasized prostate cancer remains incurable despite these advances. Particularly due to acquired resistance during the first-line treatment, drug efficacy decreases in subsequent therapy lines. In order to warrant a long-term adequate therapy response and counteract undesired development of resistance, unmet need exists for optimization of the current therapeutic protocols.Protein family of integrines represents a promising therapeutic target in this context. Integrins are elementary surface receptors involved in regulation of cell-cell- and cell-matrix adhesion. They participate in controlling of essential biological processes e.g. cell proliferation and differentiation, apoptosis and specifically migration and invasion as the key steps of metastatic cascade. Since overexpression of several integrin subtypes and augmented integrin-triggered tumor cell motility has been observed during resistance, their specific blockade might represent an innovative therapeutic option for metastasized prostate cancer, particularly regarding development of resistance to currently approved agents.The main focus of the current project is directed towards analysis of the potential therapeutic value of integrine receptors in the stage of treatment resistance to taxanes docetaxel and cabazitaxel as well as androgen receptor signaling inhibitors abiraterone and enzalutamide. We intend to establish hormone-sensitive and castration-resistant prostate cancer cell lines resistant to the aforementioned drugs and assess consequent modifications of the integrine expression profile. After evaluation of the functional relevancy of integrin modifications under resistance in cell culture, the findings will be validated in an in-vivo orthotopic animal model. Finally, we aim at identification of integrin-subtypes which might serve as therapeutic targets for metastasized prostate cancer resistant to taxanes and androgen receptor signaling inhibitors.

前列腺癌是德国男性最常见的实体恶性肿瘤，直到21世纪初，如果有转移，这种治疗一直是以症状为导向的。在过去的十年中，治疗全身播散性肿瘤的医疗设备已经有了相当大的扩展。最近，紫杉醇和雄激素受体信号转导抑制剂阿比特龙在治疗过程的早期与雄激素剥夺的开始，即激素敏感的转移性疾病一起使用时，都显示出在总存活率方面的优势。对于抗去势的转移癌，一些免疫和细胞毒药以及放射性核素和雄激素受体信号抑制剂已被批准，提供不到5个月的生存益处。不幸的是，尽管取得了这些进展，转移性前列腺癌仍然无法治愈。尤其是由于在一线治疗期间获得的耐药性，在随后的治疗系列中药物疗效会下降。为了保证长期有效的治疗反应并对抗不受欢迎的耐药性的发展，目前的治疗方案存在着未得到满足的需求，整合素类蛋白家族在这方面代表了一个有前途的治疗靶点。整合素是一种基本的表面受体，参与调节细胞-细胞和细胞-基质的黏附。它们作为转移级联反应的关键步骤，参与调控细胞的增殖和分化、细胞凋亡，特别是迁移和侵袭等重要生物学过程。由于在耐药过程中观察到了几种整合素亚型的过度表达和整合素触发的肿瘤细胞运动增强，它们的特异性阻断可能代表着转移性前列腺癌的一种创新的治疗选择，特别是关于目前批准的药物的耐药性的发展。本项目的主要重点是分析整合素受体在紫杉醇、卡巴紫杉醇以及雄激素受体信号抑制剂阿比特龙和苯扎鲁胺的治疗耐药阶段的潜在治疗价值。我们打算建立对上述药物耐药的激素敏感和去势耐药的前列腺癌细胞系，并评估由此导致的整合素表达谱的改变。在评估了细胞培养中耐药情况下整合素修饰的功能相关性后，这一发现将在体内原位动物模型中得到验证。最后，我们的目标是确定整合素亚型，这些亚型可能作为转移性前列腺癌对紫杉烷和雄激素受体信号抑制剂耐药的治疗靶点。