Potential of integrin receptors to 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中最常见的实体恶性肿瘤，直到21世纪初，如果存在转移，其治疗一直是单纯的症状导向。在过去的十年中，治疗系统播散性肿瘤的手段已经大大扩大。最近，紫杉烷多西紫杉醇和雄激素受体信号抑制剂阿比特龙在治疗过程的早期与雄激素剥夺的开始一起使用时，即在激素敏感的转移性疾病中，都显示出了总体生存的优势。对于去势抵抗性转移性癌症，许多免疫和细胞毒性药物以及放射性核素和雄激素受体信号抑制剂已被批准提供少于5个月的生存期。不幸的是，尽管有这些进展，转移性前列腺癌仍然无法治愈。特别是由于在一线治疗期间获得性耐药，药物疗效在后续治疗中下降。为了保证长期充分的治疗反应和抵消不希望的耐药性的发展，存在对当前治疗方案优化的未满足需求。在这种情况下，蛋白质整合体家族代表了一个有希望的治疗靶点。整合素是参与调节细胞-细胞和细胞-基质粘附的基本表面受体。它们参与控制细胞增殖和分化、细胞凋亡以及特异性迁移和侵袭等重要生物学过程，是转移级联的关键步骤。由于在耐药过程中观察到几种整合素亚型的过度表达和整合素引发的肿瘤细胞运动增强，因此它们的特异性阻断可能代表了转移性前列腺癌的一种创新治疗选择，特别是在对目前批准的药物产生耐药性方面。目前项目的主要重点是分析整合素受体在紫杉醇类药物多西他赛和卡巴他赛以及雄激素受体信号抑制剂阿比特龙和恩杂鲁胺治疗耐药阶段的潜在治疗价值。我们打算建立对上述药物具有激素敏感性和去势抗性的前列腺癌细胞系，并评估随后的整合子表达谱的改变。在评估整合素修饰在细胞培养抗性下的功能相关性后，研究结果将在体内原位动物模型中得到验证。最后，我们的目标是鉴定整合素亚型，这些亚型可能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。

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.