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

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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.