CDK5-A Novel Role in Prostate Cancer Immunotherapy
Abstract
Scientific objective: Our objective in this project is to exploit our recent preliminary data indicating that CDK5, a cellular signaling protein, may have a role in protecting prostate cancer from the body s immune system. In the current project, we will characterize the role of CDK5 in the antitumor immune response. In preclinical studies in well-validated animal models of prostate cancer, we will develop and optimize therapies combining a CDK5 inhibitor with immunotherapeutic agents. Rationale: A phalanx of recent impressive results in preclinical and clinical studies has triggered a remarkable sea change in outlook toward cancer therapy; specifically, widespread optimism and interest in immunotherapy -- harnessing the body s own immune system to attack cancer. At the clinical level, ipilimumab, an antibody that blocks cancer s ability to evade the immune system, was shown to elicit dramatic and often durable responses in melanoma and other cancers, and ipilimumab was approved in 2011 for treatment of melanoma. Other immunotherapies are being developed; many of these have already shown unprecedented preclinical and clinical activity. Prostate cancer appears to be a very attractive target for immunotherapeutic strategies, and immune therapies for prostate cancer have shown promise. A prostate cancer vaccine, Sipuleucel-T, induced responses in metastatic prostate cancer and resulted in a modest increase in overall survival. However, prostate cancer, like many other cancer types, illustrates the serious hurdles involved in development of effective immunotherapy. Only a subset of patients responds to immunotherapy, and clinical benefit is often transient. Nevertheless, durable complete responses, reported both in prostate cancer and other diseases, indicate the potential for immunotherapy to eradicate or control the disease. Thus, there is an urgent need for discovering mechanisms for sensitizing prostate cancer to immunotherapy. As mentioned above, we have recently found that blocking CDK5 activity in a well-validated animal model of prostate cancer resulted in a significantly increased antitumor response, accompanied by significant decreases in the cancer s evasion of the immune system. This preliminary finding suggests the exciting possibility that inhibition of CDK5 could sensitize prostate cancer to immunotherapy and that a combination of a CDK5 inhibitor and immunotherapy could be effective for eradicating or controlling advanced prostate cancer. Ultimate applicability of research: If successful, the therapeutic strategies optimized in this project can be rapidly advanced to clinical evaluation. This possibility is especially attractive, since excellent CDK5 inhibitors, as well as immunotherapeutic agents, are already in clinical trials. Therefore, this translation to clinical evaluation could potentially be initiated almost immediately after completion of this 2.5-year project. Such a combined approach could result in durable responses and dramatically increased survival, as has been seen recently with immunotherapeutic strategies in other diseases. We envision that the first group of prostate cancer patients to benefit from these therapeutic strategies will be the group with the most urgent need -- those with metastatic castration-resistant prostate cancer, the highly lethal, treatment refractory stage that accounts for virtually all deaths from prostate cancer. Subsequently, it is possible that the therapy could be applicable to patients with earlier progression stages, including those with asymptomatic disease recurrence heralded by rising PSA (prostate specific antigen). The potential risks associated with the proposed combination therapy are side effects not unlike those for other immunotherapies (e.g., autoimmune inflammation) and CDK inhibitors (e.g., gastrointestinal symptoms, fatigue, transaminitis), usually manageable by clinical oncologists. Contributions of this project to prostat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510670
Entities
People
- Barry Nelkin
Organizations
- Johns Hopkins University
- United States Army