Understanding the Role of Tumor Dormancy in Treatment-Resistant Prostate Cancer.
Abstract
Prostate cancer is one of the most frequent occurring forms of male cancer. While surgery and radiation are typically highly successful at reducing primary tumor burden, years later men often suffer clinical recurrence in the form of painful metastatic disease associated with poor clinical outcome. One explanation for this progression trend is the early distribution of cancer cells in a process called dissemination. This occurs when cancer cells escape the primary tumor to distant sites in the body, persisting for years (called "residual disease") and then recurring to form metastatic castration-resistant prostate cancer (mCRPC) later in life. One mechanism for such extended cancer survival is attributed to cells being able to live in a state of dormancy or quiescence. The ability for such cancer cells to resist standard-of-care therapies, including chemotherapy and androgen deprivation therapy, while retaining the capacity to reconstitute mCRPC suggests the presence of stem or cancer-initiating qualities. The ability of cancer to reside for long periods of time also implies escape from recognition by the immune system. Immunotherapy provides significant promises as an alternative therapy to potentially toxic chemotherapy or hormonal-based regimens. Despite this, little is understood about how and when immunotherapy could be used to kill treatment residual disease in prostate cancer patients. In my laboratory, we are using sophisticated genetically modified mouse models to study cancer dormancy and treatment resistance. Notably, these state-of-the-art preclinical models progress through similar stages as human prostate cancer including castration resistance and metastasis. We have engineered these models for in vivo monitoring of dormant cancer cells allowing both quantitative and qualitative analysis. Using a process called adoptive T-cell vaccination (immunotherapy), we will introduce cancer specific T cells to mice with the goal of inducing an immune response against residual disease. Collectively, our proposed studies are highly innovative since our unique model design facilitates addressing the complex and challenging problem of treatment resistance and immunotherapy. Given the tremendous motivation to reap the potential benefits of immunotherapy and the translational relevance of our cancer models, we anticipate patient benefits from our findings in the near term.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710283
Entities
People
- David Mulholland
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army