Combining Androgen Deprivation and Immunotherapy to Prevent Progression to Castration-Resistant Prostate Cancer
Abstract
Scientific Objective and Rationale: Prostate cancer (PCa) is one of the most commonly occurring malignancies among men in the United States. Metastatic PCa (cancer that has spread from the prostate to other tissues and organs) leads to about 30,000 deaths each year in the United States. While treatments exist for resistant PCa, these do not cure patients and therefore ultimately fail. Much research effort is focused on improving treatments for metastatic disease. In this proposal, we take a different approach. Specifically, our scientific objective is to improve the initial treatment for non-metastatic cancers that are at higher risk of progressing by devising therapies that prevent PCa progression and, eventually, metastasis. The scientific rationale for our distinct approach is as follows. We have observed that, in model systems, the standard therapy for advanced PCa (androgen deprivation therapy [ADT]) initially slows the growth of the main (primary) tumor, yet increases the ability of the cancer to recur or progress and possibly metastasize. There is also evidence that this holds in human cancers. Thus, the primary goal of this proposal is to understand the mechanism producing this effect and then use that understanding to develop a path to improve current treatments for locally advanced PCa. In particular, we present evidence in our proposal that the mechanism for therapy-induced immune suppression involves a portion of the tumor that contains so-called “cancer stem cells.” These are tumor cells that are more resistant to therapy and can give rise to continued tumor growth even after therapy. We have found that these cancer stem cells secrete molecules that, in turn, trigger the development of an immune-suppressive state in the model tumors. These secreted molecules then undermine the effectiveness of ADT. Ultimate Applicability: The key group of patients that could benefit from halting the progression of PCa are those with “high risk” or “locally advanced” PCas. These are individuals who appear to definitely have more advanced disease than the typical “early-stage” or “localized” PCa patient who can be cured with surgery or radiation treatment (or are even candidates for active surveillance). The immune suppressive effects of ADT are not easy to clinically document in human PCa patients and therefore may be an underappreciated opportunity for new therapies. Specifically, since up to 20,000 patients are diagnosed with high-risk or locally advanced PCa each year, a significant group of patients could benefit from developing this therapy. The proposed therapy would supplement (but not replace) current therapies, making it more likely to be adopted in clinical practice and much easier to initiate new trials to test this idea. Our lead candidates include drugs currently available for certain immunological (autoimmune) diseases that have been demonstrated to be exceedingly safe, even when administered for years in patients. Thus, the risks of the proposed therapy are very small with respect to safety. There is also little risk of under-treatment, since this combination therapy supplements existing therapies, so there is no reduction in its efficacy relative to existing therapy. Moreover, since a number of the drugs are already Food and Drug Administration-approved, testing the effectiveness in humans could begin shortly after the completion of our proposed studies. Advancing the Field of PCa: This research project will also advance our mechanistic and biological understanding of PCa in three ways. First, we will test the hypothesis that therapy-induced immune suppression is due to the stem cell-like subpopulation of the PCa. Second, we will test the idea that the mechanism of therapy-induced metastasis is modulated by molecular interactions affecting the non-tumor cells surrounding the tumor cells within the complex milieu of the tumor—that is, within the so-called tumor microenvironment. Thi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910378
Entities
People
- John Krolewski
Organizations
- United States Army