Development of Precision Neoadjuvant-Adjuvant Therapies
Abstract
Radical prostatectomy (RP) is almost invariably curative in men whose prostates contain only Gleason pattern 3 (Gleason score 6), but a subset of men with Gleason score 7 prostate cancer (PCa) will relapse systemically after RP, and this subset may be up to 30%-50% in men with higher Gleason scores and other high-risk features. These relapses reflect occult metastatic disease present at the time of RP. Clinical trials have attempted to decrease relapse rates by giving hormonal or chemotherapy prior to the RP (neoadjuvant therapy) or immediately after RP (adjuvant therapy). Treatment with agents that suppress testosterone production such as leuprolide (termed androgen deprivation therapy, ADT) given prior to RP (neoadjuvant ADT) have been shown to decrease tumor volume, but they rarely result in complete responses in the prostate and have not been shown to improve survival. Overall, these observations highlight the need to improve outcomes for men who present with high-risk primary PCa and support efforts to develop more effective neoadjuvant/adjuvant therapies. ADT works by suppressing activity of the androgen receptor (AR), which is activated by testosterone and related androgens. ADT is the standard initial therapy for metastatic PCa, but patients invariably relapse despite castrate levels of androgens (castration-resistant prostate cancer, CRPC). It is now clear that increased androgen synthesis by tumor cells is a major mechanism driving AR in CRPC, and that responses can be obtained by further suppression of androgen synthesis using agents such as abiraterone that block a critical enzyme (CYP17A1) or by more effective direct AR antagonists such as enzalutamide. Based on these observations, we initially hypothesized that more aggressive neoadjuvant therapies using these agents in combination with leuprolide would further suppress AR activity and improve responses. Indeed, in our recent neoadjuvant trial of leuprolide in combination with abiraterone for 24 weeks prior to RP, we confirmed that the addition of abiraterone further markedly reduced intraprostatic androgen levels and appeared to improve responses relative to historical controls. However, while several patients had complete or near complete pathological responses, residual PCa was found in the majority of patients. We have now focused on analyses of residual tumor cells in the RP specimens to determine mechanisms of resistance and to identify potential additional therapeutic targets and agents that may overcome resistance and enhance responses in neoadjuvant/adjuvant trials as well as in CRPC. A major finding has been mutations in distinct genes known to stimulate cancer growth in separate foci from the same index tumor, indicating that treatment is selecting for multiple preexistent subclones containing genomic alterations more typically found in advanced therapy-resistant CRPC. Significantly, many of these alterations can be targeted therapeutically, but this would require a personalized approach based on molecular analyses of residual tumor foci and determination of the focus or foci that are contributing to occult metastatic disease. Therefore, our objective in this proposal is to characterize resistant tumor foci in a series of additional neoadjuvant PCa clinical trials and determine their contribution to the development of metastatic disease. Our rationale is that the early identification of mutations stimulating the growth of occult metastatic tumor will allow us to develop personalized adjuvant therapies, which may include immunotherapies, with the potential to prevent relapse. Our objective is to test the hypothesis that these residual tumor foci drive the development of metastatic disease and to thereby set the stage for personalized neoadjuvant/adjuvant clinical trials. This project is responsive to the Overarching Challenge to develop treatments and address mechanisms of resistance, and the Focus Area of therapy and mechanism of r
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610431
Entities
People
- Steven P Balk
Organizations
- Beth Israel Deaconess Medical Center
- United States Army