Autophagosomal Sequestration of Mitochondria as an Indicator of Antiandrogen Therapy Resistance of Prostate Cancer (PCa)
Abstract
Objective: Most patients with recurrent prostate cancer (PCa) undergo androgen deprivation therapy (ADT). Unfortunately, a large majority of them develop therapy resistance and progress to castrate-resistant PCa. In the last few years, several new therapies for advanced, recurrent prostate cancer (PCa) have been approved by the Food and Drug Administration. These therapies include abiraterone acetate (Zytiga) and enzalutamide (Xtandi) that mainly target androgen-signaling axis. Patients, however, respond differentially to these agents -- some develop resistance within a few months, while others continue to respond for several years. These drugs, however, are expensive and not without side effects. Predictive assays that could decide who would benefit from any of these therapies at an early stage of recurrence should reduce both pain and suffering as well as healthcare cost by eliminating unnecessary and expensive treatment. Accumulative evidence suggests that cellular oxidative stress plays a key role in cell proliferation in the absence of androgen giving rise to castration-resistant PCa (CRPC). An intracellular mechanism called autophagy is activated in the PCa cells to reduce the stress. Autophagy, however, also provides some survival advantage that leads to therapy resistance. Here, we propose to establish a simple fluorescence microscopy based method of determining the degree of autophagy in circulating tumor cells in patient blood samples. This will enable the clinicians to identify patients who will not respond or will develop resistance either before or within a very short period of therapy initiation. This should save these patients from experiencing side effects as well as substantial out-of-pocket expense of prolonged and ineffective treatment. Clinical Application and Impact: We believe, within the end of this study period (3 years), we will have a clinically validated assay that can be applied in a prospective clinical trial for Clinical Laboratory Improvement Amendments (CLIA) certification and clinical application. As patients who refract from enzalutamide therapy do so within 3-6 months, the prospective clinical trial for CLIA certification is anticipated to be completed in less than a year. Thus, within 4-5 years of the beginning of this grant period, we should have a clinically approved blood test to detect ADT non-responders. This should not only substantially reduce patient ordeal, but should also help clinicians to combine enzalutamide with approved drugs such as chloroquine, metformin, etc. to prolong enzalutamide response. As the assay is based on blood sample analysis, the clinical trial would be simple and of minimal risk to the patients. Ultimately, this should have a profound impact on the clinical management of recurrent, advanced prostate cancer. In addition, this should expand the field of anti-autophagy drug research for the treatment of advanced, ADT-refractory PCa as well.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510509
Entities
People
- George Wilding
Organizations
- United States Army
- University of Wisconsin–Madison