Concurrent Administration of Bipolar Androgen Therapy and Nivolumab in Men with Metastatic Castration-Resistant Prostate Cancer (COMBAT-CRPC)
Abstract
Background: Metastatic prostate cancer is not curable, but is effectively treated with androgen deprivation therapy, in which testosterone levels in the body are lowered to near zero (i.e., castration). Since testosterone drives the growth of prostate cancer, castration results in decreasing PSA levels and cancer remission. Inevitably, the cancer develops resistance and is able to grow in low levels of testosterone. However, prostate cancer remains addicted to testosterone and “reprograms” itself to adapt to this low testosterone environment. This is called castration resistance. We have found that administration of high doses of testosterone can stop the growth of castration-resistant prostate cancer. The cycling of testosterone from high to low levels over a 28-day period in a process called bipolar androgen therapy (BAT) is difficult for the cancer cells to tolerate, resulting in cell death. We have conducted several clinical trials with BAT in patients with metastatic castration-resistant prostate cancer that showed that patients benefit from this approach. We have also observed that patients who received BAT and were next treated with immunotherapy had profound disease regression. BAT may sensitize the prostate cancer cells, making them more vulnerable to immune-based treatments. We are now conducting a Phase 2 clinical trial in men with metastatic castration-resistant prostate cancer to test this hypothesis. Objectives: The overall objective of this research project is to develop a new treatment for men with incurable metastatic prostate cancer that has become resistant to androgen deprivation therapy. For this grant, our objectives are to understand the mechanism by which BAT may lead to cancer cell death and also to determine whether BAT may sensitize prostate cancer to immunotherapy. 1. Based on our laboratory research, we hypothesize that BAT can cause damage to the DNA (i.e., genes) of cancer cells. In some patients, the genetic damage itself can cause the cells to die. In other patients, the resulting DNA damage may enhance the ability of the immune system to recognize the cancer. We will take biopsies from sites of cancer in patients on this study of BAT with immunotherapy that will be analyzed to answer this question of DNA damage. 2. It is also becoming clear that the normal bacteria that live in the intestines (i.e., “the microbiome”) can be stimulating to the immune system. Certain bacterial species may have similar proteins to cancer cells. When present in the gut, these culprit bacteria can enhance the immune system to now attack cancer cells under the proper circumstances (i.e., following immunotherapy treatment). Our studies in the laboratory show that hormone manipulation treatment can alter the gut bacteria. In this clinical trial, we will obtain rectal swabs from patients (which samples the gut microbiome) during the course of treatment. We propose to study how BAT changes the gut microbiome and determine whether certain species of bacteria are found in patients that received the most benefit from immunotherapy. 3. Patients that benefit from immunotherapy have their own immune system start recognizing their cancer as foreign and removing it from the body. As a field, we do not understand why certain patients benefit from immunotherapy and others do not. We have developed a new laboratory technique that can identify the different antibodies circulating in the blood and what these antibodies can recognize. We will take blood samples from patients on this study of BAT and nivolumab and monitor the changes in antibodies that occur during the treatment. Specifically, we will focus on antibodies that recognize human proteins (i.e., autoantibodies). We hypothesize that we will see the production of autoantibodies only in those patients that see their cancer regress during therapy. Career/Project Goals: Dr. Markowski is a medical oncologist with an expertise in treat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910692
Entities
People
- Mark C Markowski
Organizations
- Johns Hopkins University
- United States Army