Targeting the p38/Snail/PD-L1 Axis in Hormone Therapy Resistance and Metastasis
Abstract
Prostate cancer in the United States kills nearly 80 men each day. Almost all of these men die because their cancer becomes resistant to our best drugs and spreads beyond the site of the original tumor. Because these features are the major causes of death for nearly all patients, we are focused on targeting these two processes of drug resistance and metastatic spread. The current therapies for metastatic prostate cancer are drugs that inhibit the testosterone pathway, including abiraterone and enzalutamide. The testosterone pathway is the major pathway through which prostate cancer cells survive. The loss of this critical testosterone resource for the cancer cells is analogous to loss of any important resource in an ecosystem. When a resource is taken away, organisms in a population can respond in one of three ways: (1) alter their eating habits or hibernate (turn on stress responses); (2) escape predation (immune evasion); and (3) disperse to a new location with more access to resources (migration/invasion). Our preliminary data suggest that enzalutamide-resistant prostate cancer cells activate all three of these responses: (1) cells enter a pro-survival phenotype by upregulating the p38a stress response pathway; (2) cells engage an immuno-evasive phenotype by upregulating the immune evasion gene, PD-L1; and (3) cells upregulate migration/invasion pathways through the gene, Snail. Together, these alterations present a formidable challenge clinically. How can all three of these key pathways possibly be targeted to provide clinical benefit to patients? Fortunately, our data provide a strong rationale that all three of these pathways converge on two promising therapies to treat advanced prostate cancer: (1) p38a inhibition and (2) PD-L1 immune checkpoint blockade. The major goal of this proposal will be to provide the necessary preclinical testing of p38a inhibition and/or PD-L1 blockade to justify clinical trials for men with metastatic, therapy-resistant prostate cancer. Our research team is made of both MD clinicians and PhD basic scientists. We leverage our complementary strengths from both clinical and preclinical laboratory studies to rapidly translate novel treatment strategies into clinical practice. If successful, our proposed studies can lead to initiation of clinical trials by year 3 of the grant. Our proposed study will not only inform broadly on the biology underlying therapy resistance and metastatic spread, but it has the potential to directly benefit, in the near term, the subset of patients who have progressed to a drug-resistant, metastatic disease state.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810189
Entities
People
- Jason Somarelli
Organizations
- Duke University
- United States Army