Mechanisms of Resistance to Androgen Deprivation Therapy in Advanced Castration-Resistant Prostate Cancer (CRPC)
Abstract
When men develop prostate cancer that spreads or metastasizes to other parts of their body, the first- and second-line treatments used by doctors attempt to block the effects of the androgen hormones testosterone and dihydrotestosterone (DHT) on prostate cancer cells. This type of therapy is called androgen deprivation therapy or ADT because it deprives the prostate cancer cells of these important androgen hormones. Testosterone and DHT bind to the androgen receptor (AR) within cancer cells and stimulate the growth and progression of prostate cancer. Gonadotropin-releasing hormone agonists (GnRH-agonists), abiraterone, and enzalutamide are three drugs commonly used to block the pro-cancer hormone signaling that occurs through testosterone and DHT. GnRH agonists inhibit the testicular production of androgen hormones. Abiraterone inhibits an enzyme called CYP17A1, which decreases the levels of testosterone and DHT. Enzalutamide blocks the ability of testosterone and DHT to stimulate prostate cancer cells. These drugs are initially effective at stopping prostate cancer progression, but in nearly all men the cancer eventually becomes resistant. The subject of this research proposal is determining how downregulation of the gene DPP4 and its protein product helps prostate cancer to become resistant to ADT and how DPP4 inhibitors used to treat Type II diabetes influence prostate cancer progression. In our laboratory, we have used RNA sequencing technologies to identify factors in abiraterone-resistant prostate cancer that have not yet been studied and could be responsible for the resistance that develops in men with prostate cancer treated with abiraterone. Using these results in combination with experiments on mouse models of prostate cancer treated with castration and enzalutamide, I have identified the gene DPP4 as being significantly downregulated in resistant prostate cancer. DPP4 protein is an enzyme that targets numerous pro-survival growth factors for degradation and cancer cells would benefit greatly from downregulating its expression. Additionally, chemical inhibitors of DPP4 activity are widely used to treat Type II diabetes and, based on my preliminary research results, DPP4 inhibitor treatment makes prostate cancer more resistant to ADT. The studies in this proposal will seek to validate DPP4 downregulation/inhibition as a mechanism of ADT resistance in metastatic prostate cancer and identify the pro-survival growth factors degraded by DPP4 that are responsible for resistance. Additionally, through histological assessment of patient prostate cancer samples and collaboration with cancer epidemiologists, I will determine if there is a link between DPP4 inhibitor use in Type II diabetes and progression of metastatic prostate cancer. The proposed experiments would be the first in a sequence of studies that eventually could lead to treatments that target the pro-survival growth factors to overcome prostate cancer resistance that results from DPP4 downregulation, prolonging patient survival and increasing quality of life. Finally, if DPP4 inhibitor treatment in Type II diabetes is shown to be associated with increased resistance to ADT in men with metastatic prostate cancer, then the impact of this finding cannot be understated. There is likely significant overlap between the Type II diabetes and metastatic prostate cancer patient populations and many men who would be receiving both medications. A significant clinical association and strong preclinical data would immediately call for the careful examination of the use of DPP4 inhibitors to treat Type II diabetes in men with metastatic prostate cancer undergoing ADT. As a prostate cancer early investigator, my career goal is to become an independent academic research scientist with a focus on determining the causes of advanced metastatic prostate cancer resistance to ADT and developing therapies to combat this resistance. The studies proposed in this gra
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810531
Entities
People
- Joshua W. Russo
Organizations
- Beth Israel Deaconess Medical Center
- United States Army