Eliminating Lethal Micrometastic Prostate Cancer Through High Intensity Short Duration AR Suppression
About Eliminating Lethal Micrometastic Prostate Cancer Through High Intensity Short Duration AR Suppression
- Current prostate cancer patient treatment protocols often comprise sequential therapies that target the androgen receptor (AR) pathway which prostate cancer cells are addicted to for growth and survival. Androgen deprivation therapy (ADT) is given initially, but once tumors develop resistance, patients may go on to receive the more potent AR-targeting therapies enzalutamide or abiraterone, to which they also inevitably become resistant.
- Dr. Taplin and team are leading clinical trials testing a high-intensity AR-inhibition strategy that combines three AR-targeting therapies (LHRH antagonist + abiraterone + enzalutamide) in previously untreated high-risk prostate cancer patients. Delivery of high-intensity AR-inhibition at a time when tumor cells have fewer genomic alterations and have not yet adapted to a lack of androgens may prohibit the evolution of treatment-resistance and progression to untreatable lethal disease.
- Whether high-intensity AR-inhibition better eliminates detectable disseminated tumor cells (DTCs) and reduces tumor recurrence compared with less intense AR-inhibition therapy (subtracting enzalutamide or abiraterone) will be determined. DTCs that survive treatment will be assessed for acquired mutations and genes expressed to determine mechanisms of resistance to high-intensity AR-inhibition. Finally, to determine if metastatic environments contribute to the resistance of tumor cells to high-intensity AR-inhibition, bone marrow and lymph node biopsies will be examined for gene expression, location of tumor cells, and the levels of androgens that can feed tumor growth.
What this means for patients: Designing treatment strategies that prohibit tumor cells from progressing to an aggressive treatment-resistant disease state is critical. This project will determine the efficacy of a high-intensity AR-inhibition strategy and discover tumor cell mechanisms of resistance. If successful, this project will result in new treatment paradigms that extend the lives of prostate cancer patients and may actually cure some with otherwise lethal disease.
Mary-Ellen Taplin, MD (Harvard: Dana-Farber Cancer Institute)
Rana Mckay, MD (Dana-Farber Cancer Institute); Eli Van Allen, MD (Dana-Farber Cancer Institute); Peter Nelson, MD (University of Washington, Fred Hutchinson Cancer Research Center); Cyrus Ghajar, PhD (University of Washington, Fred Hutchinson Cancer Research Center); Ken Pienta, MD, PhD (Johns Hopkins University); Ashley Ross, MD, PhD (Johns Hopkins University)