Synthetic Lethal Metabolic Targeting of Senescent Cells after Androgen Deprivation Therapy
Abstract
An underappreciated area of prostate cancer management is the persistent cancer cells that remain after treatment with androgen-deprivation therapy (i.e., hormone removal) for advanced prostate cancer. Eradication of these persistent prostate cancer cells is likely to be critical to improve treatment outcomes. Our research has demonstrated that these persistent cells often adopt a "senescent" phenotype in which they stop growing, but survive and secrete substances that promote tumor growth. We have discovered that these persistent cells have certain characteristics that may make them susceptible to cell killing through exposure to drugs that effect metabolism, specifically metformin, a commonly used oral agent used to treat diabetes with a proven safety record. Senescent cells are highly metabolically active and show signs of "proteotoxic stress" due to their high rates of protein synthesis. In this proposal, we will examine the hypothesis that this "proteotoxic stress" represents a potential "Achilles heel" that plays a key role in the therapeutic response of prostate cancer cells to the combination of hormone removal and metformin. Specifically, we will test this novel approach in cell culture models and clinically relevant mouse modes of human prostate cancer and develop markers that predict treatment response. In addition, we will examine prostate cancer progression data from the Veterans Affairs Hospitals system to determine whether diabetic men with advanced prostate cancer on androgen deprivation therapy who were treated with metformin had better prostate cancer survival rates than diabetic men who were not treated with metformin. Our studies could lead to a new treatment paradigm for prostate cancer to eradicate persistent senescent cells after hormone removal that has the potential to dramatically improve treatment outcomes. This study addresses the development of cancer resistance in men and furthermore could be readily translated into the clinic since both metformin and androgen-deprivation therapy are safe and currently in use.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610279
Entities
People
- Vincent Cryns
Organizations
- United States Army
- University of Wisconsin–Madison