Synthetic Lethal Metabolic Targeting of Senescent Cells after Androgen Deprivation Therapy
Abstract
Progression to castrate resistant prostate cancer for men with advanced prostate cancer (PC) results after the initiation of androgen deprivation therapy (ADT). One underutilized strategy that has the potential to dramatically improve outcomes is eradicating persistent senescent cancer cells that remain after ADT and likely play a key role in castration-resistant PC. We have demonstrated that ADT induces senescence in androgen-dependent PC cells and acts synergistically with the diabetes medication metformin to induce apoptosis in PC cells. ADT activates Akt, AMPK, mTORC1 and XIAP at various time points and silencing XIAP augments apoptosis induced by ADT, pointing to XIAP as a promising drug target to increase the activity of ADT in advanced prostate cancer. We have also shown that metformin enhances the antitumor activity of ADT in two PDX PC models. Analysis of the VA database revealed that metformin use in patients with advanced prostate cancer receiving ADT is associated with improved OS and cancer-specific survival. Our results point to metformin as a novel therapeutic strategy for castration-resistant PC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2019
- Accession Number
- AD1086161
Entities
People
- David F Jarrard
Organizations
- University of Wisconsin–Madison