A common technique for thwarting cancer involves administering drugs that block the actions of errant proteins. But tumors can be crafty, and they often find ways to persevere. Occasionally, cancer cells will alter their genomes, creating mutations that restore signaling downstream of the targeted protein. Charles Sawyers first described this mechanism of resistance more than 15 years ago while studying ABL kinase inhibitor therapy in chronic myeloid leukemia. Since then, his insights have guided the development of next-generation targeted cancer therapies that can delay, or even prevent, resistance.
Most recently, Sawyers shifted his focus to prostate cancer and its resistance to hormone therapy. This work began with the observation that tumors resistant to anti-androgen hormone therapy often have increased levels of androgen receptor. In collaboration with Michael Jung at the University of California, Los Angeles, Sawyers and his team discovered a small-molecule inhibitor, called enzalutamide, that blocks the androgen receptor by preventing DNA binding and impairing nuclear translocation. Phase 3 clinical trials showed that enzalutamide prolonged survival, and the drug is now being used to treat metastatic prostate cancer.
Despite the clinical success of enzalutamide, drug resistance still remains a challenge. Sawyers’s recent studies reveal that prostate cancers treated with enzalutamide can develop resistance through mutations in the androgen receptor, or by bypassing the androgen receptor blockade. The molecular basis for this resistance includes genetic and epigenetic changes, and Sawyers is investigating strategies to obviate these changes by targeting chromatin-modifying enzymes.
Sawyers’s team is also participating in several prostate cancer genome sequencing projects that have revealed mutations associated with cancer initiation, progression, and resistance to hormone therapy. The team is currently exploring how these genomic alterations affect cellular function, using genetically engineered mouse models and primary prostate tissue organoid culture.
This research is also supported by the National Cancer Institute, Stand Up to Cancer, and the Prostate Cancer Foundation.