Cancer Biology, Medicine and Translational Research
Memorial Sloan Kettering Cancer Center
Charles Sawyers is also director of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center.
Mechanisms of Prostate Cancer Initiation and Progression
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.
Charles Sawyers is using a detailed understanding of tumors’ survival strategies to create cancer treatments that are molecularly fine-tuned to defeat drug resistance.
Sawyers began studying BCR-ABL, the defective enzyme that drives the overproliferation of white blood cells in patients with chronic myelogenous leukemia (CML), as a postdoctoral fellow in the laboratory of HHMI Investigator Owen Witte at the University of California, Los Angeles (UCLA). Sawyers went on to join the faculty at UCLA, where he began a collaboration with Brian Druker of the Oregon Health & Science University (now an HHMI investigator) and became involved with the early clinical trials of Gleevec, a drug that wipes out cancer cells by blocking BCR-ABL. The drug was remarkably effective: six months after clinical trials began, remissions had occurred in all patients.
“It was a transforming experience to participate in something that played out exactly as the work in the laboratory would have predicted,” says Sawyers. “It created in my mind a sense of urgency that there are things we know now that could really change patient care.”
Over time, however, patients began to relapse. “Patients were responding to Gleevec, then they’d completely lose their response and the leukemia would come roaring back,” says Sawyers.
Sawyers and his team discovered that mutations affecting a particular part of the BCR-ABL enzyme can lead to Gleevec resistance. By examining the structural consequences of those mutations, they predicted that a drug designed to bind in a different way to BCR-ABL might effectively block its activity, even in patients whose cancer had become resistant to Gleevec.
Sawyers worked with scientists at Bristol-Myers Squibb to design a second-line therapy for people who no longer responded to Gleevec. In clinical trials led by Sawyers and collaborators at MD Anderson Cancer Center, that drug, dasatanib (marketed as Sprycel), was found to be effective against all but one commonly occurring BCR-ABL mutation. “That’s now the last nut to crack with CML,” Sawyers says.
The FDA approved Sprycel for the treatment of Gleevec-resistant CML in 2006, and as a first-line treatment for CML in 2010. A potential treatment for patients with that stubborn BCR-ABL mutation, T315I, is now in clinical trials. Sawyers believes physicians will one day be able to offer patients a pill containing a cocktail of BCR-ABL inhibitors that work against all common mutations of the enzyme, dramatically reducing the likelihood of drug resistance.
Sawyers moved from UCLA to Memorial Sloan Kettering Cancer Center in 2006, drawn to opportunities for synergy between research and patient care.
Today, his focus is on developing new treatments for prostate cancer patients who have developed resistance to hormone therapy. Resistance can arise when receptors for the androgen hormone mutate or when new receptors are produced, so Sawyers and his colleagues are looking for ways to block hormone binding.