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
Resistance to molecularly targeted cancer therapies often occurs through mutations/genomic alterations that restore signaling downstream of the targeted pathway, a mechanism we first described more than 15 years ago with ABL kinase inhibitor therapy in chronic myeloid leukemia. These insights guided the development of next generation targeted therapies that can delay or prevent resistance. Our current focus is on prostate cancer and mechanisms of resistance to hormone therapy. This work began with our observation of increased levels of androgen receptor expression in tumors that progress to the hormone-refractory stage, which we found was necessary and sufficient to confer resistance to current antiandrogens. We then collaborated with chemist Michael Jung (University of California, Los Angeles) to discover the small-molecule inhibitor (enzalutamide) that inhibits androgen receptor in hormone-refractory disease by blocking DNA binding and impairing nuclear translocation. Enzalutamide is now a widely used therapy for metastatic prostate cancer based on phase 3 clinical trials showing prolonged survival.
Despite the clinical success of enzalutamide, drug resistance remains a challenge. Our recent studies reveal that prostate cancers treated with enzalutamide can develop resistance through mutations in the androgen receptor, through bypass of androgen receptor blockade by signaling through the glucocorticoid receptor or by lineage plasticity, whereby androgen-dependent luminal epithelial cells undergo an identity change to more basal-like epithelial cells. The molecular basis for these resistance mechanisms includes genetic as well as epigenetic changes and point to new strategies to overcome resistance through targeting chromatin modifying enzymes. These findings reveal the complexity and context dependence of adaptive responses to targeted therapy and reinforce the importance of combination therapy to achieve long term clinical benefit.
We are also active participants in prostate cancer genome sequencing projects that have revealed a heterogeneity set of mutations associated with prostate cancer initiation, progression and resistance to hormone therapy. We are currently exploring the functional consequences of several of these genomic alterations (ERG, ERF, FOXA1, FOXP1 and SHQ1) using genetically engineered mouse models and primary prostate tissue organoid culture.
In addition to HHMI, work in my laboratory is supported by the National Cancer Institute, Stand Up to Cancer and the Prostate Cancer Foundation.
Cancer cells are crafty, but Charles Sawyers knows from experience that detailed understanding of a tumor's survival strategies can help scientists develop better treatments. Sawyers and other researchers have built on the success of the molecularly targeted cancer drug Gleevec (imatinib) to develop a new generation of treatment options for patients.
Gleevec blocks activity of the Abelson tyrosine kinase (ABL) enzyme, which is activated when a chromosomal mix-up occurs during blood cell development. The genes abl and bcr, located on different chromosomes, fuse and express a hybrid BCR-ABL enzyme that is always active; this hyperactive BCR-ABL drives the overproliferation of white blood cells that is the hallmark of chronic myelogenous leukemia (CML).
Building on the development of Gleevec as a model, Sawyers contributed to the design of a new cancer drug called Sprycel (dasatinib), which overcomes resistance to Gleevec in some patients. His approach combines genetic studies of patients' DNA with structural biology data. This paradigm worked well for Gleevec, Sawyers says, and there is reason to believe that it will aid in developing new drugs for other cancers, including prostate cancer and glioblastoma.
Sawyers collaborates with structural biologists whose studies are crucial for seeing how drugs “fit” with a potential target, usually a protein in the body. This information can tell scientists how well a drug might prevent or enhance a protein's function. The genetic studies involve sequencing each patient's resistance-enhancing mutation to understand how a drug responds to each mutation as it develops.
Looking back, Sawyers says he could not have predicted that he would conduct patient-oriented translational research. “The truth is that I never really thought it would play out this way as a postdoc or early faculty member,” he says.
Sawyers connected his laboratory and clinical work when he began working with Gleevec. He had first studied BCR-ABL in 1988 while a postdoctoral fellow in the laboratory of HHMI investigator Owen Witte at the University of California, Los Angeles (UCLA). He continued to focus on BCR-ABL when he joined the faculty at UCLA but began to see the impact that translational research could have for patients when he became involved with the early clinical trials that evaluated Gleevec and collaborated with other translational researchers, most notably Brian Druker of the Oregon Health & Science University, now an HHMI investigator.
“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 that we know now that could really change patient care.”
Over time, however, some of the patients who responded so well to Gleevec began to relapse. “Patients were responding to Gleevec, then they'd completely lose their response and the leukemia would come roaring back,” says Sawyers. “This happened despite the fact that they were still on the drug. It is a puzzle that we are still trying to solve.”
Sawyers began working with scientists at Bristol-Myers Squibb on a new drug designed as a second-line therapy for people who no longer responded to Gleevec. In clinical trials led by Sawyers and collaborators at M.D. Anderson Cancer Center, Sprycel was shown to be effective against all but one of the commonly occurring BCR-ABL mutations. “That's now the last nut to crack with CML,” Sawyers says.
A potential treatment for patients with that stubborn mutation, T315I, is now in phase I clinical trials. Ultimately, Sawyers believes physicians will 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, where he was an HHMI investigator, to Memorial Sloan Kettering because of the close interactions between its hospital and research institute. “It's a great environment for synergy,” he says.
Sawyers' current focus is on developing new treatments for patients with prostate cancer who have developed resistance to drugs that fight the cancer by blocking male sex hormones, called androgens. Resistance to drug therapy can arise when androgen receptors mutate or when new receptors are produced. Sawyers and colleagues have used their knowledge about how one of these drugs (bicalutamide) works to find ways around this resistance. One promising candidate is now being evaluated in a clinical trial.
“There are so many ideas that you can really move them into the clinic now,” he says. “If you do this with the scientific tools of genetics and genomics in your back pocket, you can pick the patient population intelligently and make progress much faster. That's the idea.”