Last week, cancer researchers gathered in Washington, D.C., to attend the American Association for Cancer Research (AACR) annual meeting. At the meeting, two large-scale projects to improve the treatment of prostate cancer and prolong patients’ survival were outlined in presentations by two prominent researchers and clinicians: Arul M. Chinnaiyan, MD, PhD, a professor of urology at the University of Michigan and director of the Michigan Center for Translational Pathology in Ann Arbor, Michigan, and Eric J. Small, MD, the deputy director of clinical sciences at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center.
The two initiatives represent the collaborative efforts of two new scientific ‘Dream Teams’ funded by the Stand Up to Cancer (SU2C) philanthropic program that was launched in 2008. There are now nine Dream Teams working on major cancer types and novel therapeutic approaches. These initiatives are unique inter-institution collaborations that take advantage of rapid translational research to benefit cancer patients. The two prostate cancer projects are additionally funded by the Prostate Cancer Foundation.
Dr. Chinnaiyan, a Dream Team leader, outlined the ‘Precision Therapy for Advanced Prostate Cancer’ project, which is a collaboration between seven U.S. and UK cancer institutes, including the University of Michigan and the Memorial Sloan-Kettering Cancer Center in New York City.
“The focus is bringing precision therapy to castration-resistant prostate cancer,” Chinnaiyan said. He and his collaborators aim to identify novel genomic targets for therapy development. Their work could serve as a model system for ways to bring precision medicine to other cancer types. The project will comprehensively sequence clinical tumor samples, including metastatic bone tumors, in order to identify novel ways to treat prostate cancer.
Chinnaiyan’s Dream Team is focused on the androgen receptor signaling pathway as well as the androgen-regulated ETS gene fusions. Thus far, the team has assembled all existing prostate cancer mutational data, including the more than 300 transcriptomes and 60 whole-genome sequences of prostate cancer. While whole-genome sequences represent the entire set of DNA sequences present in a tumor, the transcriptome is the set of all RNA molecules including their abundance in tumor cells.
“We are very excited, as this is probably the first of its kind: multi-institutional, prospective clinical sequencing programs that could provide the framework for drug development,” said Chinnaiyan.
Patients’ germline genomes, tumor genomes, and tumor transcriptomes will be sequenced to identify established or novel “actionable” mutations; that is, mutations that can be targeted by existing drugs or for which drugs could be developed. These molecular “snapshots” will be used to create a framework to develop new targeted therapies and new ways to understand whether a patient can benefit from a given therapy.
There are currently four clinical trials included in this project: two that focus on advanced prostate cancer patients who have previously been treated with the drug abiraterone and two that involve advanced cancer patients who have never been treated with abiraterone.
The researchers will also identify genetic predictors of why some patients respond to targeted therapies, as well as predictors of resistance to targeted therapies. The team will capture a molecular snapshot of each patient’s cancer and incorporate this information into the clinical trials.
After Chinnaiyan’s presentation, Dream Team Leader Eric J. Small discussed the ‘Targeting Adaptive Pathways in Metastatic Treatment-Resistant Prostate Cancer’ project. This ‘West Coast’ team consists of U.S. cancer centers, including UCSF and University of California, Los Angeles, as well as one Canadian institute, the Vancouver Prostate Center. This team will study signaling pathways in prostate cancer—including androgen receptor signaling, the PI3K, and MAPK pathways—that are important in resistance to therapies used to treat advanced prostate cancer.
In recent years, the FDA has approved six drugs for prostate cancer, including two agents—abiraterone acetate and enzalutamide—that target the androgen receptor pathway.
“The problem with these agents is that, while there is a 50% response rate, it is generally short-lived, and access to [advanced disease], which is primarily in the bone, is complicated and difficult,” Small said.
Small’s Dream Team aims to identify the adaptive tumor responses to treatment that lead to tumor resistance. If these resistance mechanisms can be identified and inhibited as part of primary therapy, that should lead to longer treatment responses and an impact on patient mortality, according to Small and his colleagues.
The team has designed a three-part approach that includes collecting patient biopsies and blood samples, comprehensive analyses of these samples to determine which pathways are active in these advanced tumors, and development of new individualized treatment approaches. The patient samples will be sequenced and analyzed for both RNA and circulating tumor cells.
Another important goal of the project is to create a central database and online platform that can be used for simple access and information sharing and to develop molecular disease models for prostate cancer. Pathway-guided treatment is the goal, Small said. “Using our data, we will validate targets and move forward with specific [clinical] trials based on these data to develop biologically-driven combination therapies.”
So far, one clinical trial that is part of this endeavor aims to identify novel resistance mechanisms to the drug enzalutamide.
Cancer Commons is participating in the West Coast Dream Team through collaboration with scientists from UCSC and UCSF. See our previous post, ‘Cancer Commons and the $10 Million Prostate Cancer Dream Team,’ for more info.