American Association for Cancer Research

SU2C-PCF Dream Team: Precision Therapy of Advanced Prostate Cancer

Overview:
Prostate cancer is the second most common cause of death for men in the United States. According to PCF, one man dies every 18 minutes from this disease. In addition, a new case occurs every 2.4 minutes. More than 2 million American men are currently living with prostate cancer and more than 16 million men are affected worldwide.

One avenue for treatment of patients diagnosed with prostate cancer is the reduction of androgen hormones, such as testosterone and dihydrotestosterone, by chemical or surgical means. However, as with most hormone dependent tumors, prostate cancer becomes resistant to hormone-deprivation therapy. This type of cancer is referred to as “castration-resistant prostate cancer” (CRPC).

Prostate cancer, like other types of cancer, is not a homogenous disease. The diversity in the genetic makeup of each individual’s cancer may explain why therapies that work for some patients seem ineffective for others. More and more, researchers and physicians realize that treatment decisions will require a personalized or precision approach whereby the type of treatment is chosen based on the specific genetic characteristics of a patient’s tumor.

The Stand Up To Cancer-Prostate Cancer Foundation Dream Team, led by Chinnaiyan and Sawyers, will harness the power of so-called next-generation sequencing technology to decode 500 patients’ cancer genomes, the 3.1 billion bases of DNA sequence which constitute the entire set of genetic instructions found in a cell. This state-of-the-art technology allows researchers to sequence entire genomes relatively inexpensively, yet with speed and accuracy never achieved before.

Armed with the information about the genetic makeup of these 500 CRPC patients, the Dream Team expects to be able to direct patients toward the treatment most likely to have an effect on their tumor. The hope is that this approach, often referred to as “personalized medicine,” will lead to more effective and lasting treatments, and potentially spare the patients from unnecessary treatments that are expensive, highly toxic and all too often provide little or no benefit.

Chinnaiyan and Sawyers have surrounded themselves with an all-star cast of world-class physicians, biologists, geneticists and bioinformatics specialists. This Dream Team will focus on patients with metastatic prostate cancer treated with abiraterone as well as participants in four clinical trials for novel therapies in metastatic CRPC. They will systematically evaluate patients to identify predictors for those patients whose cancer responds to these therapies, but also predictors of those patients whose cancers resist these therapies.

For patients with cancers that do not respond to a given therapy, the team will use individual genetic aberrations that might determine potential alternative therapeutic intervention. In parallel, the team will also perform preclinical studies of CRPC therapeutics to test these predictors of response and/or resistance. These in vivo functional studies will provide strong rationale for identifying and prioritizing therapeutic targets.

Specific Research Goals:

  • Establish a multi-institutional infrastructure incorporating five leading prostate cancer clinical sites and two sequencing and computational analysis sites that will coordinate sample and data acquisition and analysis;
  • Systematically evaluate biopsies from 500 patients with metastatic CRPC, using next-generation sequencing technology, to identify biomarkers of response to treatment; 
  • Conduct parallel preclinical studies to elucidate resistance and response mechanisms to treatment using panels of CRPC xenografts (mouse “avatars”); Conduct clinical trials of novel combinations targeting androgen receptor (AR) and/or PTEN pathway; and
  • Identify molecular determinants of response to PARP inhibitors, as well as molecular determinants of sensitivity and acquired resistance to abiraterone and MDV3100 in patients.

Amount of Funding:
$10 million over a three-year period

Leader:
Arul M. Chinnaiyan, M.D., Ph.D., clinical pathologist and investigator at the Howard Hughes Medical Institute; S.P. Hicks endowed professor of pathology and professor of urology at the University of Michigan

Co-Leader:

Charles L. Sawyers, M.D., chair of the Human Oncology and Pathogenesis Program at Memorial Sloan-Kettering Cancer Center and a Howard Hughes Medical Institute investigator; professor in the Cell and Developmental Biology Program and the Department of Medicine at the Joan & Sanford Weill Graduate School of Medical Sciences of Cornell University

Principals:

Johann S. de Bono, M.D. professor, Institute of Cancer Research, The Royal Marsden NHS Foundation Trust
Levi A. Garraway, M.D., Ph.D., assistant professor of medicine, Dana-Farber Cancer Institute
Philip W. Kantoff, M.D., professor of medicine, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute
Peter S. Nelson, M.D., assistant professor, Division of Human Biology, Fred Hutchinson Cancer Research Center
Mark A. Rubin, M.D., director, Translational Research Laboratory Services, Weill Cornell Medical College of Cornell University

Page updated: September 4, 2012