UCSF project to explore mystery behind advanced prostate cancer

Many men survive prostate cancer, but thousands of others -- whose cancer spreads -- inevitably develop resistance to even the most promising treatments, leaving them with few medical options and a dwindling span of life. 

Now, armed with a new $10 million grant, a multi-center "dream team'' of scientists, led by UCSF, is embarking on a groundbreaking undertaking into personalized medicine. The goal: to overcome therapeutic resistance in the disease and revolutionize treatment for patients with advanced prostate cancer.

"I am incredibly excited about this project. It has the potential to completely transform the way we take care of our patients with advanced prostate cancer,'' said Eric J. Small, MD, a UCSF professor and deputy director of the UCSF Helen Diller Family Comprehensive Cancer Center. He is the principal investigator of the project.

"Despite a number of new drugs that have been approved for this disease, some of which we helped develop at UCSF, many of our patients still develop resistance to these agents and die from progressive disease,'' Small said. "This work will help identify the causes of resistance in an individual patient, and help us tailor therapy for that patient.'' 

Partnering on this west coast project are four campuses from the University of California (UCSF, UCLA, UC Davis, UC Santa Cruz), the Oregon Health & Sciences University, and the University of British Columbia.

The co-leader of the project is Owen Witte, MD, a professor of microbiology, immunology and molecular genetics and director of the Broad Stem Cell Research Center at UCLA.

Resistance to therapeutic approaches to cancer has become a core, baffling challenge for cancer scientists. Treatment of patients with hormone-dependent prostate cancer generally includes chemical or surgical castration, using drugs or surgery to reduce androgen hormones such as testosterone. But, as with most hormone-dependent tumors, the cancerous tumors often become resistant to treatment.

The dream team scientists will focus on identifying the causes of resistance in some 500 patients with advanced prostate cancer and tailoring therapy for them. Through this approach, known as precision or personalized medicine, the researchers hope that more effective therapies will be developed, and in the process, patients will be spared unnecessary treatment.

"So often when we start to use a new drug, the patient feels well and he responds well therapeutically -- you have a moment of hope,'' said Phillip G. Febbo, MD, a professor of medicine and urology, and co-director of the prostate cancer program at the UCSF Helen Diller Family Comprehensive Cancer Center. Febbo was the architect of the dream team, helping to design the proposal and to bring together the various participants and institutions.

"But all too soon, the hope fades,'' Febbo said. "The benefits of therapy become short-lived, the cancer figures out how to adapt to the therapy, and it begins to grow again. It is incredibly frustrating for the physician, and deeply disturbing to the patient and his family. This project centers on determining how the cancer so quickly learns how to outsmart our therapy.''

In the United States, prostate cancer is the second leading cause of death in men after lung cancer. A new case is diagnosed every 2.4 minutes, and one man dies every 18 minutes from it, according to the Prostate Cancer Foundation. Altogether, more than 2 million men in the U.S. have been diagnosed with the disease.

In about a third of cases, patients require no treatment because the cancer does not spread. In another third of cases, patients are treated and cured. But for the remaining patients, the cancer recurs after treatment or it spreads to the bones, lymph nodes or other parts of the body.

The dream team project, involving more than 30 investigators at the six institutions, consists of three components:

* Biopsies and blood samples of some 500 patients with advanced prostate will be obtained;

* The samples will undergo a comprehensive molecular assessment and pathway-based analysis - the scientists will search for biomarker predictors of sensitivity to specific therapies, along with predictors of resistance to the therapies; 

* Treatment approaches will be developed for each patient based on his individual genetic information.

Davide Ruggero, PhD, a UCSF associate professor of urology and the Helen Diller Family Endowed Chair of Basic Research in Urologic Cancer, will lead the development of genetically engineered mouse models to determine the pathways of therapeutic resistance. 

"Once we discover the mechanisms of resistance, we can develop new therapies,'' Ruggero said. "This is a very big problem and with this project, we are hoping to make a leap forward.''

Researchers at UC Santa Cruz will develop a novel application called MedBook to connect patients, doctors, and researchers. Inspired by social media, MedBook is the brainchild of UCSC graduate student and former Apple executive Ted Goldstein, who describes it as a "Facebook for cancer.''

MedBook will support information exchange and discussion, connecting researchers in a way that will help them work collaboratively to discover new models of disease and match patients with targeted treatments. This information will be instrumental to the team's clinical working group for recruiting patients to specific trials.

The grant, which will provide up to $10 million over three years, is funded by the Prostate Cancer Foundation and Stand Up To Cancer (SU2C). The American Association for Cancer Research - the scientific partner of SU2C - oversees the selection and grant administration process, and provides scientific oversight during the research phases.