Collaborative Effort Aims to Find Strategies to Preempt Resistance to Prostate Cancer Therapies

The ‘Targeting Adaptive Pathways in Metastatic Treatment-Resistant Prostate Cancer’ 3-year project aims to understand how prostate tumors become resistant to two newer drugs for prostate cancer that target the androgen receptor pathway—enzalutamide and abiraterone acetate.

“What we are interested in is to understand much better what happens [at the molecular level], when the cancer becomes resistant to these drugs,” says Tomasz M. Beer, MD, professor of medicine and deputy director of the Oregon Health and Science University Knight Cancer Institute. Beer is one of the four principle investigators, two team leaders, and many researchers and clinicians involved in the collaboration. Team members are from six cancer centers on the west coast, including one in British Columbia, Canada.

“This new generation of drugs in prostate cancer is really changing the management of the disease,” Beer says. But some patients do not respond to these drugs and development of resistance is almost inevitable.

The team wants to ‘change the game’ of prostate cancer treatment to significantly impact the survival of those with advanced prostate cancer. “We are trying to replicate what happened with both tuberculosis and HIV,” Beer says. Treatments for both of these diseases evolved from being barely effective to curative, thanks to multidrug approaches.

The crux of the project is serial collection of tumor and blood samples from at least three categories advanced disease patients: those who are already resistant to either androgen receptor inhibitors, those who are resistant to chemotherapy, and those who have just started abiraterone or enzalutamide treatment. The researchers will use the samples to identify mutations that are linked to resistance and pathways that become important when a cancer stops responding to treatment. They hope to use the information to design new therapies for prostate cancer. Targeted agents that are already available for other cancer types may also be used if the pathways targeted are also found to be important in prostate cancer.

“What is unique is that this project brings researchers around a single problem,” Beer says. “It turns these six institutions into a single organism.” The team members will share all cancer samples to tackle the goal from different angles.

Using a clinical laboratory that is certified to provide molecular information to patients, researchers at the Knight Cancer Institute will analyze mutations in samples from patients currently in treatment, providing results in a matter of weeks. Beer says the idea is to find mutations that will allow clinicians to select better therapies for these patients. Options may include enrollment in clinical trials or the use of a drug available for treatment of another cancer, but not yet for prostate cancer, called ‘off-label’ use.

“We hope to be a lot smarter about using agents to treat prostate cancer going forward,” Beer says.

The study will accumulate detailed molecular and clinical information from each participating patient. A portion of the project is focused on creating a data-sharing platform that will store confidential patient data, allowing patients to access their own information.  This goal is still in very early stages—the database does not exist yet.

The effort is one of two large, collaborative prostate cancer projects funded by the Stand Up to Cancer (SU2C) philanthropic program, launched in 2008, with contributions from the Prostate Cancer Foundation. The projects, announced in March, are linking clinical and basic research. The ultimate goal is to develop new treatments and combination therapies to prevent, or at least stave off, resistance to these drugs.