Newswise — Researchers at UCLA's Jonsson Cancer Center have identified for the first time a way to predict which prostate cancer patients will benefit from an experimental therapy that blocks a cell signaling pathway responsible for driving the growth of the cancer.
The discovery, which appears in the most recent issue of the peer-reviewed journal Clinical Cancer Research, may allow oncologists to customize "targeted" cancer treatments for each patient based on the molecular make-up of their tumors. These "smart drugs" selectively stop the growth of tumor cells with the molecular abnormality. This is in striking contrast to chemotherapy drugs, which are not administered on the basis of the molecular abnormality responsible for the tumor, but rather target cell growth, resulting in significant toxicity as they destroy both normal and tumor cells.
"We have identified a set of biomarkers that allows us to chart a patient selection roadmap," said George Thomas, first author of the study, an assistant professor of pathology and a Jonsson Cancer Center researcher. "Not all prostate cancers share the same genetic abnormalities. We have discovered a way of identifying a specific set of abnormalities that makes the cancer very susceptible to these targeted drugs. We can now select the right patient for the treatment."
The study, done with Dr. Charles Sawyers, a Jonsson Cancer Center researcher and a Howard Hughes Medical Institute investigator, builds upon earlier work at UCLA done on cell lines and in animal models. It shows, for the first time, in tissues from men with prostate cancer how loss of PTEN, a gene that inhibits tumor growth, results in the uncontrolled activation of a tumor promoting protein, AKT. AKT then activates the enzyme mTOR, which subsequently activates S6. This is the basis of a tumor promoting cascade, similar to a domino effect. These biomarkers can be used to predict response to an experimental therapy known as CCI-779, an inhibitor of mTOR.
"We discovered that tumors missing PTEN seem to be very responsive to CCI-779, and it's very clear at a molecular biology level why," Sawyers said. "When you've lost PTEN, mTOR activity gets turned up and tumors become dependent on it for their growth. So a drug that inhibits mTOR should impact the tumor cells but have no effect on the normal cells."
When mTOR is inhibited, the cascade comes to a standstill and tumors stop growing. Prior to identifying this method, there was no molecular method to predict which men with prostate cancers would be sensitive to CCI-779, Thomas said.
About 220,000 men will be diagnosed with prostate cancer in the United States this year alone. Of those, about 25 to 30 percent are predicted to have tumors that are missing PTEN, Thomas said. So, theoretically, the experimental drug could potentially help about 60,000 prostate cancer patients a year, if the laboratory results are confirmed in clinical trials.
The trials, ongoing now at UCLA's Jonsson Cancer Center as well as MD AndersonCancer Center in Texas and Fox Chase Cancer Center in Philadelphia, seek to prove the drug is indeed hitting the intended target in patients and stopping growth of their cancer. The UCLA study is accepting patients with advanced prostate cancer now to participate. The study is part of the Specialized Program of Research Excellence (SPORE) in prostate cancer at UCLA's Jonsson Cancer Center, a program funded by the National Cancer Institute.
Using the same method they discovered for predicting the men who would do well on CCI-779, the UCLA researchers also will be able to determine if the drug is, in fact, working.
"This is exciting, when we can use these tests first to select the patients most likely to respond and then simultaneously to monitor the effect of the treatment," Thomas said.
The study "is a template for patient selection, when considering molecularly targeted therapies," Thomas said.
Dr. Jonathan Braun, professor and chairman of pathology and laboratory medicine at UCLA and director of the Tumor Immunology Program at UCLA's Jonsson Cancer Center, called the study results significant.
"We are learning that diseases are caused by abnormal cells that misbehave. Their misbehavior is due to abnormal molecules. We are now finding drugs that can inactivate or normalize these disease-related molecules," Braun said. "Thomas and Sawyers have uncovered biomarkers that we can detect to know which molecules are abnormal, and hence which drugs to use for treatment."
Prostate cancer is the most common type of cancer found in American men, other than skin cancer, and is the second leading cause of cancer deaths, according to the American Cancer Society. About 28,900 men will die of prostate cancer this year.
UCLA's Jonsson Comprehensive Cancer Center is made up of more than 240 cancer researchers and clinicians engaged in cancer research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson Center is dedicated to promoting cancer research and applying the results to clinical situations. In 2004, the Jonsson Cancer Center was named the best cancer center in the western United States by U.S. News & World Report, a ranking it has held for five consecutive years.
RSS