Their study, the first to uncover a new role for this powerful gene, may lead to clinical “barcoding” of a patient’s prostate cancer to help direct therapy
(PHILADELPHIA) – The retinoblastoma tumor suppressor gene (Rb), long thought to protect cells against cancer development, appears to play a very different role in prostate cancer, say scientists at the Kimmel Cancer Center at Thomas Jefferson University. As reported today, disruption of this gene now appears to be a major factor contributing to therapeutic failure.
Their study, published in the December issue of the Journal of Clinical Investigation, shows that loss of either the Rb gene or its protein is a major contributor of progression to the incurable “castration resistant” stage of the disease – cancer that no longer responds to standard androgen deprivation therapy, and is linked to poor survival. In other tumor types, Rb is generally viewed as a powerful tumor suppressor through its ability to block cell division. In fact, Rb loss is associated with development of up to half of all solid tumors, including breast and lung cancers.
The first clues that Rb was doing something different in prostate cancer came when postdoctoral fellow Ankur Sharma, Ph.D., and the study’s lead investigator Karen E. Knudsen, Ph.D., a Professor of Cancer Biology, Urology, & Radiation Oncology, found this paradigm did not hold true for human prostate cancers. In these tumors, the researchers observed that Rb loss was strongly associated not with prostate cancer development but with advanced disease that responds poorly to therapy. Further, Dr. Knudsen and her collaborators found that if they reduced Rb levels in human prostate cancers grown in a dish or in a mouse, tumors did not ramp up their growth. That suggested Rb was not acting in its canonical tumor suppressor role, of controlling cell division.
In the laboratory, the researchers then mimicked androgen deprivation therapy, which is the mainstay of treatment for patients whose tumors have spread beyond the prostate. “We took tumors that still responded to androgen deprivation therapy, and suppressed Rb. All of a sudden these tumors grew,” Dr. Knudsen says. “With Rb, tumors respond to androgen deprivation therapy. Without Rb, they don’t.”
Androgen deprivation therapy acts by blocking the action of the androgen receptor, and prostate cancer cells are typically ‘addicted’ to androgen receptor action, Dr. Knudsen says. “We found that in human prostate cancers, Rb loss allows for enhanced production of the androgen receptor. This event overwhelms androgen deprivation therapy,” she says. “In effect, Rb serves a special role in prostate cancer by limiting androgen receptor production, activity, and resultant tumor cell growth. Conversely, Rb loss releases that brake, androgen receptors are then overproduced, and the transition to castration-resistance can ensue. ”
Linking Rb loss to therapy- resistance in prostate cancer explains a puzzle long seen in treatment clinics – why it is that a subset of prostate tumors suddenly displays dramatically high levels of the androgen receptor, says Dr. Knudsen. “This finding was unexpected, as it provides some of the first evidence that tumor suppressor genes can control progression to an incurable phase by dampening androgen action. However, it was necessary to further test these ideas in samples from patients who sadly failed androgen deprivation therapy.”
The research team from Thomas Jefferson University/Kimmel Cancer Center then worked collaboratively with Peter Nelson, M.D., and his associates at the University of Washington and the Fred Hutchison Cancer Research Center, which has expertise in analyzing tumors from patients that have failed therapy. Together, they found loss of Rb occurred with high frequency in the therapy resistant tumors, and corresponded to high levels of the androgen receptor. “So what we had seen in our laboratory and animal models of human disease studies held true in patients as well,” Dr. Knudsen says.
The researchers say these new findings may prove useful in a number of ways.
One is that researchers may be able to “barcode” prostate tumors in the same way that breast cancer is molecularly profiled, in order to help direct clinical therapy.
“Based on our data, Rb status in a prostate tumor may tell us whether or not a patient is likely to respond to androgen deprivation therapy,” Dr. Knudsen says. “Currently, we have no way of knowing that.”
Multiple tests are being developed to check for presence of the Rb gene in tumor samples or for Rb protein – in much the same way that breast cancer screens look for the presence of estrogen and progesterone receptors and HER2 genes, she says.
Furthermore, now that oncologists know the molecular reasons why Rb-deficient tumors may not respond to androgen deprivation therapy, it may be possible to design new therapies that interrupt the pathway that leads to, or is associated with, Rb loss, says Dr. Knudsen. In this study, the research team detailed a number of molecular players in that pathway, and new clues in the laboratory have uncovered novel means to more effectively treat tumors showing Rb loss.
“Based on what we’ve seen so far, assessing Rb status in a tumor may provide a means to tailor therapeutic intervention for better outcomes,” says Dr. Knudsen. “We are well into the next steps, and with appropriate support, we hope to move our ideas into the clinic as quickly as possible.”
“This was a team science initiative, wherein basic scientists and expert clinicians from the Greater Philadelphia Prostate Cancer Working Group and beyond worked together to model and test our hypotheses in the condition that matters most – human disease,” Dr. Knudsen adds.
This study was funded by grants from the National Cancer Institute, the Department of Defense Pre-doctoral Prostate Cancer Fellowship Program, and the Prostate Cancer Foundation.
The authors declare no conflicts of interest.