Durden & Castellino Discover New Biomarker for Medulloblastoma Tumor Growth

Dr. Donald Durden

La Jolla, July 14, 2010 – In an investigative study published in May 2010 Issue of PLoS One, Dr. Donald Durden, Vice Chair of Research, Department of Pediatrics, UC San Diego and Rady Children’s Hospital, teamed up with Dr. Craig Castellino at Emory University to report a new role for the PI-3 kinase signaling pathway in a pediatric brain tumor. Dr. Durden, who developed the first PI-3 kinase inhibitor to enter human clinical trials in cancer cells, has discovered a new marker for tumor-growth and prognosis in medulloblastoma: PTEN expression.

Medulloblastoma is the most common malignant brain tumor of childhood. Although several effective modes of therapy are used in combination – surgery, radiation, and chemotherapy - these treatments often leave long-term toxins that severely devastate the neurocognitive abilities and growth potential of the survivors. In an effort to develop more effective, and less toxic therapies, Durden turns to understand the signaling mechanisms that trigger medulloblastoma tumor growth in the first place.

In molecular biology, phosphatase and tensin homolog (PTEN) is a protein that, in humans, is encoded by the PTEN gene. PTEN acts as a tumor suppressor gene through the action of its phosphatase protein product. This phosphatase is involved in the regulation of the cell cycle, preventing cells from growing and dividing too rapidly. During tumor development, mutations and deletions of PTEN occur that inactivate its enzymatic activity leading to increased cell proliferation and reduced cell death.

While scientists have known for years that PTEN inactivation occurs in glioblastoma, endometrial cancer, prostate cancer, and reduced expression in many other tumor types such as lung and breast cancer, this is the first discovery of its role in medullablastoma – a cancer prevalent among children and adolescents.

The study was done using a mouse model as the basis. Castellino and Durden crossed mice with constitutive activation of Smoothened, SmoA1, with Pten deficient mice. Both constitutive and conditional Pten knockout doubled the incidence of mice with symptoms of medulloblastoma and resulted in decreased survival. Analysis revealed a clear separation of gene signatures, with up-regulation of genes in the PI-3 kinase signaling pathway. Interestingly, in contrast, Pten deficient tumors exhibited extensive nodularity with neuronal differentiation separated by focal areas of intense staining for proliferation and virtually absent programmed cell death. This correlated with examinations of human medulloblastomas which revealed low to absent Pten expression in over half of the tumors. This analysis confirmed worse overall survival in patients whose tumor exhibited low to absent PTEN expression.

“This discovery suggests PTEN expression is a new biomarker that predicts survival in medulloblastoma,” Dr. Durden remarks. “Not only will it help in determining a patient’s the prognosis, this suggests new possibilities in developing therapeutics for the treatment of medulloblastoma including the application of PI-3 kinase inhibitors to patients where the tumor is missing PTEN.”

Written by: Shivani Singh, Sr. Writer, Department of Pediatrics s1singh@ucsd.edu

SCIENTIFIC CONTACT: Dr. Donald Durden, MD, PhD, Vice-Chair of Research, UCSD Department of Pediatrics. ddurden@ucsd.edu