Spotlight on Research

Accelerate Brain Cancer Cure Project Award Recipient, Paul S. Mischel, M.D

Paul S. Mischel, M.D.
Neuropathologist and Cancer Biologist
David Geffen School of Medicine
Jonsson Comprehensive Cancer Center, UCLA

Each year, Accelerate Brain Cancer Cure funds leading investigators with novel translational research ideas that hold significant near-term potential to hasten a cure for brain cancer. One of our past awardees, Paul Mischel, M.D., from the David Geffen UCLA School of Medicine, focuses his work on the most common malignant primary brain tumor in adults (glioblastoma), which is among the most lethal of all cancers. “Survival with glioblastoma is usually approximately fifteen months from the time of diagnosis, so this is a very serious and challenging disease,” Dr. Mischel explained.

Mischel believes primary brain tumor patients are particularly suited to benefit from developments in the growing medical trend of predictive individualized care based on molecular classification and targeted therapy. “I would ask us to step back and think about how we would normally diagnose and treat cancer – there are individual differences in each patient’s cancer, yet we are not good at predicting how people individually should be treated,” Dr. Mischel noted.

“Numerous new therapies hold great promise for treating glioblastoma patients, but a key challenge is determining which treatment is most likely to benefit an individual patient,” said Kate Carr, Accelerate Brain Cancer Cure’s President and CEO. “Paul Mischel is a leader in the exploration of how the concepts of targeted molecular therapy and individualized medicine can be applied to brain cancer research.”

Diagnosis currently relies on the classification and grading of tumors according to what can be seen by a pathologist in a microscope and this provides little insight into the molecular makeup. Glioblastoma (GBM) is a molecularly diverse disease. Past data shows that patients with certain tumor molecular make-ups respond similarly to certain treatments, while others respond differently. Dr. Mischel commented, “There are emerging technologies through which we are developing an understanding of genes, proteins, and networks. Working with patient tissue samples, we can revolutionize therapies, and create paradigm shifts, including population-based risk assessments and predictive individualized care.”

This means that instead of applying a one-size-fits-all model, tumors would be molecularly evaluated to determine which treatments hold the greatest potential for success in each patient. This approach would redefine the nature of the diagnosis and the treatment of brain cancer.

In addition to providing more individualized therapy, this approach could, perhaps, prevent patients from undergoing unnecessary and expensive treatments and could allow some people to be treated with the most effective therapy immediately, before tumors can grow and develop new mutations that make them more difficult to treat. The overall goal of Dr. Mischel’s work is to identify and refine molecular subclasses and to show that molecular data can be incorporated into clinical decision making for brain tumor patients as it has for other cancer patients, such as the highly publicized estrogen-receptor and/or progesterone-receptor positive, Her2/neu-negative molecule in breast cancer.

In a study published in the Nov. 10, 2005 New England Journal of Medicine, Dr. Mischel and his colleagues performed genetic analysis on tissue from recurrent malignant glioblastoma patients, finding that this type of analysis can predict tumors’ sensitivities to specific drugs. The findings show that adjusting treatment based on each tumor’s genetic activity could significantly prolong life for some patients. Molecular information on clinical samples is becoming a reality and new drugs that block specific molecular targets are demonstrating clinical benefits. This type of “personalized therapy” is creating the next level of exciting therapies for many cancers.

Currently, Dr. Mischel and his colleagues are in the process of designing clinical trials to determine whether selecting treatment based on each tumor’s genetic activity can lead to better patient survival. They also want to examine other susceptibility factors to develop new treatments that target those factors, and try to learn how some patients become resistant to treatment. Dr. Mischel commented, “Researchers need to develop their genetic screening techniques into a diagnostic test so all glioblastoma patients can benefit – it is important to remember that we can also learn valuable lessons about what makes a person not respond to therapy.” Understanding the molecular mechanisms underlying these phenomena could enable the development of more effective combination therapies to induce long-term disease suppression or even a cure for brain cancer.

This research holds the potential to provide an entirely new and progressive paradigm in the diagnosis and treatment of brain cancer – and the design of smaller “SMART” clinical trials to better identify effective therapies in GBM. While brain cancer (glioblastoma) patients typically undergo aggressive surgery, radiation, and chemotherapy, the average one-year survival rate is still less than 30 percent. We believe we can do better and this research could yield a quantum leap in the numbers of therapies for GBM patients – from few effective therapies to several targeted therapies in individualized medicine.

 

Dr. Mischel has served on the UCLA School of Medicine faculty since joining the Department of Pathology and Laboratory Medicine in 1998. He became a full professor in 2006 and is currently the scientific director of the Sarkaria Biomarkers Program and the co-director of the Cancer Program Area for the UCLA Institute for Stem Cell Biology and Medicine. Dr. Mischel graduated with a B.A. in philosophy from the University of Pennsylvania in 1984 and earned his M.D. from Cornell University Medical College in 1991, graduating with Alpha Omega honors.

 

Dr. Mischel completed his residency training in anatomic pathology and his fellowship in neuropathology at UCLA. He fulfilled his post-doctoral training in the laboratory of Dr. Louis F. Reichardt at the Howard Hughes Medical Institute of UCSF, working on Trk receptor signaling in brain development. Since joining the faculty at UCLA, Dr. Mischel’s research focus has been the molecular pathogenesis of brain tumors and the development and implementation of novel targeted therapies.

 

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