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Physicians Update

 
Spring 2012

New Research Focuses on Diverse Nature of Deadliest Form of Brain Tumor

While advances in surgical techniques, including use of functional brain mapping and diffusion tensor imaging tractography, along with, radiation and chemotherapy treatments have extended average survival for patients with glioblastoma multiforme (GBM), a key to fighting this most common and deadliest form of malignant brain tumor in adults is to unravel the heterogeneity of the disease.

Dr. Linda Liau is working in the lab to understand the diverse nature of glioblastoma multiforme.

"There are three to four subgroups of glioblastomas that differ by patterns of gene expression and by patients' clinical characteristics," explains neurosurgeon Linda M. Liau, M.D., director of the UCLA Brain Tumor Program. "In the last few years, we've observed that, based on these subtypes, some patients do well on standard therapies, while others live longer when we supplement standard therapies with newer approaches, such as immune-based therapies (i.e., brain-cancer vaccines) or molecularly targeted drugs."

By more precisely characterizing each tumor, Dr. Liau says, the development of personalized treatments leading to better outcomes is possible. "If you can screen for genetic mutations and develop drugs that can potentially target those mutations, then you can potentially treat that person with drugs that block a low-grade tumor from becoming a high-grade tumor," Dr. Liau says.

"Brain cancers are tricky," says UCLA pediatric neurologist Harley I. Kornblum, M.D., Ph.D. "Not only are there different kinds of tumors, there are different kinds of cells within the tumors that respond differently to specific therapies." To better understand why certain therapies kill malignant cells in some tumors and drive their proliferation in others, Dr. Kornblum studies brain-tumor stem cells in order to identify critical pathways that undermine therapeutic effectiveness.

MRI Diffusion Tensor Imaging (DTI) tractography enables fiber tracking of subcortical tracts (white matter) relative to tumor (yellow object on figure).

"We've been able to establish cultures from a large variety of patients, grow large numbers of cells from these cultures, and then test the ability of thousands of molecular compounds in order to identify several that may be good lead compounds to develop into potential drugs," Dr. Kornblum says. An important area of focus is the isocitrate dehydrogenase-1 (IDH1) mutations, which are found in more than 75 percent of lower-grade gliomas (grades II-III) and secondary glioblastomas (grade IV) in humans.

UCLA experts have established the infrastructure to support research that will advance what is known about the mechanisms underlying glioma development and progression, improve understanding of the role of metabolic defects in causing brain cancer and potentially lead to the development of novel molecularly directed therapies targeting glioma-cell metabolism.

"We have put a very clean signature on how, why and where these tumors form that probably could not have been done by any other group in the country because of the way we collect and harness data," says Timothy Cloughesy, M.D., director of the UCLA Neuro-Oncology Program. Only 5 to 10 percent of patients with brain cancer enroll in clinical trials, and data for the remaining is lost. At UCLA, however, tumor specimens and data have been collected on all patients with brain cancer since 1999, approximately 5,000 cases to date. According to Dr. Cloughesy, in the next five-to-10 years, researchers will be able to better characterize each tumor, opening the door for development of more personalized therapies for GBMs.





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