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From OncoLog, August 2013, Vol. 58, No. 8

Graphic: In Brief

New Test Helps Identify Glioblastoma Patients Who Could Benefit from Bevacizumab

Glioblastomas that express low levels of genes associated with mesenchymal cells may be more sensitive than other glioblastomas to bevacizumab, according to a recent study.

In a correlative analysis done as part of a phase III clinical trial, researchers led by Erik Sulman, M.D., Ph.D., an assistant professor in the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center, sought to identify potential molecular markers for bevacizumab sensitivity in glioblastoma.

Glioblastoma is one of the most common and difficult to treat brain tumors. It is often very aggressive and has a high risk of recurrence, but the mechanisms of glioblastoma tumorigenesis and recurrence are still poorly understood. Consequently, despite much effort, the treatment options for these tumors remain limited.

Bevacizumab specifically targets vascular endothelial growth factor, which is a secreted protein involved in tumor growth and angiogenesis. It was previously known that some glioblastoma patients with recurrent tumors responded well to bevacizumab treatment and experienced longer progression-free survival and fewer symptoms than most patients with glioblastoma. This led to a multicenter phase III trial (RTOG-0825) to evaluate bevacizumab treatment for patients with newly diagnosed glioblastoma.

Dr. Sulman and colleagues sought potential molecular markers that would allow clinicians to identify which patients are most likely to respond to bevacizumab treatment. The researchers found that tumors with lower expression of some genes associated with mesenchymal cells responded better than other tumors to bevacizumab treatment. The researchers then used this information to create a predictive test for bevacizumab response.

Dr. Sulman said, “One of the key things about this predictor is that it’s designed to be used on archival tissue samples, so it doesn’t require fresh tissue.” This will allow the test to be used widely because surgical resection is the initial treatment for most patients with glioblastoma and the tissue obtained is most commonly stored as paraffin-embedded specimens.

The results of the study were presented at the annual meeting of the American Society of Clinical Oncology in June. In the future, Dr. Sulman and his colleagues hope to validate their predictive test in additional glioblastoma patients and assess whether the method is generalizable to other tumor types. These measures could help identify patients who will respond well to bevacizumab treatment.

Researchers Identify Potential New Target in EGFR-Activated Cancers

Epidermal growth factor receptor (EGFR), a well-known cancer drug target, regulates MCM7, a protein vital to the first step in DNA replication, a team led by researchers at The University of Texas MD Anderson Cancer Center reported.

MCM7 is important to DNA licensing, the initial step in DNA replication. MCM7’s function—which is often deregulated in human cancers—had not previously been tied to EGFR signaling, which leads to DNA synthesis and cell growth. The researchers found that EGFR activated MCM7 by activating another signaling molecule, Lyn.

“We established that this signaling pathway correlates with EGFR status and poor survival in breast cancer patients,” said Mien-Chie Hung, Ph.D., a professor in and chair of the Department of Molecular and Cellular Oncology and the study report’s senior author.

The researchers assessed the expression statuses of activated Lyn and MCM7 in tumor samples from breast cancer patients, and Kaplan-Meier analyses revealed that the overall survival rates of patients with low expression of either activated protein were significantly higher than those of patients with high expression of either activated protein. Seventy-five months after the completion of their initial therapy, about 60% of patients with high levels of activated Lyn or MCM7 expression were alive, whereas more than 80% of those with low levels of activated Lyn or MCM7 expression were alive.

In a mouse model of breast cancer, the researchers found that mice with high expression of either Lyn or MCM7 had tumor volumes that were two to three times larger than those of mice with low expression of either molecule.

Dr. Hung said, “Lyn overexpression might be indispensable for cancer cells that rely on EGFR signaling to proliferate,” which suggests that Lyn is a promising therapeutic target in EGFR-activated cancers. Drugs that target EGFR often become less effective over time, he noted, so Lyn provides a potentially effective target downstream from EGFR.

Lyn inhibitors have been tested preclinically and in an early-stage clinical trial. Combining Lyn and EGFR inhibitors could have a synergistic effect on EGFR-driven cancers.

The study’s findings were published in the June issue of Cancer Cell.

For more information, talk to your physician, visit www.mdanderson.org, or call askMDAnderson at 877-632-6789.

Other articles in OncoLog, August 2013 issue:

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