M.D. Anderson Cancer Center

“Identification of compensatory molecular pathways using functional genomic and synthetic lethality screening in glioblastoma treated with PI3K inhibitors”

The goal of Dr. Yung’s study is to evaluate the potential of combination cancer therapeutics specifically directed against multiple molecular alterations that underlie the malignant phenotype to offer a new therapeutic strategy.

Dr. Yung will conduct investigations based on the current understanding that kinases and phosphatases are abnormally regulated in many cancers including glioblastoma.  These signaling abnormalities represent important therapeutic targets for the development of highly specific compounds to inhibit these abnormal signals that drive tumor progression through tumor cell proliferation, invasion, and angiogenesis.

Dr. Yung will work to better understand if and how tumor heterogeneity and complex compensatory or collateral pathways may negate the therapeutic efficacy of suppressing a single target.  He theorizes that a novel approach using technologies like siRNA, oncogenomic and reverse phase protein microarrays (RPPA) has major strengths in identification and validation of synergistic therapeutic targets, in characterization of signaling pathways and networks, as well as in determination of on- and off-target activity of novel drugs.

In this project, Dr. Yung will employ a systematic and multi-pronged approach for identifying novel targets that have a synergistic effect on tumors treated with PI3 kinase (PI3K) inhibitors.
To identify co-targets, he aims to obtain and integrate data from 1) high-throughput oncogenomic analysis, 2) proteomics, and 3) functional RNAi screening to identify compensatory pathway activation and resistance to PI3K inhibitors. He will conduct studies in a panel of established glioma cell lines and glioma stem cell lines bearing different PTEN and EGFR signatures.

The outcome of this project will be the identification of co-targets that, when inactivated, confer lethality to tumors in combination with the PI3K inhibitor, PX-866. Dr. Yung’s studies will further advance our knowledge of complex signaling pathways and mechanisms of tumor escape in response to molecular targeted agents.



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