Apr. 18, 2007 Genetic and epigenetic variations ensure that no two people are exactly alike, and the same holds true for any two cancers. Now, researchers have the tools and the knowledge to help predict how individuals will respond to cancer therapies, enabling them to create more effective therapies for individual cancers -- personalized medicine. At the 2007 Annual Meeting of the American Association for Cancer Research, researchers present new biomarkers -- and techniques for determining biomarkers -- that could determine how an individual might respond to drug or radiation therapy.
A new high-throughput genetic analysis technique can reveal gene markers -- by the dozens -- that determine how a patient might respond to certain cancer drugs, according to scientists at the Translational Genomics Research Institute (TGen). The TGen researchers have found 164 genes that are involved in regulating the sensitivity of squamous cell head and neck cancer cells to lapatinib, a cancer drug that was recently approved for use in metastatic breast cancer under the name Tykerb.
The study, a collaboration with GlaxoSmithKline, evaluated 7,000 genetic targets in human head and neck cancer cells to discover specific genes that might shade an individual's response to Tykerb.
"Our goal is to apply advanced cellular genomic strategies to assist clinical drug development by finding gene states that predict a patient's response to a specific drug, and which combination of drugs produce the most favorable response." said Spyro Mousses, Ph.D., director of the Pharmaceutical Genomics Division at TGen. "In this study, we were able to discover new candidate gene states that may be useful in determining a patient's sensitivity or resistance to Tykerb, and the results have revealed several sensitizing drug targets that reveal a set of candidate combination drugs that are predicted to be synergistic with Tykerb."
Tykerb is an enzyme inhibitor that effectively blocks two cell receptors, ERBB2 and EGFR, from receiving molecular signals. By blocking these signals, Tykerb could effectively shut down the growth of solid tumors, such as those found in breast, lung and head and neck cancer. However, molecular mechanisms within the cell, largely determined by genetics, could determine how effective cancer drugs are for a particular recipient, Mousses said.
To search for target genes that regulate Tykerb response, Mousses and his colleagues performed a genome-scale scan of two cancer cell lines using high-throughput RNAi, "interfering" RNA strands that bind to and knock out one gene individually, across the genome. It is a systematic and highly efficient technique that uses high-speed mechanization to quickly evaluate how specific genes might affect the cell's sensitivity to an agent, Tykerb in this case.
The TGen researchers are currently in the process of refining their genetic "hits" and learning more about how cancer specific variations in these sensitizing genes might further affect Tykerb response. While their findings are still at a preliminary stage, Mousses and his colleagues believe their studies will provide important insights into how to predict oncology drug response and much needed genomic intelligence to support commercial drug development.
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