Gordon Mills, chair of the Department of Systems Biology at MD Anderson Cancer Center (MDACC) and a "Dream Team" co-leader in the Stand Up To Cancer (SU2C) program, has determined that amplification of certain mutant PIK3 alleles causes resistance to selective PI3K inhibitors in HER2-positive breast cancer. This amplification keeps the tumor cells alive. Therefore, for treatment to be effective in these breast cancers, both the HER2 and PI3 Kinase pathways must be targeted with combination therapies.
The PI3K pathway is now known to be the most commonly activated pathway in cancer. It is amplified in breast and ovarian cancer. Dr. Mills's team is working to develop therapies designed to block abnormal signaling in the PI3K pathway. They are undertaking clinical trials to determine which cancers will respond positively to these therapies. To that end, they conducted genome-wide screening in FFPE samples to detect copy number signatures that are markers of resistance to therapies that target the HER2 gene and inhibit the PI3K pathway. "A whole-genome approach is required to reveal what parts of the pathway are affected," he says. Ultimately, the team aims to identify all the genetic aberrations that can be targeted at once, so they can also identify other targets. Dr. Mills's team has multiple ongoing studies using several approaches based on detecting copy number mutations, known as C class mutations, from FFPE samples. These include studies that reveal the responses of specific tumors to different drugs. There has been remarkable progress in improving responsiveness to therapies in breast cancer, lung cancer, and melanoma by linking molecular changes to drugs.
Work such as this is changing the whole concept of companion therapeutics as we gain a better understanding of tumor biology. Five years ago the focus was on testing the effectiveness of available drugs. Now researchers focus on druggable targets. Dr. Mills anticipates that ultimately we will realize real cost savings by reducing ineffective therapies while advancing more personalized therapies.
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