Clinical studies indicate that a humanized monoclonal antibody against the Epidermal Growth FactorReceptor (EGFR), cetuximab, confers an objective tumor response in a subset of patients with metastaticcolorectal cancer. However, most patients do not respond to cetuximab and therefore receive limited or nobenefit from this drug. Currently, there is no test that can predict if a cancer will respond to cetuximab.Compelling evidence supports the view that targeting the receptor tyrosine kinases (RTK), particularly thosethat engage the Phosphoinositide 3-Kinase (PI3K) signaling pathways, is a highly effective strategy for killingfor cancers. Accordingly, the therapeutic response to anti-RTK therapy has been shown to be modulateddramatically by the mutational status of key signaling components in the PI3K pathway. The PI3K/Aktsignaling pathway drives many epithelial cancers, and its importance in colorectal cancers is underscored bythe presence of PIK3CA mutations (the gene encoding for PI3K) in 20-30% of these cancers. PI3K can beactivated by multiple different signaling pathways including EGFR, and there is accumulating evidence thatEGFR regulates PI3K via distinct mechanisms in cancers sensitive to anti-EGFR therapies. We propose tostudy the PI3K signaling pathway, biochemically and genetically, in colorectal cancers with the translationa)goal of identifying markers that will predict sensitivity to cetuximab. This will enable the selection of patientsthat are most likely to benefit from cetuximab. Additionally, these studies may also reveal additionaltherapeutic targets to enhance cetuximab sensitivity.
Our specific aims i nclude: (1) Identify the mechanismsfor activating the PI3K/AKT pathway in colorectal cancers; (2) To determine the differences in PI3Kregulation between cetuximab sensitive and resistant colorectal cancers in xenograft tumor models; (3) Todetermine if we can use the information discovered in the first two aims to identify markers that will predictwhich colorectal cancers will respond to cetuximab.Brief Summary: Cetuximab, a monoclonal antibody against the Epidermal Growth Factor Receptor, iscommonly used to treat patients with metastatic colorectal cancer. However, not all patients benefit from thistherapy and currently there are no reliable molecular markers to select patients that will benefit. The goal ofthis project is to find such markers that can be used to select patients most likely to respond to cetuximab.
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