The translational goal of this project is to conduct mechanistic studies on a novel molecular switch between PI3K/AKT and PDPK1/TORC that could lead to resistance to PI3K and AKT inhibitors;and of amino acid forms of mutant KRAS that activate different downstream signaling pathways that could lead to resistance to specific therapies and then two novel clinical trials with PI3K, AKT and MEK inhibitors, namely 1) an adaptively randomized multiarm targeted Phase II clinical trial and 2) a post-treatment biopsy Phase II trial of the AKT inhibitor MK-2206 in PTEN negative and positive CRC. The hypothesis to be tested in this proposal is that the phosphatidylinositol 3-kinase (PI3K) and RAS signaling pathways play major roles in CRC development and when aberrantly regulated make CRC resistant to many new molecularly targeted therapies.
Three specific aims are proposed to test this hypothesis, and include: 1) determine the mechanisms of alternate pathways of PI3K signaling for sensitivity and resistance to targeted therapy for CRC;2) determine the mechanisms of alternate downstream signaling by different amino acid-substituted forms of mutant KRAS for sensitivity and resistance to targeted therapy for CRC;and 3) conduct clinical trials of inhibitors of AKT, PI3K, and mut-KRAS signaling in patients with advanced CRC using patient tumor biopsy results to identify potential biomarkers for selecting patients with CRC for therapy. We will use a panel of CRC cell lines and isogenic mutant KRAS immortalized colonic epithelial cell lines in mechanistic studies in aims 1 and 2. Patient-derived CRC tumorgrafts will facilitate a direct comparison of tumor responses to drug treatment in vivo with patient response to therapy in aim 3. The long-term goal of this project is to develop an understanding of the mechanisms of resistance to therapy for CRC so that we can design more effective therapies, identify new drug targets for treatment, and develop biomarkers that identify CRC patients most likely to have responses to specific therapies.

Public Health Relevance

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. Personalized therapy with drugs against specific genetic defects is a new approach but is limited by the intrinsic resistance of some patients'tumors. Understanding mechanisms of resistance will lead to more effective therapies, identify new drug targets and biomarkers for selecting CRC patients most likely to respond to treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Developmental Therapeutics Study Section (DT)
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Timmer, William C
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University of Texas MD Anderson Cancer Center
Internal Medicine/Medicine
Other Domestic Higher Education
United States
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Morris, Van; Overman, Michael J; Jiang, Zhi-Qin et al. (2014) Progression-free survival remains poor over sequential lines of systemic therapy in patients with BRAF-mutated colorectal cancer. Clin Colorectal Cancer 13:164-71
Bailey, Ann M; Zhan, Le; Maru, Dipen et al. (2014) FXR silencing in human colon cancer by DNA methylation and KRAS signaling. Am J Physiol Gastrointest Liver Physiol 306:G48-58
Mao, Muling; Tian, Feng; Mariadason, John M et al. (2013) Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin Cancer Res 19:657-67