Pancreatic Ductal Adenocarcinoma (PDA) is a deadly malignancy. Early systemic spread and resistance to chemotherapy combine to make PDA one of the most dismal diagnoses in modern medicine. However, hundreds of experimental anticancer medicines are now in development and could be considered for Pancreatic Ductal Adenocarcinoma (PDA). Our studies to date show that PDA can be divided into distinct subclasses that differ biologically and that may respond differently to treatment. Our goal now is to advance treatment of PDA by refining molecular descriptors of Pancreatic Ductal Adenocarcinoma (PDA), identifying therapeutic agents on the Ras pathway that are effective in specific tumors, and eventually testing these in biomarker-marker guided clinical trials. This will be accomplished through work in two aims.
Aim 1 will identify and model omic determinants of response to inhibitors of the Raf-MEK-ERK and PI3 Kinase/Akt pathways in a well characterized panel of PDA cell lines. Since we suspect that combined blockade will be required, we plan to test these agents both alone and in combination.
Aim 2 will validate the biomarkers of sensitivity and resistance discovered in cell lines in a selected panel of PDA xenografts resected from patients and propagated and treated in the mouse. Biomarkers identifying specific responses in both preclinical systems will be tested in biomarker-guided clinical trials with inhibitors of the Ras pathway (beyond the scope of this proposal). Overall, we expect to test the hypothesis that biomarkers identified in efficient, preclinical model system screens will prospectively identify drug responsive and drug resistant patients in clinical trials. If true, this will allow experimental drugs now under development to be quickly tested for efficacy in subclasses of PDA and then moved quickly into trials in patient subpopulations in which they are most likely to be effective. This work is 100% relevant to Pancreatic Ductal Adenocarcinoma.
Clinical Trials in oncology often fail because the tested drugs do not work in patients. This project will employ molecular analysis of pancreatic tumors to predict which tumors and patients will be most sensitive to certain treatments. These studies hold promise in expanding treatment options for pancreatic cancer patients, and changing the way clinical trials are conducted.
|Hoadley, Katherine A; Yau, Christina; Wolf, Denise M et al. (2014) Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 158:929-44|
|Lin, Luping; Asthana, Saurabh; Chan, Elton et al. (2014) Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer. Proc Natl Acad Sci U S A 111:E748-57|
|Cancer Genome Atlas Research Network (2014) Comprehensive molecular profiling of lung adenocarcinoma. Nature 511:543-50|
|Sadanandam, Anguraj; Lyssiotis, Costas A; Homicsko, Krisztian et al. (2013) A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med 19:619-25|
|Nan, Xiaolin; Collisson, Eric A; Lewis, Sophia et al. (2013) Single-molecule superresolution imaging allows quantitative analysis of RAF multimer formation and signaling. Proc Natl Acad Sci U S A 110:18519-24|
|Trejo, Christy L; Green, Shon; Marsh, Victoria et al. (2013) Mutationally activated PIK3CA(H1047R) cooperates with BRAF(V600E) to promote lung cancer progression. Cancer Res 73:6448-61|
|Mirzoeva, Olga K; Collisson, Eric A; Schaefer, Peter M et al. (2013) Subtype-specific MEK-PI3 kinase feedback as a therapeutic target in pancreatic adenocarcinoma. Mol Cancer Ther 12:2213-25|
|Heiser, Laura M; Sadanandam, Anguraj; Kuo, Wen-Lin et al. (2012) Subtype and pathway specific responses to anticancer compounds in breast cancer. Proc Natl Acad Sci U S A 109:2724-9|
|Collisson, Eric A; Sadanandam, Anguraj; Olson, Peter et al. (2011) Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med 17:500-3|
|Collisson, Eric A (2011) An uphill battle downstream of RAF. J Clin Oncol 29:2298-300|
Showing the most recent 10 out of 11 publications