Oxaliplatin is an active agent in metastatic colorectal cancer regimens, but most patients either fail to respond to 5-FU and oxaliplatin (FOLFOX) combinations or subsequently develop resistance. A candidate molecule that might contribute to oxaliplatin resistance is the protein tyrosine kinase, Src, the activity of which is increased during colorectal tumor progression and highest in metastatic disease. Our preliminary studies demonstrate that Src is activated in colon cancer cell lines after oxaliplatin treatment in vitro and in vivo. We have shown that inhibition of Src by siRNA increases sensitivity to oxaliplatin. Likewise, pharmacologic inhibition of Src with dasatinib, an oral tyrosine kinase inhibitor, is synergistic with oxaliplatin in vitro and demonstrates at least supra-additive reductions in tumor size in an orthotopic murine model. These findings lead to the following hypothesis to be tested in this proposal: Src activation resulting from oxaliplatin treatment is a pro-survival mechanism and inhibition of Src will therefore improve oxaliplatin cytotoxicity in metastatic colorectal cancer.
Specific aim 1 is to determine if constitutive Src activation is sufficient to induce oxaliplatin resistance in both cell cultures and an orthotopic nude mouse model of colorectal liver metastases by molecular approaches to develop colorectal tumor cell lines in which Src activity cannot be regulated. These studies will use transfected Src with a point mutation rendering Src constitutively active, thereby allowing evaluation of oxaliplatin sensitivity and the subsequent impact of dasatinib therapy.
Specific aim 2 is to determine the frequency of Src activation in liver metastases after oxaliplatin treatment in colorectal patients undergoing liver metastasectomy in order to demonstrate the clinical relevance of these preclinical findings.
Specific aim 3 is designed to evaluate the safety, preliminary efficacy, and pharmacodynamics of the combination of dasatinib and FOLFOX + cetuximab in patients with metastatic colorectal cancer. This investigator-initiated study, to which we have recently initiated accrual, includes extensive correlative studies to demonstrate inhibition of Src and Src targets in the tumor.
Specific aim 4 further evaluates the efficacy of this regimen in a Bayesian adaptively randomized, placebo-controlled phase II study of FOLFOX + cetuximab +/- dasatinib, with concurrent evaluation of a biomarker of Src inhibition. Successful implementation will improve the effectiveness of current chemotherapies for metastatic colorectal cancer, resulting in improved outcomes for the metastatic colorectal cancer population.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23CA136980-05
Application #
8320755
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lim, Susan E
Project Start
2008-09-26
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$134,796
Indirect Cost
$8,796
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Menter, David G; Kopetz, Scott; Hawk, Ernest et al. (2017) Platelet ""first responders"" in wound response, cancer, and metastasis. Cancer Metastasis Rev 36:199-213
Morelli, M P; Overman, M J; Dasari, A et al. (2015) Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment. Ann Oncol 26:731-6
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
Kopetz, Scott; Lemos, Robert; Powis, Garth (2012) The promise of patient-derived xenografts: the best laid plans of mice and men. Clin Cancer Res 18:5160-2
Ihle, N T; Powis, G; Kopetz, S (2011) PI-3-Kinase inhibitors in colorectal cancer. Curr Cancer Drug Targets 11:190-8
Lieu, Christopher; Heymach, John; Overman, Michael et al. (2011) Beyond VEGF: inhibition of the fibroblast growth factor pathway and antiangiogenesis. Clin Cancer Res 17:6130-9
Lieu, Christopher; Kopetz, Scott (2010) The SRC family of protein tyrosine kinases: a new and promising target for colorectal cancer therapy. Clin Colorectal Cancer 9:89-94
Kopetz, Scott; Hoff, Paulo M; Morris, Jeffrey S et al. (2010) Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 28:453-9
Kopetz, Scott; Lesslie, Donald P; Dallas, Nikolas A et al. (2009) Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress. Cancer Res 69:3842-9