Colorectal cancer is the second leading cause of cancer deaths annually, with over 49,920 deaths estimated for 2009. Despite multiple new FDA-approved therapies in the last decade, the 5-year survival remains extremely poor. In addition, although there has been much excitement about """"""""targeted"""""""" patients with the incorporation of KRAS gene codon 12/13 testing for EGFR-targeting antibodies, this discovery came 5 years after the FDA approval of these drugs, resulting in the waste of billions of dollars (as well as side effects) """"""""treating"""""""" patients who had a 0% chance of benefit. New approaches, as well as new therapies, are desperately needed. To this end, a patient-derived colorectal cancer human explant xenograft model has been created to help develop novel therapies for colorectal cancer. A promising drug target is the non-receptor kinase, Src. This protein regulates multiple cascades that impact cellular adhesion, migration and invasion, factors that when dysregulated enable tumor cells to disrupt their microenvironment, travel to distant sites and invade host tissues independent of normal regulatory signals. The result of this phenotype is metastasis, the critical mechanism by which cancer cells cause organ dysfunction and ultimately death. We have discovered a subset of human colorectal tumor cell lines and explants sensitive to Src inhibition. Using gene sequencing, gene micro-array (top scoring pairs analysis), and FISH, we have developed a putative integrated genomic predictor to select sensitive tumors/patients prior to initiating therapy. The next steps are to refine the predictor in expanded preclinical testing (including a novel mouse liver metastases model) as well as conduct a two-stage phase II clinical trial. We have assembled a team of nationally recognized experts in Src inhibitors and clinical biomarker development who are well-qualified to perform this work. The goal is to demonstrate that using archival tumor tissue, a cohort of biomarker-positive patients treated with saracatinib will have a higher response/nonprogression rate than a simultaneously enrolled group on biomarker-negative patients. We will also perform serial tumor biopsies on a subset of patients to explore Src inhibitor effects at the tumoral level. The clinical trial represents a highly unique opportunity to qualify and extend the results of the human xenograft experiments in colorectal cancer for possible phase III testing. We also expect this dataset to be a rich source with which to develop rational combination studies with Src inhibitors. Moreover, there are also broader implications with regard to the utility of human explant xenograft models, currently being explored across the globe in many cancer types, as simulators of the cancer clinic.
The purpose of this project is to develop and use a set of laboratory tests to find out which colorectal cancer patients will benefit from Src inhibitors. We will use several methods to analyze patient tumor samples from when they were diagnosed with colorectal cancer, and then see if we can predict whether a Src inhibitor will work. This grant also explores the theme that cancer models from the laboratory will help guide us to better use of drugs individually directed to specific patients (personalized medicine) in the clinic.
|Arcaroli, John J; Quackenbush, Kevin S; Powell, Rebecca W et al. (2012) Common PIK3CA mutants and a novel 3' UTR mutation are associated with increased sensitivity to saracatinib. Clin Cancer Res 18:2704-14|
|Arcaroli, John J; Touban, Basel M; Tan, Aik Choon et al. (2010) Gene array and fluorescence in situ hybridization biomarkers of activity of saracatinib (AZD0530), a Src inhibitor, in a preclinical model of colorectal cancer. Clin Cancer Res 16:4165-77|