The Fight Colorectal Cancer-AACR Career Development Award, in memory of Lisa Dubow, is eligible to junior faculty who are in the first four years of a faculty appointment at the initiation of the grant term. Eligible research projects are restricted to translational or clinical research that focuses on novel THERAPEUTIC APPROACHES for late-stage metastatic colorectal cancer. This grant will support a project designed to lead to individualized therapeutic options for treatment or the development of promising new cancer therapeutics for patients with metastatic colorectal cancer. Emphasis will be placed on proposed projects which will translate into clinical applications within a few year period, including those with predictive biomarker studies.
Andrea Bertotti, M.D., Ph.D.
Assistant Professor, Institute for Cancer Research and Treatment (IRCC), Candiolo, Italy
Improving Targeted Therapy in Colorectal Cancer Through Xenopatients
"After years of enormous research efforts for the systematic cataloguing of genetic alterations with causative function in cancer, the goal of 'personalized medicine' in clinical oncology is now at reach. However, the categorization of molecularly circumscribed tumor subpopulations featuring specific genetic lesions, the validation of such lesions as therapeutic targets, and the definition of biomarkers capable of accurately predicting sensitivity or refractoriness to rational treatments still face technical, logistic and ethical limitations in patients.
"These observations also apply to the case of colorectal carcinomas (CRCs). In the last decade, huge efforts aimed at improving the management of this tumor type, including the adoption of targeted therapies, have been implemented. However, the prognosis for metastatic CRC patients remains poor, with a median overall survival of 18 to 21 months.
"We aim at the identification of genetic interactions and compensatory mechanisms that may impair – or boost– the efficacy of selected therapeutic approaches. In particular, we will concentrate our attention on a significant fraction of tumors, which respond to anti-EGFR treatment – the gold standard targeted therapy in this tumor setting – with disease stabilization (SD) but not with tumor shrinkage. We aim at assessing the preclinical efficacy of investigational combination therapies potentially turning SDs into regressions. If we succeed in obtaining shrinkage in 30 percent of these cases, the potential impact will be to provide benefit for more than 10,000 patients per year.
"This proposal is founded on a proprietary and unique experimental platform that relies on direct transplantation of extensively annotated patient-derived tumor material into mice – “xenopatients” – with a disease-specific focus on metastatic CRC (mCRC). During the past four years we have collected more than 300 mCRC samples; of these, more than 150 have been profiled for response to anti-EGFR antibodies. At the same time, tumor samples are undergoing extensive molecular profiling to allow for biomarkers identification and validation. Overall, the results obtained from this line of research will potentially impact both clinical decision processes and more basic research issues, and this award will be critical in developing such an ambitious research program."
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