The Fight Colorectal Cancer-AACR Fellowship, in memory of Lisa Dubow, is a one-year grant to support the salary and benefits of the fellow. A partial amount of funds, up to 25 percent of the total grant, may be designated for direct research expenses. Research projects are restricted to translational or clinical cancer research that has an ultimate goal of developing or improving therapeutic interventions for patients with metastatic colorectal cancer.
Maria Pia Morelli, M.D., Ph.D.
Postdoctoral Fellow, Department of Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
Detecting/Predicting Acquired Chemotherapy Resistance in Colorectal Cancer
The development of anti-epidermal growth factor receptor (EGFR) monoclonal antibody, such as cetuximab and panitumumab, significantly improved clinical outcome in metastatic colorectal cancer patients. Although, anti-EGFR monoclonal antibodies demonstrate to improve clinical outcome in metastatic colorectal cancer patient with a KRAS wild type tumor, not all patient treated obtain clinical benefit. Thus, refinement of the predictive biomarker may improve outcome for these patients.
This proposal focuses on two critical aspects of tumor biology that are anticipated to have profound impact on clinical outcomes. The first is increasing recognition that tumor heterogeneity plays a substantial role in determining the tempo and mechanisms of resistance to chemotherapy. While tumor heterogeneity has been appreciated for many years, the technology has recently evolved to allow the assessment of the clinical significance of this heterogeneity. As KRAS is a strong predictive biomarker for epidermal growth factor receptor monoclonal antibodies in colorectal cancer this provides a unique opportunity of clinical impact of heterogeneity in KRAS mutations. Specifically, it has now been identified that there are low frequency KRAS mutations that are present at levels below that which can be detected by standard sequencing methodologies used in clinical care (“de novo” mutations). The implications of these low frequency KRAS mutations are unclear although early retrospective data from non-randomized studies suggest that they may be important biomarkers of resistance to treatment. This has implied that improved methodologies may be able to identify patients who may not be benefiting from a toxic and expensive agent. The second aspect is the recognition that acquired mutations in KRAS and EGFR have been identified and are associated with resistance to treatment. This suggests that “de novo” and “acquired” resistance can have important similarities and also differences.
"As we improve our understanding of the dynamics of colorectal cancer biology, it is increasingly clear that novel methods of noninvasively assessing the tumor are needed. In cancer patients, circulating free DNA (cfDNA) is substantially derived from the tumor and is detected in the blood of cancer patients. The introduction of cfDNA as tool to monitor the changing cancer mutations will make possible a more dynamic follow up of the tumor genome without the need of extra biopsies. The information obtained by this research will answer specific clinical questions relevant to the biology of colorectal cancer, and provide insights that may advance the care of colorectal cancer patients in the near future."
"I am honored to receive the 2013 Fight Colorectal Cancer-AACR Fellowship, in memory of Lisa Dubow as it provides the opportunity to further improve my skills as scientist physician and to contribute to improve cancer patient care."
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