Grant: Operating Grant

The goal to improving mortality from cancer is to achieve complete response to therapy. However, chemotherapy resistance has been a difficult problem to overcome. In order to better understand this phenomenon, our laboratory used a whole genome approach to obtain a snapshot of the changes that occur when cancer cells develop resistance to chemotherapy. This allowed us to identify SPARC as a gene that plays a role in changing the sensitivity of cancer cells to chemotherapy. We have been able to demonstrate that low SPARC levels in chemotherapy resistant human MIP101 colon cancer cells is associated with cancer cells that were resistant to therapy. However, if SPARC is restored by either re-expressing this gene at higher levels, or by introducing the SPARC protein in tissue culture, colon cancer cells become more sensitive to chemotherapy. In animal models, treatment with SPARC also allowed colon cancer cells to respond better to chemotherapy, and this is demonstrated by greater tumor regression in animals receiving SPARC with chemotherapy than in animals receiving chemotherapy alone. In this grant application, we propose to conduct experiments that will allow us to gain a better understanding of the mechanisms by which SPARC improves the sensitivity of colorectal cancers to chemotherapy. The results will allow us to determine if SPARC has any potential as a therapeutic, and as well, allow us to develop better drugs and tests that will be useful in the treatment and management of patients with colorectal cancer, especially in cases where therapy has failed.