For patients with colorectal cancer treated with curative intention using surgery (with or without chemotherapy) microscopic areas of cancer may still remain and release their DNA into the bloodstream. When detected during a blood test, this circulating tumor DNA (ctDNA) can accurately forecast an eventual return of the cancer. Alternatively, if ctDNA is not detected, the colorectal cancer will likely not return. At this time, it is unknown if patients with detectable ctDNA benefit from receiving chemotherapy, or if small, incurable metastases which have already developed.

In this proposal, our team seeks to understand better the biology that uniquely defines these microscopic tumor depo...

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For patients with colorectal cancer treated with curative intention using surgery (with or without chemotherapy) microscopic areas of cancer may still remain and release their DNA into the bloodstream. When detected during a blood test, this circulating tumor DNA (ctDNA) can accurately forecast an eventual return of the cancer. Alternatively, if ctDNA is not detected, the colorectal cancer will likely not return. At this time, it is unknown if patients with detectable ctDNA benefit from receiving chemotherapy, or if small, incurable metastases which have already developed.

In this proposal, our team seeks to understand better the biology that uniquely defines these microscopic tumor deposits of colorectal cancer, as detected by ctDNA in the blood, in order to design more effective treatments. We believe that the TGF-beta pathway drives the return of cancer, is known for promoting cancer metastases, and makes immunotherapy ineffective in treating colorectal cancer. In our first goal, we will test whether or not the presence of CMS4, which is linked to high TGF-beta activity, is linked to (a) recurrence of colorectal cancer and (b) the ability of chemotherapy to remove ctDNA from the blood of patients at high risk for recurrence. In the second goal, we will demonstrate that microscopic areas of colorectal cancer have less TGF-beta than larger tumors in those patients. Finally, we will develop and test a new cell treatment that makes immune T cells resistant to the immunosuppressing activity of TGF-beta so that these newly made T cells can be used against colorectal cancer. We propose to apply our findings towards future clinical trials that use treatments to shut down TGF-beta activity, remove ctDNA, and cure more patients with colorectal cancer.

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