Madison Weber

Date of Award

2018

First Advisor

Sue Mechanic-Meyer

Second Advisor

Sarah Snyder

Abstract

Colorectal carcinoma is the 4th most common cancer in the United States and accounts for roughly 8% of all cancer deaths. Researchers have been pursuing treatments in the form of targeted therapies for several years. Targeted therapies work by counteracting the dysregulation of certain molecular pathways on which cancer cells are dependent. These treatments affect cancerous cells much more than healthy cells, thus minimizing harm to patients. I worked in the Pitts laboratory at the Anschutz Medical Campus in Aurora, CO researching three experimental therapeutic drugs: TAK-228, Ritanserin, and R59022. TAK-228 is a mammalian target of rapamycin (mTOR) inhibitor which has shown success in treating cancer in vitro but failed to show meaningful efficacy in a clinical setting due to resistance mechanisms. One mechanism of resistance to mTOR inhibition is the diacylglycerol kinase (DOK) pathway, which can reactivate mTOR despite the effects of TAK-228. Ritanserin and R59022 are DOK-inhibiting drugs. It is hypothesized that combining T AK-228 with Ritanserin or R59022 will demonstrate an increased anticancer effect by preempting resistance to mTOR inhibition. The full DOK pathway, including all the ways in which it interacts with the mTOR pathway, is poorly understood, and literature on the subject is spread across many research fields with minimal cross-talk between them. In order to comprehend my experimental results and propose further avenues for future research, I will explore relevant research literature on this pathway and propose a map of this molecular pathway.

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