Colorectal Cancer

Challenge
Colorectal cancer (CRC) remains the second leading cause of cancer mortality in the United States. Despite an increasing number of therapeutic options for CRC patients, those diagnosed with metastatic disease (mCRC) have a five year survival rate of 11%. Further, toxicities from targeted therapies are substantial: for example, most approved therapies inhibit FLT1, which is closely associated with kidney toxicity and hypertension. Our team is using our emerging model organism-based platform to develop therapies designed to optimize whole body therapeutic index.

Drosophila Colorectal Cancer Model

We are currently building dozens of patient-specific Drosophila models. Each fly transgenic line represents a different patient, with each line having typically 7-10 altered genes. Our goal is to explore the effects of genetic complexity on drug response, with an emphasis on RAS-mutant disease. 

To date, we have screened ~60 compounds/drugs/drug combinations for their ability to improve survival of RAS(G12V)-P53(RNAi)-APC(RNAi) flies. Seven drugs and two drug combinations showed significant ability to rescue. In addition to known drugs, we identified multiple novel compounds developed with our fly/chemistry approach. Next step: testing these hits on our more complex models.

Mouse Xenograft Models Respond to Fly-Derived Hits

One of the most interesting Drosophila hits was examined in Patient-Derived Mouse Xenograft (PDX models to examine tumor progression. The ability of APS5-86-2 to rescue tumor progression was striking, especially when benchmarked against standard-of-care regorafenib (Image). This suggests that Drosophila CRC models can be predictive for mammalian efficacy.