Bob Bast Translational Research Grant *
- RAS is a gene that plays a major role in cancer. The three members of the RAS family are HRAS, NRAS, and KRAS. One of these genes is mutated in about 15% of cancers. The mutant form is hyperactive.
- In pediatric solid tumors, RAS is mutated in about 1-3% of cancers and more often in rhabdomyosarcoma.
- Inhibiting RAS activity has been a difficult task in cancer drug development. One type of drug, the farnesyl transferase inhibitors (FTI), were developed twenty years ago. Clinical trials using these drugs were disappointing. We now have a better understanding of how to select patients that will best respond to FTI.
- Only mutant HRAS is dependent on the farnesyl transferase enzyme. So, FTI should work best in patients with HRAS mutant cancers.
- In a clinical trial of patients with HRAS mutant head and neck cancer, patients were treated with tipifarnib, an FTI. Trial outcomes showed that patients’ tumors got smaller (responded).
- We are now studying FTI in pediatric solid tumors. We want to know what adaptive events occur in the cell and whether these changes only occur in mutant HRAS tumors. We also want to learn how tumors may escape the anti-cancer effects of FTI.
- Studying these changes and paths of resistance can help us develop more complete and lasting responses. Our study aims to address these issues to find effective treatments for patients with HRAS mutant cancer.