Rohan Freedman, a junior neuroscience major at Brown University, investigated inhibitor drugs for repurposed use in cancer therapy.
The process of drug discovery is expensive, taking up to 15 years without a guarantee of high success rates. BSRP 2021 has been one of the most memorable and enlightening experiences on my journey to become a scientist. At the Broad I was able to network and learn from researchers at the top of their fields. Working alongside them, I was given the opportunity to conduct cutting edge research in cancer genomics which pushed me to develop skills necessary to be a successful scientist. I am so grateful for the meaningful lessons, valuable skills, and people I met from my time at BSRP.To address this, drug repurposing has become a popular method of saving time and money by investigating new uses for already approved drugs. For our experiment we set out to assess inhibitor drugs for repurposing as cancer therapies. We acquired drug sensitivity data from PRISM, a novel method of drug screening at the Broad, which consists of 4,581 drugs tested across 578 human cancer cell lines. The PRISM sensitivity values measure the level of cancer cell death/growth that occurred in response to our drug inhibitors. In addition, we acquired cancer dependency scores from project Achilles which is an ongoing project at the Broad consisting of 17,645 genes knocked out by CRISPR to measure whether a gene is an oncogene or a tumor suppressor. We correlated the PRISM sensitivity values with the Achilles’ dependency scores to identify the highest correlated inhibitor-gene associations, indicating oncogene targets that responded with cancer cell death. After analysis of the highest correlated pairs, we found Gedunin, a heat shock protein inhibitor, along with its gene target, HSP90AA1. HSP90AA1 is known to stabilize several proteins required for tumor growth making Gedunin an ideal candidate for anticancer therapy. We analyzed the PRISM sensitivity values by cancer type and discovered that skin cancer showed the greatest cell death and among skin cancer cell lines two cell lines showed a statistically significant response (p-value<0.05 and p-value>0.01). Our preliminary analysis shows that Gedunin has the potential to successfully inhibit skin cancer cell growth by targeting the HSP90AA1 gene. Further research is recommended to investigate Gedunin’s potential as a skin cancer therapy as well as the two significant cell lines to uncover key insight into the mechanism of action of Gedunin and to identify subsets of skin cancer patients who will respond best to it.
Project: Drug Repurposing for Cancer Therapy
Mentors: Andrew Boghossian Cancer Data Science, PRISM Lab
Vera Valakh, Klarman Cell Observatory, Nehme Group