2022 Recipient Amrita Salvi, PhD

Amrita Salvi, PhD

Investigating the mechanism of action of PHY34 in HGSOC

Project Summary

High grade serous ovarian cancer (HGSOC) is the most common and lethal form of ovarian cancer with the lowest five-year survival rate. Current treatment for HGSOC involves surgical debulking and a combination of platinum-based and taxane chemotherapy. Despite the significant progress with respect to new therapies such as Poly ADP ribose polymerase inhibitors (PARP inhibitors), most patients develop chemoresistance and succumb to the disease. One avenue to prevent chemoresistance, is by exploring novel natural anti-cancer drugs with unique modes of actions and chemical structures such as Phyllanthusmins (PHYs). PHY34 is the most potent analogue from the PHY class of compounds and was discovered by a series of structure-activity relationship studies. PHY34 is shown to be cytotoxic at nanomolar potency in HGSOC cells. Specifically, PHY34 induces cancer cell death by inhibition of late stage autophagy. Autophagy is a process by which cells recycle their intracellular components, macromolecules and organelles. Since autophagy is a survival mechanism adopted by cells, disruption of autophagy can be lethal to cells and can be a viable therapeutic strategy for treating disease. Notably, PHY34 significantly reduced tumor burden in a xenograft model of ovarian cancer. The main goal of this proposal is to understand the mechanism of action of PHY34 in HGSOC and determine if PHY34 can enhance the therapeutic effect of existing therapies for HGSOC. In order to identify the molecular targets of PHY34, we undertook an unbiased proteomics approach and identified protein targets from the nuclear cytoplasmic transport pathway. Cellular apoptosis susceptibility (CAS, also known as CSE1L) was identified as the top hit in HGSOC cells OVCAR3 and OVCAR8. CAS is an essential protein in cancer cells and an interesting target in HGSOC because expression of CAS correlates with the severity of disease and no inhibitors currently exist targeting CAS. Our preliminary data strongly suggests that PHY34 regulates autophagy via CAS inhibition in HGSOC. Overall, this study has the potential to develop PHY34 as a new drug for the treatment of ovarian cancer.