Texia Loh
Overcoming Resistance to PARP Inhibition in Small-Cell Lung Cancer
Abstract
Small cell lung cancer (SCLC) is an aggressive cancer with rapid progression and high relapse rates. Standard of care therapies invariably lead to relapse and have a five-year survival rate of ~7%, therefore new treatments are urgently needed. SCLC cells express high levels of poly-(ADP)-ribose polymerases (PARP), enzymes involved in DNA repair. While PARP inhibitors (PARPi) slowed SCLC growth in cell and mouse models, early clinical trials showed limited success. Recent studies revealed that deleting a specific helicase boosts sensitivity to PARPi, but targeting helicases is challenging. To address this, I developed a novel helicase degrader using protein degradation techniques. Our initial studies show this degrader synergizes with PARPi to reduce SCLC growth. Here, I will investigate the mechanism for how helicase degradation sensitizes SCLC to PARPi and assess the degrader’s efficacy in vivo. If successful, I will have validated a new therapeutic target for SCLC.
The PhRMA Foundation Predoctoral Fellowship will provide invaluable support for advancing my research training. This award will enable me to explore innovative approaches in drug discovery with the hope of improving patient outcomes.
