UC San Diego

Pancreatic Cancer is one of the most lethal cancers worldwide due to its delayed diagnosis which precludes curative resection, and rapid development of resistance to conventional chemotherapy. Pancreatic Ductal Adenocarcinoma (PDAC) is the most prevalent and aggressive form of pancreatic cancer, and PDAC cells are often found to express high amounts of NRF2, a basic leucine zipper transcription factor (TF) and the master activator of the antioxidant response. NRF2 controls the expression of pro-survival genes, stimulates cell proliferation via metabolic reprogramming, suppresses apoptosis, and enhances self‐renewal, contributing to chemoresistance, radiation resistance and inflammation‐induced carcinogenesis (Zhang et al. 2018, Su et al., 2021). In this thesis, we are aiming to provide a well-founded basis for the development of new strategies for treatment of PDAC with high expression of NRF2. We approached this with two methods. One method is based on the use of an inhibitor of macropinocytosis (MP), EIPA, in combination with a common chemotherapeutic drug gemcitabine. This combination increased PDAC cell sensitivity to gemcitabine and resulted in smaller tumors in vivo compared to control and gemcitabine treatment alone. This combination also resulted in a significantly decreased stem cell population compared to both the control and gemcitabine treatment groups, showing promise towards stem cell related therapy resistance and tumor metastasis. A second method is based on the use of a pro-drug in combination with gemcitabine. The prodrug, C29h, can be specifically activated by NQO1, which is a downstream target of NRF2. The combination between C29h and gemcitabine resulted in a selected targeting of high NRF2 expressing PDAC cells, and decreased cancer cell survival in vitro.