Unlike normal cells, tumors sustain high ROS levels, which they need to drive oxidant signaling for optimal malignancy. Yet tumors also need to prevent the damaging effects of ROS from triggering anti-tumor pathways. This duality of ROS in cancers is an underexplored therapeutic Achilles heel. We seek to define adaptive mechanisms utilized by aggressive tumors to inhibit the damaging tumor-suppressive role of ROS and thus drive their tumor-promoting functionality. This approach is preferable to targeting oncogenic signaling pathways that are prone to chemoresistance-causing mutations and pleiotropy. Our lab focuses on KRAS-driven lung and pancreatic cancer and castration-resistant prostate cancer (CRPC) models, which are all highly aggressive and treatment-refractory cancers.
The RAS oncogene, the most commonly activated oncogene in human tumors, is extremely refractory to direct inhibition. Research from our laboratory has shown that the oxidized nucleotide pool-cleansing enzyme, MTH1 is elevated in RAS-driven tumors relative to corresponding normal tissue and that MTH1 facilitates every step of RAS-driven malignancy, from evasion of the oncogene-induced senescence barrier in normal cells to acquisition of transformation-associated traits and maintenance of multiple pro-malignant mechanisms in established tumors. Significantly, our work has shown that MTH1 inhibition forces tumors to lose the highest oncogenic RAS-expressing cells, in effect phenocopying RAS inhibition and providing a potential solution to directly inhibiting RAS itself. Our pioneering research on MTH1 biology laid the foundation for development of the first-in-class MTH1 inhibitors and continues to stimulate national and international research in this area. In collaboration with chemists and biochemists, we are developing and validating unique chemical probes for interrogating MTH1 enzymatic activity and related DNA repair pathways in tumor cells and tissues. We are also developing animal models of RAS-driven tumorigenesis in the background of MTH1 loss. Collectively our research in this area is geared towards optimizing the eventual use of MTH1 inhibitors in the clinic by establishing the molecular contexts and mechanisms of their tumor-suppressive action.
In prostate cancer models, our research has uncovered that redox-protective mechanisms drive CRPC. Our lab was the first to show that the standard of care for advanced PC, androgen deprivation therapy (ADT) potentially fails due to induction of sub-optimal tumor suppressor responses that drive emergence of the incurable disease through creation of a pro-inflammatory, pro-survival microenvironment. Such changes facilitate outgrowth of ADT-refractory subpopulations through key redox-protective adaptive changes. Using a novel model for CRPC emergence developed in our lab, we recently identified thioredoxin-1 as an important factor in limiting oxidative stress associated with the inappropriate activation of androgen receptor (AR) under low ligand conditions, which is the hallmark of incurable (castration-resistant) prostate cancer. We have shown that inhibiting thioredoxin-1 through a Phase I-approved inhibitor PX-12 significantly reduces castration-resistant tumor formation. We have identified several other novel putative drivers of CRPC and are investigating the molecular mechanisms underlying their role in CRPC emergence and progression.
Our research projects are currently funded by NIH/NCI and DOD PCRP mechanisms.