Research & Projects
The goal of our laboratory is to uncover novel treatments for hard-to-treat cancers. Our approach is to understand how defects in a tumor's ability to repair its DNA and maintain its energy supply result in vulnerabilities that can be exploited for therapeutic gain. In addition, our lab seeks to better understand how targeting DNA repair and metabolic pathways impacts the immune response against tumors, making them more sensitive to immunotherapies.
Targeting tumor metabolism
Cancer cells, because of their fast growth, require more nicotinamide adenine dinucleotide (NAD+) to meet energy requirements. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme of the NAD+ salvage pathway. NAMPT inhibitors have been tested in adult clinical trials, but their efficacy has been limited. We recently uncovered that tumors with mutations in citric acid cycle genes harbor silencing of nicotinic acid phosphoribosyltransferase (NAPRT), a key enzyme in the complimentary Press-Handler NAD+ salvage pathway. In particular, renal cell carcinoma with mutations in fumarate hydratase, which results in an aggressive disease with limited treatment options, display epigenetic silencing of NAPRT and increased sensitivity to NAMPT inhibitors. Moreover, NAD+ is a vital cofactor for the DNA repair function of PARP1, and NAMPT inhibitors improve the efficacy of PARP inhibitors. We are now building on these findings by identifying sarcomas in children that harbor genetic vulnerabilities which improve response to NAMPT inhibitors and discovering synergistic interactions with DNA damaging agents.
Targeting DNA repair
In tumors harboring mutations in citric acid genes, the oncometabolites 2-hydroxyglutarate, succinate, and fumarate accumalate resulting in suppression of DNA repair pathways. Our work has uncovered novel synthetic lethal interactions with DNA damaging chemotherapy and DNA damage repair (DDR) inhibitors. We showed that ATR (ataxia telangiectasia and Rad3-related protein kinase) inhibitors are active against IDH1/2-mutant glioma and synergize with PARP inhibitors, resulting in cytotoxicity from premature mitotic entry in the face of unrepaired DNA damage. Similarly, we demonstrated that renal cell carcinoma harboring fumarate hydratase and succinate dehydrogenase mutations are more sensitive to combined PARP inhibition and temozolomide in an additive fashion, allowing for decreased dosing that maintains antitumor efficacy with decreased toxicity.
Improving response to immunotherapy
While immune checkpoint blockade has shown remarkable efficacy for many patients, there remain many cancer types, such as glioma and sarcoma, for which this modality has failed to improve outcomes. Our lab studies how targeting DNA repair and metabolic pathways in cancers mediates anti-tumor immunity and immunotherapy response. In particular, we are working to understand the immunomodulatory effects of alkylating chemotherapy and DNA damage repair inhibitors across unique DNA repair genotypes of glioblastoma. We are also working to uncover how inhibition of NAD+ metabolism in rhabdomyosarcoma mediates cancer-cell intrinsic cell death, immune signaling, and remodeling of the tumor microenvironment. To facilitate this research, we have generated multiple syngeneic murine tumor models isogeneic for molecular mediators of chemotherapy response.