Our work addresses a fundamental issue in oncology, namely, that age represents a strong cancer risk factor. We focus on the biology of the sirtuin (SIRT) gene family and have developed murine models connecting the organismal physiology of aging and metabolic bioenergetics to carcinogenesis and tumor cell resistance. Dysregulation of antioxidant and energy regulating enzymes leads to perturbations in metabolic homeostasis and the accumulation of oxidized metabolites and reactive oxygen species that adversely affect cellular metabolism.

My laboratory has focused on understanding cell and mitochondrial networks that help maintain metabolic homeostasis and that, when disrupted, trigger early ev...

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Our work addresses a fundamental issue in oncology, namely, that age represents a strong cancer risk factor. We focus on the biology of the sirtuin (SIRT) gene family and have developed murine models connecting the organismal physiology of aging and metabolic bioenergetics to carcinogenesis and tumor cell resistance. Dysregulation of antioxidant and energy regulating enzymes leads to perturbations in metabolic homeostasis and the accumulation of oxidized metabolites and reactive oxygen species that adversely affect cellular metabolism.

My laboratory has focused on understanding cell and mitochondrial networks that help maintain metabolic homeostasis and that, when disrupted, trigger early events in tumorigenesis and tumor cell resistance. We have made several foundational discoveries in this area, most notably, that Sirt3 functions as a tumor suppressor (Cancer Cell) by controlling a key switch in manganese superoxide dismutase (MnSOD) activity (Mol. Cell). Recently, we identified a novel mitochondrial signaling axis, which when dysregulated, leads to aberrant cellular metabolism (Nature Comm.), lineage plasticity (PNAS), and tumor permissive/therapy resistant phenotypes. Our insights into mitochondrial biology, through lysine acetylation mediated by SIRT3, accords us the unprecedented opportunity to define the complex relationship of aging, oncogenesis, and drug resistance phenotypes.

Specifically, we will use murine models altered for Sirt3-mediated deacetylation of MnSOD and Acetyl-CoA synthetase-2 to help fill major knowledge gaps. We will also conduct a clinical trial of the FDA-approved MnSOD chemical mimetic GC4419 that we have shown to reverse the tumor permissive phenotype of Sirt3 and MnSOD cell culture and mouse models. We are confident that the knowledge garnered from our endeavors will allow medical practitioners to counsel patients, identify likely responders to therapy, predict the durability of drug response, and explain acquired drug resistance.

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