Cytotoxic chemotherapeutic agents are a key component of cancer therapy, but they have unpredictable
treatment responses and considerable treatment-related morbidity and mortality. Factors such as patient
demographics, comorbidities, tumor types, genetic polymorphisms, and the gut microbiome may contribute to
interindividual variations in chemotherapy treatment response. Of these factors, the gut microbiome is most
amenable to manipulation to improve the efficacy and limit the toxicity of chemotherapy. However, the
mechanisms and extent to which the microbiota affects drug disposition, and thus efficacy, remain elusive.
P-glycoprotein (P-gp), a key mammalian drug efflux transporter, plays a critical role in chemotherapeutic
treatment outcomes since it affects the pharmacokinetics of many cytotoxic agents and renders cancer cells
resistant to anticancer drugs. Preliminary results demonstrate that the prevalent human gut Actinobacterium
Eggerthella lenta inhibits P-gp function in mice, resulting in increased drug concentrations in the serum. In vitro
models with human colorectal cancer (CRC) cells replicated this in vivo finding and suggested that the P-gp
inhibition is mediated by a secreted bacterial metabolite. Furthermore, the P-gp inhibitor sensitized human CRC
cells against a P-gp substrate anticancer drug doxorubicin. Together, these findings provide a strong scientific
evidence to support the hypothesis that E. lenta secretes small molecule(s) that inhibit P-gp leading to increased
drug accumulation in the tumor and improved efficacy of doxorubicin anticancer therapy. This hypothesis will be
tested through 2 aims.
P-gp inhibitor will be identified using comparative genomics, comparative metabolomics, and activity-
guided biochemical fractionations (Aim 1a). The mechanism and the transporter specificity will be investigated
with various in vitro methods (Aim 1b, 1c). The effect of E. lenta colonization on the efficacy and toxicity of
doxorubicin treatment will be evaluated in a mouse rectal tumor xenograft model (Aim 2). Results from these
aims will elucidate the mechanism of microbiome-transporter interactions that impacts cancer treatment
outcomes. These experiments will lay a strong foundation to use the candidate genes and metabolites as
prognostic biomarkers for treatment response and potential adjuvants to therapy.
These research projects will be conducted at the University of California San Francisco (UCSF), which
offers a unique combination of an exceptional microbiome research environment with a top-tier medical school.
These research goals, in combination with a comprehensive training plan from the UCSF Medical Scientist
Training Program, will be crucial to shaping the applicant's career as a physician-scientist.