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.
Interindividual variation in the effectiveness of cancer chemotherapy cannot be fully explained or predicted, resulting in health risks to patients and inefficient utilization of limited healthcare resources. While variations in the gut microbiome of patients have been shown to influence treatment outcomes, the mechanisms by which these microbes change chemotherapeutic drug disposition remain poorly understood. Based on our strong in vivo and in vitro data showing that a prevalent gut microbe inhibits a key drug efflux transporter, this proposal will expand our mechanistic understanding of host-microbiome interactions in drug disposition and provide the first step towards using microbial genes and/or metabolites as predictive markers for cancer chemotherapy.
