PROJECT SUMMARY
In the United States, colorectal cancer (CRC) mortality is markedly higher in African-American (AA) patients than
any other racial or ethnic group. Treatment options, socioeconomic status (SES), comorbidities, and tumor
characteristics contribute to survival disparities. Tumor characteristics focused on metabolism and microbiology
have been rarely studied in relation to CRC mortality and racial/ethnic group, and thus requires further
investigation. Metabolites are substrates and products of metabolism required by tumor cells for gene regulation,
growth, and immune responses. They can modulate the metabolism and efficacy of chemotherapeutic drugs,
therefore are linked to CRC treatment response and mortality rates. Differences in lifestyle factors (i.e., diet,
physical activity), social determinants of health, and environmental exposures exist between racial/ethnic groups
and affect metabolite production in CRC. In addition, the colon microbiome is a major modulator of metabolites
and has been implicated in CRC. Given that metabolites are susceptible to modulation by lifestyle factors that
differ between racial/ethnic groups, and tumor characteristics contribute to disparities in CRC mortality, we
hypothesize that differences in CRC metabolites and microbiome between racial/ethnic groups account
for disparities in clinical outcomes. Our objective is to address the lack of knowledge in this area by
performing a discovery metabolomics approach to identify salient features of CRC metabolism inherent to race.
We will also examine how the microbiome and metabolome change during the continuum of CRC care, associate
with treatment responses, and are affected by SES. In specific aim 1, we will use untargeted metabolomics,
metabolic pathway analysis, and molecular networking approaches to identify CRC tumor tissue metabolites
specific to AAs, with stratification by sex, stage, and SES. This will generate the first ever metabolic signatures
of CRC in AAs and will include exogenous metabolites derived from environmental exposures and the
microbiome. For specific aim 2, we will identify the impact of surgery and chemotherapeutic treatments on the
CRC stool microbiome. We will identify microbiota unique to AA patients and determine if factors related to SES
including diet, physical activity, and body mass index may confound this association. We will ultimately determine
how the response to treatment differs between AA and non-Hispanic white patients to better understand
mechanisms of increased mortality in AAs with CRC. The immediate outcomes of this proposal are: 1) generation
of the first metabolic signature of CRC by race, 2) identification of novel microbial and environmental metabolites
of CRC by race, 3) the first characterization of microbiome and metabolite changes at crucial time points along
the continuum of CRC care (e.g., diagnosis, surgery, chemotherapy) and associations to SES. This data will
generate new hypotheses regarding tumor characteristics and cancer outcomes. Our long-term goal is to
improve patient outcomes by identifying key metabolic pathways and microbiota that differ between
race/ethnicity, SES and may be exploited for the development of more effective therapeutic interventions.