Project 2: Discovery and validation of novel molecular and immune predictors of colorectal cancer mortality and response to treatment in racially and ethnically diverse patient populations

PROJECT SUMMARY/ABSTRACT Disparities in colorectal cancer (CRC) incidence and mortality are appreciable and continue to persist in the United States particularly among Alaska Native and African American people. To address these disparities, we propose a CRC tumor molecular profiling strategy that will provide novel insights and take full advantage of the

existing infrastructure of our Translational Research Program in Colorectal Cancer Disparities (TRPCD) with its available biospecimens from highly annotated CRC patients. Specifically, novel spatial proteomic analyses enable deep characterization of the tumor microenvironment and immune response which in other cancers has

been shown to be of high translational relevance. Few studies though have applied this powerful approach to CRC or to advance our understanding of cancer disparities through studying patients from racially and ethnically diverse populations. Using data and biospecimens from African American, Alaska Native, Hispanic, and non-

Hispanic White CRC patients this project will complete the following specific aims: Aim 1. Discover novel colorectal tumor-tissue based spatially resolved prognostic biomarkers using the PhenoCycler platform (n=840); Aim 2. Discover colorectal tumor tissue based spatially resolved predictors of response to both first-line CRC

therapy (n=840) and immunotherapy (n=100); Aim 3. Develop and validate predictors of treatment response and CRC-specific mortality. This aim will use 70% of samples for discovery, and 30% for validation. Our optimized panel to predict risk of CRC-specific mortality will be translated into a multiplex immunofluorescence (mIF) ~8

biomarker assay (using the Vectra Polaris platform) and its performance will be evaluated on our 30% validation set. The results of this work will have short-term potential translational impacts through improving the identification of: 1) patients at high risk of dying from CRC who may benefit from advanced monitoring or

alternative first-line treatments, including the development of the first version of a potentially clinically useful mIF assay; and 2) predictors of treatment response that can guide clinical decision making, treatment selection, and patient stratification. Our comprehensive evaluations of tumoral immune response and mechanism of immune

evasion may have longer-term potential translational impact as they could inform the development of novel therapeutic approaches that could be particularly relevant for certain racial and ethnic groups. We anticipate that through identifying new treatment strategies and improving risk prediction across different racial and ethnic

groups, this project will have a positive impact on reducing long-standing disparities in CRC outcomes.