Project 2: Translating Genomics to Practice to Overcome Disparities in Diffuse Large B-Cell Lymphoma (DLBCL)

PROJECT 2_ TRANSLATING GENOMICS TO PRACTICE TO OVERCOME DISPARITIES IN DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL): ABSTRACT Patients with diffuse large B-cell lymphoma (DLBCL) have widely divergent outcomes: some patients are cured with frontline therapy, but ~40% relapse and often have a poor prognosis. Investigation of biologic factors contributing to differences in outcomes have been stymied by limited representation of some groups even in the largest clinicopathologic cohorts and clinical trials. Our research team is uniquely equipped to address this challenge, given our access to (1) large collaborative biorepositories distinguished from similar lymphoma databases by availability of specimens and data from patients in proportions that match the US population, and (2) established clinical trial networks of community oncology practices that serve patients with lymphoma. To bridge this knowledge gap, we will analyze RNA and whole-exome sequencing data from large DLBCL patient cohorts and examine whether existing molecular prognostic classifiers adequately risk-stratify all patients with DLBCL. We will expand our library of patient-derived xenograft tumors to provide a resource for investigating the molecular etiology of DLBCL and assess response to novel therapies in tumors with ancestry-related biologic characteristics. Finally, we will evaluate evidence-based strategies to promote enrollment to a DLBCL clinical trial that incorporates next-generation sequencing into selection of frontline chemoimmunotherapy regimen conducted in community practices. By incorporating a cells-to-society approach, our proposal will (1) define specific molecular and immune features of DLBCLs and their microenvironment across populations; (2) directly test their therapeutic vulnerabilities using innovative, ancestry-specific model systems; and (3) deploy diagnostic and treatment workflows geared for community practices.