Project 3: Pharmacogenomic advancements for improved treatment of acute lymphoblastic leukemia in Latino children and adolescents

Project 3: Pharmacogenomic advancements for improved treatment of acute lymphoblastic leukemia in Latino children and adolescents Project Summary There is existing and emerging evidence that germline genetic variants can strongly influence the risk of toxicity of acute lymphoblastic leukemia (ALL) therapeutics and supportive care medications. For example, variants in TPMT and NUDT15 are known to confer an increased risk of mercaptopurine-induced myelosuppression. Additionally, recent genomic studies have been instrumental in identifying other novel genes and variants associated with various treatment-related effects, including but not limited to 1) CPA2 and asparaginase-induced toxicities, 2) CEP72 and vincristine-induced peripheral neuropathy, and 3) G6PD and rasburicase-induced hemolytic anemia. These data warrant the emerging effort to incorporate key variants from these genes in clinical pharmacogenomic (PGx) testing panels for children diagnosed with ALL for use in guiding clinical care. Despite the promise of clinical PGx panels, key implementation gaps remain, especially among at-risk populations. First, there have been few efforts to evaluate the frequency of actionable variants among Latino children compared to children of European ancestry or whether there are differences based on self-reported demographic factors versus estimated genetic ancestry; these knowledge gaps limit our understanding of the utility of these panels in all populations. Second, there have been no well-developed clinical trials focused on at-risk populations to evaluate the impact of returning clinical PGx panel results to families affected by ALL; this limits the ability to provide these families with effective counseling and recommendations regarding treatment and surveillance options. Third, the majority of PGx assessments have been conducted among individuals of European ancestry, which limits the addition of Latino-specific variants on clinical PGx panels that might more accurately predict treatment-related effects. Based on these gaps, our overall hypothesis is that Latinos experience more treatment-related toxicity and may particularly benefit from PGx-guided individualization of therapy to mitigate adverse outcomes. Co-led by Drs. Brooke Bernhardt, Stacey Pereira, Hadley Stevens Smith, and Philip Lupo Project 3 will leverage the REDIAL Retrospective and Prospective Cohorts to evaluate our hypothesis in the following aims: 1) Implement a clinical PGx panel in a large population of ALL patients and evaluate clinical and family-centered outcomes and 2) Identify Latino-specific PGx variants in ALL drug-gene pairs that are associated with treatment-related toxicities. There is compelling evidence that pharmacogenomics can be leveraged to mitigate treatment-related effects, particularly toxicities, among Latinos. We will comprehensively address the implementation of PGx testing and identify novel, Latino-specific PGx-related variants in a population of children and adolescents with ALL. Ultimately, findings from this project will inform novel risk stratification strategies and genetic testing protocols among children and adolescents diagnosed with ALL. Project Number: 1U54CA302464-01 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Philip Lupo | Institution: BAYLOR COLLEGE OF MEDICINE, HOUSTON, TX | Award Amount: $262,326 | Activity Code: U54 | Study Section: Special Emphasis Panel[ZCA1 RPRB-L (M1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11199464