R01CA261898

Predicting and Preventing Chemotherapy-Induced Cardiotoxicity in African American Children - Project Summary

Doxorubicin is a member of the anthracycline group of chemotherapy drugs prescribed to approximately 60% of pediatric cancer patients suffering from sarcomas, blastomas, leukemia, and lymphoma. Although doxorubicin is highly effective in these patients, approximately 16% of pediatric patients suffer from doxorubicin-induced cardiotoxicity (DIC), which can lead to heart failure requiring a heart transplant. Recent research has shown that DIC is 2.5 times more prevalent in African American (AA) survivors of childhood cancer. Despite over 50 years of research in this field, there is currently little potential for either predicting or preventing DIC. Therefore, there is a clear need for novel and innovative approaches to overcome this hurdle.

Candidate gene and genome-wide association studies, predominantly in Europeans, have identified over 100 single nucleotide polymorphisms (SNPs) that are statistically correlated with DIC. However, experimental validation has not been feasible due to the difficulty in isolating and culturing human cardiomyocytes in vitro. In recent work, it has been shown that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are efficient predictors of a patient's likelihood of developing DIC, confirming for the first time that there is a genomic basis to DIC.

Here, we hypothesize that hiPSC-CMs can be utilized in three different modalities to study genetic variants associated with DIC in AA survivors. Firstly, to discover novel predictive SNPs; secondly, to validate SNPs; and thirdly, to examine the modulated pathways and determine genotype-specific cardioprotective methodologies.

In Aim 1, we will generate hiPSCs from 100 AA adult survivors of childhood cancer with diverse biological covariates who were exposed to doxorubicin. We will assess their response to doxorubicin in vitro to validate our previous findings and verify the power of this tool.

In Aim 2, we will use these 100 patient-specific lines to identify drug response differential expression, splicing, and chromatin accessibility quantitative trait loci (DEQTL, DSQTL, and DCAQTL), assessing biological covariates such as doxorubicin dose, age at cancer diagnosis, attained age, sex, BMI, radiotherapy (other than involving the chest), and cancer diagnosis both individually and combined. We will then validate these variants with genome editing and mechanistically examine pathways causative to DIC susceptibility, focusing on genes with known roles in cardiomyopathy, cardioprotection, and doxorubicin metabolism. We will use these discoveries to discover/repurpose genome-informed cardioprotective drugs to prevent DIC in a genotype-specific manner.

In Aim 3, we will build a risk prediction model for DIC among AA survivors, incorporating clinical risk factors and functionally assessed genetic variants. We will evaluate its prediction performance, validate it in independent AA survivors, and implement it in a web-based and user-friendly tool for broader clinical and research use.

In summary, this work will deliver the genetic rationale for why AA survivors experience DIC and provide fully human validated SNP data for clinical application through a user-friendly tool. Additionally, it will uncover novel cardioprotective pathways that can be targeted to protect against DIC.

Northwestern University

TO IDENTIFY CANCER RISKS AND RISK REDUCTION STRATEGIES, TO IDENTIFY FACTORS THAT CAUSE CANCER IN HUMANS, AND TO DISCOVER AND DEVELOP MECHANISMS FOR CANCER PREVENTION AND PREVENTIVE INTERVENTIONS IN HUMANS. RESEARCH PROGRAMS INCLUDE: (1) CHEMICAL, PHYSICAL AND MOLECULAR CARCINOGENESIS, (2) SCREENING, EARLY DETECTION AND RISK ASSESSMENT, INCLUDING BIOMARKER DISCOVERY, DEVELOPMENT AND VALIDATION, (3) EPIDEMIOLOGY, (4) NUTRITION AND BIOACTIVE FOOD COMPONENTS, (5) IMMUNOLOGY AND VACCINES, (6) FIELD STUDIES AND STATISTICS, (7) CANCER CHEMOPREVENTION AND INTERCEPTION, (8) PRE-CLINICAL AND CLINICAL AGENT DEVELOPMENT, (9) ORGAN SITE STUDIES AND CLINICAL TRIALS, (10) HEALTH-RELATED QUALITY OF LIFE AND PATIENT-CENTERED OUTCOMES, AND (11) SUPPORTIVE CARE AND MANAGEMENT OF SYMPTOMS AND TOXICITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO STIMULATE TECHNICAL INNOVATION, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, AND FOSTER PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS.

93.393 - Cancer Cause and Prevention Research

National Cancer Institute (NCI) [HHS - NIH]

Illinois United States

State-Wide

Research to Reduce Morbidity and Improve Care for Pediatric, and Adolescent and Young Adult (AYA) Cancer Survivors (R01 Clinical Trial Optional) (RFA-CA-20-027)

Amendment Since initial award the End Date has been shortened from 07/31/26 to 07/31/25 and the total obligations have increased 323% from $684,513 to $2,892,098.