UF Health researchers have used a promising approach by integrating CRISPR-cas9-based drug screening with patients’ clinical outcome to identify genes and pathways that predict how patients will respond to the standard firstline chemotherapy treatment regimen used to treat patients with acute myeloid leukemia, or AML.
Led by Jatinder Lamba, Ph.D., co-leader of the UF Health Cancer Center’s Cancer Targeting and Therapeutics research program, the team identified genes that were associated with resistance or sensitivity to chemotherapy and linked these with patients’ treatment outcomes. The findings, published recently in the American Society of Hematology’s journal Blood Advances, could help develop new treatments to overcome resistance to chemotherapy.
“These results are very exciting as they not only open up opportunities for predicting outcomes and personalizing treatment regimens, but also targets for novel drug discovery or the potential for drug repurposing,” said Lamba, associate dean for research and graduate education and professor in the UF College of Pharmacy.
Three drugs — cytarabine, daunorubicin, and etoposide — have been the standard backbone of chemotherapy for patients with AML for more than five decades. Yet, a significant number of patients become resistant to this regimen, known as ADE, leading to relapse and poor survival rates.
In the new study, Lamba’s team used the Cancer Center’s CRISPR Functional Screening Shared Resource, led by Christopher Vulpe, M.D., Ph.D., to perform genome-wide CRISPR/cas9-based synthetic lethal screening for the three drugs used in the ADE regimen to treat pediatric AML.
Genes that were enriched or deleted, reflecting their association with drug resistance or sensitivity, were then investigated in 775 patients with AML treated with ADE across three clinical trials.
The researchers found several hits and highlighted three resistant genes, BCL2, CLIP2, and VAV3, linked to poor clinical outcomes, and three sensitive genes, GRPEL1, HCFC1, and TAF10, linked to beneficial outcomes.
Deleting the resistant genes made cells more sensitive to treatment, the researchers said, indicating those genes should be further studied as possible therapeutic targets to overcome resistance to chemotherapy.
“Our findings emphasize the pivotal integration of CRISPR/Cas9-based synthetic lethal screens with patient outcomes, establishing this platform as a powerful instrument to collect meaningful data about prognostic markers, novel therapeutic targets, drug response mediators, and development approaches for novel drug combinations,” Lamba said.
Notably, the first selective drug that inhibits BCL2, venetoclax, has been approved to treat adults with newly diagnosed AML. Its use in pediatric patients remains limited and not well-studied. The new study suggests that using BCL2 inhibitors like venetoclax in combination with ADE could overcome drug resistance and potentially improve outcomes in pediatric patients, the researchers said.
Next, the team plans to validate the findings in adult AML and other trials, as well as establish the clinical utility of the findings as a prognostic test in patients and a decision-making tool to design a more effective treatment plan.
The study’s first author was Nam Nguyen, a recipient of one of the UF Health Cancer Center’s 2022 Predoctoral Awards and a graduate student in Lamba’s lab. Vulpe, a UF Health Cancer Center member and professor in the Department of Physiological Sciences in the UF College of Veterinary Medicine, was also a co-author.
The study received funding from the National Cancer Institute (R01CA132946 and R01CA270120: Lamba, Vulpe), UF Research Opportunity Seed funds, and UF Health Cancer Center, which receives crucial support for its research from the Casey DeSantis Cancer Research Act (Fla. Stat. § 381.915).
