(from left) Charles Chalfant, PhD; Thomas P. Loughran Jr., MD; and David Feith, PhD
UVA Comprehensive Cancer Center Director Thomas P. Loughran Jr., MD, and Professors of Medicine/Hematology and Oncology Charles Chalfant, PhD, and David Feith, PhD, have been awarded a new five-year, $13 million National Cancer Institute (NCI) program project grant to lead a multi-institution, interdisciplinary study seeking new therapies for acute myeloid leukemia (AML).
A rare cancer and the deadliest form of leukemia, AML is primarily diagnosed in older patients with a median age of 68. It occurs when myeloid cells mutate and multiply in the bone marrow and blood, crowding out the healthy blood cells that carry oxygen, form clots, and fight infections.
Treatment options for AML include chemotherapy, stem cell transplants, immunotherapy, drugs targeting proteins that support the cancer’s growth, and a growing number of combination therapies. While chemotherapy is the traditional first-line method of driving the disease into remission, its effectiveness varies between cases, it’s less tolerated by older patients, and therapy-resistant reoccurrence is prevalent, thus demonstrating the need for new and more tailored treatments.
“We’ve made great progress understanding how AML works and how patients respond to treatment differently,” Dr. Loughran said. “This project will build on that, drawing on disciplines ranging from hematology to the engineering of nanotechnology to deliver new therapies directly to cancer cells. We’re thrilled to continue this collaborative work to reduce the impact of this devastating disease.”
Through ten years’ previous NCI funding, research by Drs. Loughran and Feith, along with colleagues including Kevin Janes, PhD, the John Marshall Money Professor of Biomedical Engineering, and Bishal Paudel, PhD, Assistant Professor of Medicine/Hematology and Oncology, has advanced understanding of how to treat individual AML cases more effectively.
Inside AML cells are molecules called sphingolipids, including a subtype called ceramides. Sphingolipids support signaling between cells, and researchers believe they play a role in AML’s growth and treatment resistance. The UVA team found that measuring the sphingolipids in a patient’s cells identifies a new AML classification method that can determine whether they are at greater risk of resistance to chemotherapy and should pursue alternate therapies, including clinical trials (read more). Additionally, the team found that key “escape” pathways linked to ceramides are crucial targets to stymie the growth and survival of AML cells.
These efforts spawned an upcoming clinical trial studying the potential of nanotechnology to deliver specific ceramides to AML cells and led by Michael Keng, MD, Associate Professor of Medicine/Hematology and Oncology, “Study of C6 Ceramide NanoLiposome in Patients With Relapsed/Refractory Acute Myeloid Leukemia” (KNAN2001; NCT04716452).
The new five-year program project, titled “Ceramide-Directed Therapeutics for Treatment of AML,” seeks to further study and categorize sphingolipids in AML, and to develop and test targeted treatments to reduce ceramide metabolites that support the disease’s spread, and replace them with ceramides that will kill it.
“There is a strong clinical need to improve treatment outcomes for AML. Through this award, our team will now be able to build the foundational research to rapidly bring new therapeutic avenues for this disease to the bedside,” stated Chalfant.
Drs. Todd Fox, Francine Garrett-Bakelman, Tim Martin, Su-Fern Tan, Helen Xie, Guofen Yan, and Hong Zhu are also key UVA collaborators on the award, along with researchers at Pennsylvania State University, Wake Forest University, the University of Arizona, Jacksonville State University, and Memorial Sloan-Kettering Cancer Center. The project and upcoming clinical trial are possible thanks to funds from the National Institutes of Health/National Cancer Institute (P01CA171983, P01CA302570), the Commonwealth Fund for Cancer Research, and Scarlet Feather Fund support of UVA’s Translational Orphan Blood Cancer Research Initiative.