Pelotonia-Funded Studies That Could Have Wide Impact
Investigating a Potential New Treatment for AML
Adult acute myeloid leukemia (AML) is an aggressive form of blood cancer in which large numbers of immature white blood cells accumulate in the bone marrow, the sponge-like tissue in the center of many bones where blood cells and platelets are produced.
Complex gene and chromosomal abnormalities lock AML cells into a state of immaturity, while also pushing them to keep dividing and proliferating. Much has been learned about AML, but cures remain elusive. Treatments often fail, and older patients may be too frail to tolerate potent chemotherapy regimens.
Rosa Lapalombella, PhD, associate professor in the Division of Hematology, and John C. Byrd, MD, Distinguished University Professor of Medicine, Medicinal Chemistry and Veterinary Biosciences, and the D. Warren Brown Designated Chair in Leukemia Research, were awarded a Pelotonia Idea Grant to investigate a potential new targeted agent for AML. Their study grew from earlier discoveries they made at the OSUCCC – James, and their findings should provide important insights that could move the agent toward testing in a clinical trial.
The researchers are studying a new agent, called KPT-9274, that blocks a molecule in AML cells called NAMPT. The researchers say the preclinical study should provide important insights into the effects of this inhibitor.
“Unlike many targeted therapies that can be directed at only one subtype of AML, this drug might be useful for treating several AML subtypes that all depend on NAMPT,” Lapalombella says.
NAMPT is critical for the survival of AML cells in two ways. First, fast-growing AML cells consume more energy than slower-growing healthy cells. They make abnormally high levels of NAMPT to produce that energy, and the researchers believe that the new inhibitor will fatally starve the malignant cells of the energy they need to grow.
In addition, NAMPT is an essential part of a critical DNA-repair mechanism. Blocking the enzyme may cripple the ability of AML cells to repair DNA damage, which would make them more susceptible to chemotherapy. That might allow the use of lower doses of chemotherapy that older patients can better tolerate. The researchers are studying that question, also.
“Along with complex chromosome changes, the AML cells in patients can have many genetic differences among them,” Lapalombella says, “and there are many subtypes of AML. These complexities make it very difficult to identify molecules in AML cells that could be targets for potential new therapies. We are hoping this Pelotonia-supported research will help bring this promising agent to AML patients in a clinical trial.”
Understanding the Flow of Chemotherapy to a Tumor
A malignant tumor is much more than a mass of cancer cells. Cancerous tumors also include normal cells from the organ, immune cells and cells that form blood vessels. Also in the mix are cells called fibroblasts, which produce the scaffolding that holds the tumor together. Last, a meshwork of filaments and proteins called the extracellular matrix (ECM) cradles the cells within a tumor.
OSUCCC – James researcher Jonathan Song, PhD, assistant professor in the College of Engineering’s Division of Mechanical and Aerospace Engineering, received a Pelotonia Idea Grant to study how tumor fibroblasts alter the ECM in ways that impede the movement of chemotherapy drugs.
Using microtechnology, tissue engineering and 3-D imaging, Song and his collaborator Michael Ostrowski, PhD, at the Medical University of South Carolina, have developed a model that enables them to study molecular changes that alter the flow of fluid through the ECM. Such changes could affect the diffusion of chemotherapy drugs through the tumor.
The researchers are using fibroblasts from pancreatic cancer patients to learn how flow conditions change when mutations are present in a gene called PTEN. Their work suggests when PTEN is silenced, the flow of fluid through the ECM is significantly reduced compared to the flow when using fibroblasts from healthy tissue.
“Our findings suggest that the loss of PTEN causes tumor fibroblasts to physically alter the ECM in ways that reduce the movement of fluid to and around tumor cells,” Song says, “and that could reduce the delivery of chemotherapy to malignant cells in the tumor, making the drugs less effective.”
Their findings, if verified in a larger study, also suggest that drugs that target changes in fibroblasts or other noncancerous tumor cells might block changes in the ECM and make chemotherapy more effective.