Compound Improves Survival in Acute Myeloid Leukemia
Experimental drug could may lead to new treatments for AML, lung cancer, brain cancer, and melanoma.
A new compound showed promise for patients with acute myeloid leukemia (AML), extending the median days of survival by more than double in a recent study.
MRX-2843 was created to specifically target 2 cell signaling proteins, tyrosine kinases, which help drive abnormal cell growth in AML, non-small cell lung cancer, glioblastoma, and melanoma.
During the study, published in JCI Insight, MRX-2843 was found to block the cell growth of AML, resulting in a dramatic level of cancer cell death.
“Our data indicate that this could be a superior drug for certain resistant forms of acute myeloid leukemia; however, it has to be tested in clinical trials," said researcher Shelton Earp, MD. “We know that leukemia can develop resistance to drugs similar to ours. The questions is: Would this new UNC inhibitor give patients with resistant acute myeloid leukemia longer survival? This is a particularly salient question for older AML patients who can't tolerate high doses of chemotherapy and bone marrow transplant.”
The protein MERTK was found to be over-expressed in AML cells, and researchers looked to develop a compound that could block this protein. However, researchers later discovered that the MRX-2843 also has the ability to block the protein FLT3.
FLT3 is associated with worsening outcomes for patients with AML and is mutated in 20% to 30% of adults and 10% to 15% of children.
“We examined the structure of a small molecule bound at the active site of the MERTK tyrosine kinase enzyme, and then we designed compounds to be more potent or selective,” said lead researcher Stephen Frye, PhD.
During the study, researchers examined more than 1500 compounds that targeted MERTK.
“Our research has shown that when the MERTK protein in a cell is 'turned on,' it can give a cancer cell a survival advantage and often make the cancer cell less responsive to traditional chemotherapy drugs,” said initial discoverer of MERTK, Doug Graham, MD, PhD. “We have been working as a team across multiple labs to develop drugs that effectively 'turn off' the MERTK protein. The MRX-2843 compound is effective at targeting cancer cells with activated MERTK. With the FDA's IND approval to start a first-in-human clinical trial, we hope to bring this drug to adults battling these specific cancers, and ultimately if successful in adults, to the pediatric population.”
Mice with human AML tissue administered the compound orally once daily experienced 2- to 3-fold increased survival.
Additionally, the drug had a positive effect on AML models that developed a resistance to another potential drug. Mice with 1 of 2 additional FLT3 mutations treated with MRX-2843 saw increased survival from 35.5 to 94 days.
A different developmental drug for AML and mutated FLT3 showed an increased survival from 36 to 45 days.
“We know that mutations arise where other compounds bind in the active site of FLT3 so that they will no longer bind,” Frye said. “Data from this study show that our compound is still potent against these resistant mutants because ours has a different binding mode.”