Results of preclinical research suggest the Hedgehog signaling pathway works with FLT3-ITD mutations to accelerate the development of acute myeloid leukemia (AML).
This finding prompted investigators to look at Hedgehog signaling as a possible second target for treatment in FLT3-ITD AML.
By combining the FLT3 inhibitor sorafenib with the Hedgehog pathway inhibitor IPI-926 (saridegib), the team found they could limit AML growth in vitro and in vivo.
William Matsui, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues conducted this research and disclosed the results in Science Translational Medicine.
The investigators began this work with the goal of discovering why FLT3 inhibitors have fallen short in treating AML. They analyzed gene expression profiles from AML patients and found abnormally enhanced activity in the Hedgehog signaling pathway.
This pathway, which normally regulates embryonic development, is known to fuel many cancer types, but its role in AML has, thus far, remained unresolved.
In experiments with mice, the investigators found the Hedgehog pathway seemed to work together with FLT3 to accelerate AML development and earlier death.
When the team activated Hedgehog signaling in mice expressing FLT3-ITD, they observed enhanced STAT5 signaling, myeloid progenitor proliferation, and AML development.
“From our data, it appears that Hedgehog signaling is like an accelerator,” Dr Matsui said. “It facilitates the cellular events that lead to cancer, but it itself is not the driver of the whole process.”
The investigators also found that mice with both the FLT3 mutation and Hedgehog activity had a significantly shorter lifespan than mice with FLT3-ITD only—an average of 12 weeks and 40 weeks, respectively.
To build upon these findings, the team tested IPI-926 and sorafenib, both alone and in combination, in mice with AML. They found that mice treated with the combination had significantly fewer leukemic cells in the blood and bone marrow than mice treated with either drug alone.
In addition, 3 of the 5 mice treated with the combination survived past the 16 days of the experiment without any further treatment, but none of the mice treated with sorafenib or IPI-926 alone survived that long.
“When we treat mice that have leukemia with both drugs, they live longer than with either drug alone, and there is a portion of them that don’t die at all,” Dr Matsui noted.
He said it’s likely that Hedgehog signaling is involved in the progression of a number of cancers, and “this study brings home the idea that, in treating these cancers, clinicians may need to inhibit Hedgehog along with specific gene mutations.”
Dr Matsui and his colleagues have begun investigating how Hedgehog inhibitors work when combined with newer drugs that target FLT3 more precisely than sorafenib. If these tests continue to show signs that the two types of inhibitors can fight AML, the investigators think such combination therapy could move on to clinical trials.
