Dana-Farber researchers highlight progress with new drugs for acute myeloid leukemia

Boston Children's Kimberly Stegmaier

Researchers at the Dana-Farber Institute and the Boston Children's Cancer and Blood Disorders Center turned up at ASH in Orlando to showcase several new programs they've been working on for acute myeloid leukemia.

The first was a study using a nuclear export inhibitor, KPT-8602, which prevents the cancer cells from moving protein out of the nucleus. KPT-8602 is a next-generation inhibitor from a class of drugs called selective inhibitors of nuclear export (SINE). Thomas Look and his colleagues are hopeful that this inhibitor will outperform the currently used SINE, selinexor, both in terms of tolerability and specificity towards malignant AML cells and AML leukemia-initiating cells, which are responsible for cancer relapse.

Abstract title: "Nuclear export inhibitor KPT-8602 is highly active against leukemic blasts and leukemia-initiating cells in patient-derived xenograft models of AML" (abstract 326).

In the second study, Kimberly Stegmaier and colleagues showed that by switching off the folate metabolism enzyme, MTHFD2, located in the mitochondria cell and importantly, elevated in cancer cells, they could inhibit AML cell growth. This enzyme has been poised as a new candidate for drug development.

Abstract title: "Targeting MTHFD2 in acute myeloid leukemia" (abstract 443).

The third study introduced a novel compound BRD0705 and its efficacy in blocking the action of GSK3-alpha signaling and cell growth using an AML cell line. GSK3-alpha is known to control aspects of cell metabolism and has been previously identified as an AML drug target, but no one until now has proposed a candidate.

Abstract title: "Identification of a first in class GSK3-alpha selective inhibitor as a new differentiation therapy for AML" (abstract 870).

The fourth study, another by Stegmaier's lab, found that CKMT1B, which is co-regulated with a transcription factor EVI-1, could be a possible drug target in AML cells. In AML patients that have higher level of EVI-1, they are predicted to have a worsened outcome, and EVI-1 requires CKMT1B for the cell's survival.

Abstract title: "Identification of CKMT1B as a new target in EVI1-positive AML" (abstract 3674).

"AML led the genomic sequencing revolution in cancer," Stegmaier concluded. "The first cancer genome sequenced was from a patient with AML. We have learned a great deal since then. There are a number of new treatment approaches being tested in the clinic that are very exciting. These abstracts reflect just a few of the emerging targets of great interest."

- here's the release

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