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Novel Drug Shows Promise in Acute Myeloid Leukemia by Suppressing Two Proteins


A novel drug that targets MDMX and MDM2, which inhibit a protein that suppresses tumors when they are overexpressed, has tripled the median survival rate in an animal model of human acute myeloid leukemia, according to new research.

The first in a new class of anti-cancer agents has shown promise against acute myeloid leukemia (AML), according to findings published in Science Translational Medicine. The findings led to a phase 1/2 clinical trial for patients with advanced AML and advanced myelodysplastic syndrome.

The research, from investigators at Albert Einstein College of Medicine, describes how an experimental drug, ALRN-6924, targets p53, a protein that is inactivated in AML. The drug inhibits the proteins MDMX and MDM2, both of which inactivate p53 when they are overexpressed. When p53 is activated, it suppresses tumors.

In preclinical studies, ALRN-6924 tripled the median AML survival rate in mice transplanted with human leukemia cells, from 50 days to approximately 150 days.

“This is a very striking response,” study leader Ulrich Steidl, MD, PhD, professor of cell biology and of medicine and the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research at Einstein and associate chair for translational research in oncology at Montefiore Health System, said in a statement. “Most experimental drugs for leukemia achieve an increase in survival of only a few days in these preclinical models. Even more importantly, ALRN-6924 effectively cured about 40% of the treated mice, meaning they were disease free more than one year after treatment—essentially a lifetime for a mouse.”

AML is an often-lethal cancer with only 27% of people who are diagnosed surviving for 5 or more years. Furthermore, in the past half century, the outcomes for AML have not significantly improved, according to a press release from Albert Einstein College of Medicine.

The research found that not only did ALRN-6924 block interaction of both MDMX and MDM2 with p53 in more mature AML cells, but the effect was also seen in the immature stem cells that produce AML cells.

“This is important because AML is driven by stem cells—and if you don’t target stem cells, the disease will come back very quickly,” Steidl said.

He added that some other cancers driven by overexpression of MDMX and MDM2 and inactivation of p53, such as some forms of breast cancer and lung cancer, could potentially be treated with ALR-6924.


Carvajal LA, Ben Neriah D, Senecal A, et al. Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia [published online April 11, 2018]. Sci Transl Med. doi: 10.1126/scitranslmed.aao3003.

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