Hit the Cancer Where It Lives: A New Approach to Treating AML

Yael Waknine

January 27, 2014

Destroying a cancer's home rather than trying to pin down a mutating target might represent a new treatment paradigm, according to a letter published online January 15 in Nature.

Researchers made this suggestion after they found that many patients with acute myeloid leukemia (AML) actually have a mutation in their bone-building osteoclast cells, and that this mutation causes the cancer in mice.

"If the mutation works the same way in humans, our study suggests practical ways that we may be able to intervene with a drug or an antibody. It may give us a tool for a disease that is rarely curable, " said lead investigator Stavroula Kousteni, PhD, associate professor of medical sciences in medicine and physiology and cellular biophysics at Columbia University Medical Center (CUMC) in New York City.

"What we have shown is that leukemia arises from an interaction between a hematopoietic stem cell and its microenvironment — in this case, the osteoblast — which may be more amenable to drug therapy. It's easier to target a cell that won't mutate than a [cancer] cell constantly changing identities, Dr. Kousteni told Medscape Medical News in an interview.

Using a scientifically vetted mouse model of AML and its precursor, myelodysplastic syndrome (MDS), the researchers were able to define the mechanism by which stem cells and osteoblasts interact, which begins with a mutated β-catenin protein within osteoblasts. The mutated protein triggers production of jagged 1, which is then expressed on the cell surface, binds to Notch receptors on bone marrow stem cells, and triggers their transformation into leukemic blasts.

Moreover, the researchers were able to reverse hematopoietic deregulation and myeloid expansion — which stopped AML in its tracks — using a ɣ-secretase inhibitor to pharmacologically inhibit Notch signaling.

But the story doesn't stop there. In this prime example of bidirectional translational research, clinical investigators from both CUMC and the Memorial Sloan-Kettering Cancer Center collaborated to determine whether this basic-research pathway could translate into real-life medicine.

The team, led by Azra Raza, MD, director of the MDS Center at CUMC, found that the pathway was indeed present in 38% of bone marrow biopsies obtained from patients with AML and MDS from 2000 to 2008.

"The pathway exists and it is active; 38% of patients had increased β-catenin signaling in the nucleus, increased expression of the jagged 1 protein, and upregulation of Notch signaling in their bone marrow cells," Dr. Kousteni said.

Dr. Kousteni's team is currently working with Pfizer to develop an antibody that will block the pathway in mice, which could lead to a treatment option for a significant percentage of patients with AML and MDS.

"This incredibly important observation opens the possibilities of novel therapies for these dreaded diseases using nonchemotherapeutic approaches," Dr. Raza concluded in a news release.

The study was supported by the National Institutes of Health, the Division of Hematologic Oncology at Memorial Sloan-Kettering Cancer Center, and a European Union Marie Curie Fellowship. Dr. Kousteni reports working with Pfizer.

Nature. Published online January 15, 2014. Abstract

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