Medications designed to block a signaling protein called NOTCH3 — which plays a key role in the function and survival of cells in the body — may help eliminate myeloma cells that are resistant to conventional treatments, according to a new study led by U.S. scientists.
The researchers noted that further work is needed to explore the effectiveness and safety of this approach — thus far tested only in the laboratory — before the results can be translated to humans. Still, the scientists say these findings may form the basis for new therapies that can improve outcomes for myeloma patients.
In investigating NOTCH3, the team found a “vulnerability in both cells refractory [resistant] to therapy and dormant cells.” Testing in a mouse model suggested that this “can be exploited to overcome the diverse mechanisms by which cancer cells evade therapy, potentially preventing disease relapse and extending remission in patients with [multiple myeloma] MM.”
An early access version of the study, “Targeting NOTCH3 to eradicate dormant and therapy-resistant multiple myeloma cells,” was published in the Journal of Experimental & Clinical Cancer Research. The work was led by researchers at the University of Arkansas for Medical Sciences.
Myeloma is a type of blood cancer that develops when plasma cells, a type of immune cell, grow unchecked in the bone marrow. Treatment options typically involve chemotherapy, radiation, immunotherapy, and targeted therapies. However, some myeloma cells are resistant to these conventional treatments, allowing them to survive and drive future disease progression.
Further complicating matters, myeloma therapies are usually most effective at killing cells that are actively dividing — meaning cells that are dormant at the time of treatment can evade destruction, only to become active later on and drive disease progression.
Trying to eliminate dormant and treatment-resistant myeloma cells
In this study, the research team sought to identify molecular pathways common to both treatment-resistant and dormant myeloma cells. The researchers reasoned that, if both types of cells rely on some of the same pathways, it may be possible to create new drugs that can simultaneously eliminate both sources of disease progression.
“One potential strategy to overcome drug [resistance] and dormancy is to identify shared vulnerabilities across different therapy-resistant cell populations for simultaneous eradication,” the researchers wrote.
Through lab tests paired with analyses of previously published genetic datasets, the researchers found that dormant myeloma cells exhibit increased activity of a molecular pathway known as the NOTCH signaling pathway. The researchers also found that NOTCH3, a key component of the same signaling pathway, was present at high levels in myeloma cells that are resistant to bortezomib, an approved myeloma treatment sold as Velcade and its generics.
These results provide a compelling rationale for developing safe Notch inhibitors as a new therapeutic tool to expand the arsenal of treatment options and improve clinical outcomes in relapsed/refractory patients.
Further laboratory tests revealed that an antibody inhibiting the NOTCH3 protein could induce programmed cell death, or apoptosis, in bortezomib-resistant myeloma cells. In a myeloma mouse model, the NOTCH3-targeting antibody eliminated treatment-resistant and dormant cells, while also reducing bone disease.
More research is needed to translate these results into potential treatment strategies for people with myeloma, the scientists noted.
Still, “these results provide a compelling rationale for developing safe Notch inhibitors as a new therapeutic tool to expand the arsenal of treatment options and improve clinical outcomes in relapsed/refractory patients,” the team concluded.
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