A Promising New Candidate for Overcoming Multiple Myeloma Treatment Resistance

Dr. Zhao found that sensitivity to daratumumab, an approved multiple myeloma treatment, may be rescued and restored using miR-26a.

06/08/2020

New findings from the lab of Jianjun Zhao, MD, PhD, may offer early hope for researchers and clinicians who have long been troubled by the challenge of treating patients with multiple myeloma, a cancer of plasma cells (a type of blood cell found in bone marrow that plays an important role in the immune system).

While the U.S. Food and Drug Administration has approved daratumumab (a monoclonal antibody) as a treatment for multiple myeloma, it has only increased patient survival by a few months. Unfortunately, cancer cells quickly develop resistance to the drug, causing patients to develop a more aggressive and currently untreatable form of the disease.

Published in Cancer Research, findings from Dr. Zhao’s latest study suggest that daratumumab sensitivity may be rescued and restored using miR-26a, a micro-RNA that has been shown to be a tumor suppressor in a host of other cancers (including osteosarcoma, lymphoma and colorectal cancer). “While additional research will be important to expand upon our findings, I believe we have identified a promising candidate for combination therapy, and one which may help to overcome treatment resistance,” said Dr. Zhao.

His lab, part of the Department of Cancer Biology, found that administering miR-26a using carbon nanotubes—a site-specific drug delivery solution—significantly thwarted cancer cell spread and increased survival in preclinical models of multiple myeloma.

“On a cellular level, we saw that these cancer-fighting effects were mediated by miR-26a’s effect on another protein called CD38,” explained Dr. Zhao. CD38 is a protein, more specifically called an antigen, found on the surface of multiple myeloma cells. This is the same protein targeted by daratumumab, which works by reducing CD38 levels. When CD38 expression is reduced, as is caused by taking daratumumab, it causes multiple myeloma cells to die.

“So we see that miR-26a works to fight cancer in two ways, really,” clarified Dr. Zhao. “It inhibits the proliferation and spread of multiple myeloma cells, and it also ‘quiets’ CD38, which leads to cancer cell death.”

In the early stages of daratumumab treatment, when it is still effective, CD38 levels are low. “This is as we would expect to see,” said Dr. Zhao. “When cancer cells become resistant to the drug, however, CD38 levels climb back up to pre-treatment levels and this is wherein the trouble lies.”

When daratumumab can no longer keep CD38 expression low on its own, Dr. Zhao believes miR-26a may help, either alone or in combination with other drugs. “miR-26a could be like a jumpstart that helps resensitize multiple myeloma cells to daratumumab so that the drug may be effective for longer.”

It is important to note that this study revealed miR-26a regulates CD38 levels using an independent cell signaling pathway than the monoclonal antibody, explaining why it is an ideal candidate.

Yi Hu, PhD was first author on the study, which was supported in part by the National Cancer Institute, National Center for Advancing Translational Sciences (both parts of the National Institutes of Health), the V Foundation and the Clinical and Translational Science Collaborative of Cleveland.



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