New Target to Treat Multiple Myeloma

December 1, 2020

Multiple myeloma (MM) is a fatal plasma cell disorder, associated with the accumulation of malignant plasma cells in the bone marrow, kidney failure, and bone destruction. Though the FDA has approved 12 therapies for MM with different mechanisms of action over the past 16 years, patients still have an overall median survival of only five to six years and patients with relapsed or refractory MM have even poorer clinical outcomes.

“Unlike the tailored approach that oncologists take with different types of lymphoma and leukemia, historically, oncologists treat all myelomas the same,” says Suzanne Lentzsch, MD, PhD, professor of medicine at Columbia University Vagelos College of Physicians and Surgeons and director of the Multiple Myeloma and Amyloidosis Program at the Herbert Irving Comprehensive Cancer Center (HICCC).

Taking a different tactic, Dr. Lentzsch and her collaborators have identified a promising new drug target in a subset of MM cases, those with RAS mutations. The work was recently published in the journal Blood.

Mutations of the RAS gene family play a key role in many cancers, and frequent mutations of the RAS genes NRAS, KRAS, and BRAF are found in up to 50% of newly diagnosed cases of MM. Targeting RAS mutations in MM might improve the response rate and increase the number of patients with long-term remission. But because RAS mutations have been considered undruggable in hematologic malignancies, researchers haven’t even been looking for ways to target them, and clinicians have lacked ways to treat them.

Though the enzyme germinal center kinase (GCK) appears to play an important role in cellular processes ranging from stress responses to cell growth, proliferation, and death, researchers have only limited understanding of its role in cancers, and its role in MM remains unknown. Researchers do, however, have evidence that GCK activity is critical for regulating MM cell proliferation and survival in MM harboring RAS mutations.

In this recent publication, Dr. Lentzsch and her laboratory have identified GCK as a novel therapeutic target in MM with RAS mutations. They have demonstrated in MM both in vitro and in vivo that silencing GCK inhibits MM cell growth. Though IMiDs (a class of immunomodulatory drugs that includes thalidomide) are potent anti-MM agents associated with long-term survival, some MM cells are resistant to these drugs. GCK inhibitors might also help patients overcome MM resistance to IMiDs.

Given the severity of MM, the identification of novel critical pathways and development of specific inhibitors to induce myeloma cell death or to sensitize myeloma cells to existing treatments are of critical scientific and clinical importance.