MCL-1 inhibitors could prove effective against multiple myeloma

multiple myeloma
Multiple myeloma

While many treatments exist to manage symptoms and delay the progression of multiple myeloma, it remains uncured. Now, Australian scientists have found that drugs that inhibit the protein MCL-1 may prove effective in treating the blood cancer.

Scientists from the Walter and Eliza Hall Institute of Medical Research teamed up with colleagues from the Australian Centre for Blood Diseases, Monash University and the Alfred Hospital to study the “survival proteins” that keep myeloma cells alive, according to a statement. The survival of myeloma and other cancers hinges on a family of “survival proteins” known as BCL-2 family proteins, according to David Huang, a laboratory head in the institute’s cancer and hematology division, in a statement.

“In the past decade there has been considerable interest in the using anti-cancer agents called ‘BH3-mimetics’ to kill cancer cells by blocking the BCL-2 family proteins,” Huang said in the statement. “Recent clinical trials have demonstrated that a BH3-mimetic that switches off the protein BCL-2 is an effective treatment for certain forms of leukaemia.”

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Myeloma cells tend to express a range of BCL-2 proteins, the researchers said in a study published in the journal Blood. They homed in on which BH3-mimetic would be most effective against multiple myeloma.

When the team blocked MCL-1, the majority of myeloma samples died, but only a quarter were vulnerable to inhibiting BCL-2, said Dr. Jianan Gong of the Walter and Eliza Hall Institute in the statement. “Our research shows that switching off MCL-1 has the potential to be effective new treatment approach for the majority of patients with myeloma,” Gong said.

MCL-1 inhibitors are currently still in preclinical development. They include seliciclib, which is being developed by Dundee, U.K.-based Cyclacel for the treatment of multiple myeloma. Seliciclib also inhibits the proteins CDK2, CDK7 and CDK9, and is in clinical trials for BRCA mutated tumors, Cushing’s disease, rheumatoid arthritis and cystic fibrosis.

“Our results suggest that, once necessary laboratory testing for safety is completed, clinical trials of their effectiveness in treating patients with multiple myeloma that is no longer responding to current therapies would be well justified,” said Andrew Roberts, head of clinical translation in the institute’s cancer and hematology division, in the statement.

As for other approaches to multiple myeloma, Mount Sinai scientists are collaborating with Onconova Therapeutics on a compound that inhibits the proteins CDK4 and ARK5. They hoped to reduce cell proliferation driven by the overexpression of the protein MYC in myeloma. Myeloma cell lines and samples taken from patients with recurrent myeloma responded to treatment with the compound.

- here's the statement
- read the abstract

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