Understanding and Treating Multiple Myeloma

Multiple myeloma (MM) is a type of cancer that affects plasma cells, a kind of white blood cell responsible for producing antibodies to fight infections. Currently considered incurable, this disease causes cancerous cells to accumulate in the bone marrow, hindering the production of healthy cells. This leads to a weakened immune system, kidney damage, and other organ issues, as well as painful bone diseases. While targeted therapies exist to manage the disease, cases of relapse and drug resistance are on the rise.

New Insights into Disease Mechanisms

Although the exact cause of multiple myeloma is unknown, researchers have observed its association with the suppression of a cellular death process known as ferroptosis, a natural cell death mechanism linked to excess iron accumulation. Ferroptosis results in oxidative damage to cell membrane lipids, triggering cell breakdown. However, when this process is suppressed, cell death does not occur.

Professor Mikhail Nikiforov, a professor of pathology and biomedical engineering at Duke University, explained: “Cancer cells live as if there is no tomorrow, accumulating iron at potentially toxic levels that would normally rupture cells. But that’s not what we observed. Instead, these cancer cells adapt to resist iron-induced cell death, and the mechanisms behind this suppression were largely unknown.”

New Discoveries in Treatment

Nikiforov and his team uncovered the answer to this longstanding question by identifying kinase STK17B as a key enzyme responsible for suppressing ferroptosis in MM cells. Typically associated with cell death and T-cell activation, researchers found that STK17B is also crucial in maintaining iron balance within the cell by regulating pro- and anti-ferroptosis proteins.

Elevated levels of STK17B are linked to poor overall survival in patients with multiple myeloma. Furthermore, STK17B expression is more pronounced in cases of disease relapse, highlighting its role in treatment resistance.

A Promising Therapeutic Trial

Using a compound developed by Professor Timothy Wilson, the team was able to inhibit STK17B’s control over iron accumulation in the cell, reactivating ferroptosis. They observed that inhibiting STK17B made cancer cells more sensitive to traditional multiple myeloma treatments.

As proof of concept, Nikiforov’s team administered an oral version of the inhibitor to mouse models with multiple myeloma. They noted that the compound induced ferroptosis by increasing iron uptake from cancer cells and significantly reduced tumor growth in the mouse models.

Conclusion

These findings demonstrate that STK17B is a critical protector of cancer cells from the toxic consequences of their reliance on iron. Inhibiting this kinase holds great promise as a therapeutic strategy. In addition to plans to optimize the compound, the team has also filed a provisional patent based on their discoveries, with the ultimate goal of commercializing the treatment. They also hope to explore how the formulation can be used to regulate drug resistance in other types of cancers, as many other cancer cell types also resist ferroptosis, opening new avenues for developing effective treatments for tumors beyond multiple myeloma.