By Hendra Lukman 
Researchers at Duke University have identified a crucial enzyme, STK17B, involved in regulating iron within multiple myeloma (MM) cancer cells. By blocking this enzyme, scientists have demonstrated not only the ability to induce cell death in these aggressive cancer cells but also a significant enhancement of current therapeutic treatments. This groundbreaking discovery, published on September 12 in the esteemed journal Blood, offers a promising new avenue for tackling a disease that remains incurable and is increasingly demonstrating resistance to existing therapies.
Understanding Multiple Myeloma: A Persistent Challenge
Multiple myeloma is a complex and often devastating blood cancer that originates from plasma cells, a specialized type of white blood cell responsible for producing antibodies to combat infections. In individuals with MM, these plasma cells proliferate uncontrollably within the bone marrow, displacing healthy blood-forming cells. This uncontrolled growth leads to the production of abnormal antibodies, which can have a cascade of detrimental effects on the body. Patients often experience a weakened immune system, making them more susceptible to infections. The disease can also inflict severe damage on vital organs, including the kidneys, and is a significant cause of painful bone disease due to its tendency to create lesions in the bone.
Currently, multiple myeloma accounts for nearly 10 percent of all diagnoses within the broad category of blood cancers. While significant advancements in targeted treatments have been made over the years, offering improved management and extended survival for many patients, a persistent and growing concern is the increasing incidence of symptom relapse and the emergence of drug-resistant forms of the disease. This underscores the urgent need for innovative therapeutic approaches that can overcome these challenges.
The Intriguing Role of Iron and Ferroptosis in Cancer
While the precise initiating factors of multiple myeloma are still under investigation, a consistent observation in MM cells is the suppression of a natural cellular process known as ferroptosis. Ferroptosis is a distinct form of programmed cell death characterized by the accumulation of excess iron within a cell. This iron overload triggers a cascade of events, leading to oxidative damage to the lipids that form the cell membrane. This damage compromises the cell’s integrity, ultimately causing it to break apart.
However, in the context of multiple myeloma, this vital self-destruction mechanism appears to be circumvented. Cancer cells, in their relentless pursuit of survival and proliferation, often exhibit an unusual tolerance to high levels of iron. This adaptation allows them to thrive in an environment that would typically be lethal to healthy cells.
"Cancer cells live like there is no tomorrow," explained Mikhail Nikiforov, a professor of pathology and biomedical engineering at Duke, highlighting the aggressive nature of these malignant cells. "They accumulate iron at levels that would normally be toxic and tear cells apart, but that wasn’t what we observed. Instead, these cancer cells adapted to resist the type of cell death triggered by iron overload, and the mechanisms behind this suppression were largely unknown." This long-standing enigma posed a significant hurdle in developing effective therapeutic strategies.
Unraveling the Mechanism: STK17B as the Key Regulator
The recent research led by Professor Nikiforov and a collaborative team of scientists across Duke has finally illuminated the answer to this critical question. They have identified a specific enzyme, kinase STK17B, as a pivotal player in suppressing ferroptosis within multiple myeloma cells. While STK17B is generally known for its roles in regulating cell death pathways and activating T-cells, this study reveals its additional, critical function in maintaining cellular iron homeostasis. The enzyme achieves this by meticulously regulating the delicate balance of proteins that either promote ferroptosis (pro-ferroptotic proteins) or inhibit it (anti-ferroptotic proteins).
The research team observed a direct correlation between elevated levels of STK17B and poorer overall survival rates in patients diagnosed with multiple myeloma. Furthermore, STK17B expression was found to be particularly pronounced in cases of relapsed disease, a finding that strongly underscores its significant role in the development of therapy resistance. This correlation suggests that STK17B is not merely a passive bystander but an active contributor to the disease’s aggressive and treatment-evading nature.
A Novel Therapeutic Approach: Inhibiting STK17B
Building upon this fundamental discovery, Professor Nikiforov’s team employed a novel compound developed by Timothy Willson, the Harold Kohn Distinguished Professor in Open Science Drug Discovery at the UNC Eshelman School of Pharmacy. This specialized compound was designed to inhibit the activity of STK17B. By blocking STK17B’s control over iron accumulation within the cell, the researchers were able to effectively reactivate the ferroptosis pathway. This reactivation effectively forces the cancer cells to succumb to the toxic effects of iron overload.
Crucially, the study also revealed that inhibiting STK17B did not solely induce cell death; it also made the multiple myeloma cancer cells significantly more susceptible to conventional MM therapies. This synergistic effect holds immense promise for improving the efficacy of existing treatment regimens and potentially overcoming drug resistance.
Preclinical Success and Future Prospects
As a compelling proof of concept, the Duke researchers administered an orally available form of the STK17B inhibitor to mouse models engineered to develop multiple myeloma. The results were highly encouraging. The compound effectively induced ferroptosis by increasing the uptake of iron by the cancer cells. This, in turn, led to a significant reduction in tumor growth within the treated mouse models, demonstrating the therapeutic potential of this novel strategy in a living system.
"These findings establish that STK17B is a critical safeguard protecting MM cells from the toxic consequences of their iron independence," Professor Nikiforov stated, emphasizing the significance of their discovery. "Inhibiting this kinase holds much promise as a therapeutic strategy."
The implications of this research extend beyond immediate therapeutic applications. The team has already taken steps towards commercializing this innovative therapy by filing a provisional patent based on their findings. Their vision is to develop a new class of drugs that can effectively target and eliminate multiple myeloma cells.
Expanding the Horizon: Potential Applications in Other Cancers
Beyond the immediate focus on multiple myeloma, the researchers are keen to explore the broader applicability of their findings. The mechanism of ferroptosis suppression and the role of STK17B may not be unique to MM. Many other types of cancer cells are also known to exhibit resistance to ferroptosis, suggesting that the STK17B inhibitor could have wider therapeutic implications.
"Many other types of cancer cells are also resistant to ferroptosis," Professor Nikiforov noted. "We’re curious to see how this inhibitor could improve therapies for other tumors outside of multiple myeloma." This forward-looking perspective highlights the potential of this research to impact a wider spectrum of oncological challenges, offering hope for patients battling various forms of cancer.
The research was supported by substantial funding from several national and international bodies, including the National Institutes of Health, the National Cancer Institute (grants NCI R01CA264984 to M.A.N., NCI R21CA267275 and 17R21CA280499 to Y. K.), the NHLBI (grant R01HL168492 to E.A.L.), the Duke Cancer Institute (P30CA014236), and the Paula and Rodger Riney Foundation (to L.H.B.). Further support was provided by the Structural Genomics Consortium (SGC), a registered charity that receives funding from a consortium of pharmaceutical companies and governmental organizations, including Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Genome Canada, the EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking, Janssen, Merck KGaA, Pfizer, and Takeda. Funding for this specific project was also partially contributed by the NIH Illuminating the Druggable Genome grant 1U24DK116204-01, underscoring the collaborative and multi-faceted nature of this significant scientific endeavor. The successful translation of this research from bench to bedside will undoubtedly require continued investment and collaboration across academic institutions and the pharmaceutical industry.