Houston Methodist Scientists Pioneer Ferroptosis Strategy Against Multiple Myeloma

Researchers at Houston Methodist Neal Cancer Center have identified a promising new therapeutic target for treating multiple myeloma, a challenging form of blood cancer characterized by aggressive progression and frequent relapses.

In a study published recently in the journal Nature Communications, the team showed that leukocyte immunoglobulin-like receptor B1 (LILRB1) helps the myeloma cells evade cell death through a novel mechanism involving cholesterol metabolism and ferroptosis, a type of iron-dependent programmed cell death.

Multiple myeloma remains incurable for many patients due to its ability to recur after treatment. Dr. Siddhartha Ganguly, chief of Hematology at Houston Methodist, described the disease as particularly difficult because dormant "stem" cells often survive chemotherapy, later causing relapse.

"Traditional chemotherapy kills rapidly dividing cells, but myeloma cells often remain dormant and evade treatment," explained Dr. Ganguly. "This is why innovative therapies targeting cell mechanisms are urgently needed."

Led by principal investigator Dr. Qing Yi, the research focused on understanding and manipulating ferroptosis, a form of cell death linked to lipid metabolism and oxidative stress. According to the study, LILRB1 plays a critical role in preventing ferroptosis by maintaining cholesterol balance within the cells. By forming a complex compound with the low-density lipoprotein receptor and LDLR adapter protein 1, LILRB1 facilitates cholesterol uptake, crucial for cancer cell survival.

When LILRB1 was inhibited in laboratory models, cholesterol uptake was impaired, leading cancer cells to activate internal cholesterol synthesis pathways. This internal activation, however, also reduced protective metabolites and increased vulnerability to ferroptosis. Consequently, blocking LILRB1 significantly slowed multiple myeloma progression in mice, highlighting its potential as a therapeutic target.

Dr. Ganguly emphasized the uniqueness of this approach, noting that the single-agent use of most immunotherapy "checkpoint inhibitors, like those used in lung cancer, hasn't been effective in multiple myeloma. However, targeting cholesterol metabolism and ferroptosis represents a promising new direction."

He also described a parallel research interest in combining LILRB1 inhibition with statins to enhance the induction of ferroptosis in cancer cells. Early evidence from other cancers, including head and neck cancer, supports the effectiveness of this combined approach.

"Our next steps involve testing various statins in combination with LILRB1 blockers," Dr. Ganguly said. "Atorvastatin, known commercially as Lipitor, is particularly promising because it operates on the cell surface, the same region where LILRB1 functions."

Houston Methodist's team is working towards initiating a Phase 1 clinical trial, which Dr. Ganguly predicts will involve a combination treatment approach rather than single-agent therapy. The trial is slated to start this year, pending further validation and regulatory approval.

This research aligns with Houston Methodist's broader mission to tackle cancers disproportionately affecting its particular patient populations. Multiple myeloma has a higher incidence among African Americans, a significant demographic within Houston Methodist's geographic area.

"By better understanding how cholesterol metabolism and ferroptosis influence cancer survival, we are not only advancing treatment options but also contributing to preventive strategies," Dr. Ganguly said. "Our ultimate goal is not just to improve treatments but find actual cures for multiple myeloma."

By exploring ferroptosis as a potential therapeutic strategy to overcome resistance to chemotherapy, radiotherapy and immunotherapy, Houston Methodist continues to solidify its role as a leader in translating cutting-edge biomedical discoveries from bench to bedside, offering hope for patients with this challenging disease.