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Researchers at VCU Massey Comprehensive Cancer Center have made significant strides in the fight against acute myeloid leukemia (AML), a challenging and often deadly cancer, by discovering a novel combination of treatment approaches that synergistically induce cell death in AML cells.
The groundbreaking study, recently published in the journal Signal Transduction and Targeted Therapy, reveals that MCL-1 (myeloid leukemia cell-1) inhibitors can be effectively paired with SRC kinase inhibitors to enhance the elimination of AML cells. These findings promise to expand treatment options for a disease characterized by its resistance to conventional therapies.
“The insights gained from this research could provide new avenues for combating leukemia,” remarked Steven Grant, M.D., the study’s lead author and associate director for translational research at Massey, as well as a professor at the VCU School of Medicine.
Acute myeloid leukemia is noted for its high mortality rates, with patients facing a median survival of under nine months. The National Cancer Institute reports a mere five-year survival rate exceeding 30%. Despite the introduction of various therapeutic agents in recent years, many patients experience resistance to treatment or relapse, with a few exceptions for those who qualify for bone marrow transplants.
The progression of AML is triggered by the unregulated proliferation of undifferentiated leukemia stem cells, which have a crucial reliance on the MCL-1 protein for their survival. As MCL-1 inhibitors garner growing interest for treating AML and other blood cancers, preclinical studies indicate these agents can hinder MCL-1 function, leading to reduced survival rates of AML cells. However, a counterproductive effect has been noted, where the application of MCL-1 inhibitors and related BH3-mimetics can result in increased MCL-1 levels within the leukemia cells, diminishing the intended therapeutic effects. Identifying counter-strategies to mitigate this issue remains a key challenge in treatment development.
“Cancer cells are adept at activating alternative protective mechanisms that allow them to endure the effects of treatments that target critical signaling pathways,” Grant explained. “Identifying and disabling these escape routes significantly enhances our chances of effectively killing the cancer cells.”
To tackle the accumulation of MCL-1 within leukemia cells, Grant’s team explored combining established SRC kinase inhibitors with MCL-1 inhibitors. Their research identified that this combination therapy could efficiently diminish MCL-1 levels and subsequently induce cell death in primary AML cells while leaving healthy cells unharmed. In mouse models, this treatment not only proved tolerable but also markedly improved survival rates in models using tumor tissues from patients.
The comprehensive analysis of their findings indicated additional disruptions in cellular signaling pathways, which may further contribute to the efficacy of the SRC/MCL-1 inhibitor combination.
These results suggest that SRC inhibitors could play a pivotal role in enhancing the therapeutic action of MCL-1 antagonists against AML within clinical settings. While current MCL-1 inhibitors have been limited due to potential cardiac complications, numerous pharmaceutical companies are working on newer iterations that promise reduced cardiac risks.
Grant and his colleagues aim to explore whether incorporating SRC inhibitors can augment the effectiveness of these newer MCL-1 inhibitors while maintaining a favorable safety profile. A successful validation of this approach could lay the groundwork for clinical trials testing the SRC/MCL-1 inhibition strategy in patients with relapsed or refractory AML, for whom existing treatment avenues have proven inadequate.
“This represents a crucial advance in AML research, and it reflects an approach that Dr. Grant has long championed,” noted Gordon D. Ginder, M.D., a co-author of the study and former director of the cancer center. “These findings reinforce a clinical methodology designed to enhance the efficacy of targeted therapies in addressing the many serious cancers that often utilize escape mechanisms to withstand treatments aimed at their primary drivers.”
This collaborative research includes contributions from a wide range of experts affiliated with Massey and VCU, underscoring the multifaceted efforts needed to combat such a complex disease.
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