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Scientists at VCU Massey Comprehensive Cancer Center have identified an innovative combination of treatment strategies that work collaboratively to effectively kill acute myeloid leukemia (AML) cells, a frequently incurable form of cancer.

New research findings — published in the Nature family journal Signal Transduction and Targeted Therapy — suggest that a class of drugs known as MCL-1 (myeloid leukemia cell-1) inhibitors interact with a type of kinase inhibitor that targets the SRC gene to efficiently trigger cell death in AML cells.

“Results from this research could add another approach to the therapeutic armamentarium against leukemia,” said study author Steven Grant, M.D., associate director for translational research at Massey and professor of internal medicine at the VCU School of Medicine.

AML is the deadliest form of leukemia, with a median survival of less than nine months and a five-year survival rate of just above 30%, according to the National Cancer Institute.

Many drugs have been developed to treat the disease over the last several years, but AML in most cases remains highly resistant to standard therapies or recurs following treatment — with the exception of a subset of patients who are eligible for bone marrow transplantation.

AML represents a disease that develops from the uncontrolled growth and survival of undifferentiated leukemia stem cells. These stem cells are particularly dependent for survival upon the MCL-1 protein, which plays an important role in regulating leukemia cell death.

MCL-1 inhibitors have become an area of considerable interest in the treatment of leukemia as well as other hematologic malignancies. In preclinical studies, these agents effectively block the function of MCL-1, reducing the ability of AML cells to survive. However, it has been found that such drugs, as well as other drugs of the class collectively referred to as BH3-mimetics, simultaneously trigger the accumulation of MCL-1 within leukemia cells. This buildup antagonizes the anti-leukemic activity of MCL-1 inhibitors. However, strategies capable of opposing this undesirable phenomenon have not yet been identified.  

“Cancer cells are known for their ability to develop alternative protective pathways that allow them to survive exposure to agents that interrupt signaling cascades,” Grant said. “If one can identify those escape pathways and disable them, there is a much better chance of killing the cells.”

Grant’s research team sought to develop a strategy to prevent the accumulation of MCL-1 in leukemia cells through a clinically effective treatment option. Building upon decades of their earlier work in understanding leukemia, he and his collaborators have now discovered that a class of existing drugs targeting the SRC oncogene were highly effective in overcoming MCL-1 accumulation in leukemia cells exposed to MCL-1 inhibitors.

They discovered that this phenomenon stemmed from three separate but intertwined processes. Importantly, the SRC inhibitor/MCL-1 antagonist combination regimen effectively killed primary AML cells but spared their normal counterparts. The regimen was well tolerated in mouse models and significantly improved survival in patient-derived xenograft models — tumor tissues removed from patients.

Comprehensive analysis also revealed additional disturbances in cellular signaling pathways that might also contribute to the anti-leukemic activity of the SRC/MCL-1 inhibitor combination strategy.

Collectively, these findings raise the possibility that SRC inhibitors may significantly improve the activity of MCL-1 antagonists against AML in the clinical setting. Currently, administration of MCL-1 inhibitors is limited by the potential of these drugs to induce heart complications. However, multiple pharmaceutical companies are developing newer versions of these drugs, which are minimally associated with this cardiac toxicity.

Grant and collaborators hope to determine if SRC inhibitors can enhance the anti-leukemic activity of these newer MCL-1 inhibitors with a limited and safe level of toxicity. If successful, such studies could serve as a foundation for the development of clinical trials employing the SRC/MCL-1 inhibitory strategy in patients with relapsed/refractory AML for whom satisfactory treatment options are currently lacking.

“This is an important discovery in AML, but it’s a reflection of an approach that Dr. Grant has been a pioneer in for many years,” said study co-author Gordon D. Ginder, M.D., former cancer center director and a member of the Cancer Biology research program at Massey. “These findings support a clinical approach to make targeted therapy actually work in the majority of deadly cancers which often have escape mechanisms for survival when their primary driver is targeted. That’s the bottom line.”

Additional collaborators on this study include Massey research members L. Ashley Cowart, Ph.D., Adam Hawkridge, Ph.D., and Fadi Salloum, Ph.D.; Xiaoyan Hu, Ph.D., Lin Li, Jewel Nkwocha, Shengzhe Shang, Ph.D., and Yang Yue, Ph.D., of the VCU School of Medicine; Maciej Kmieciak, Ph.D., from Massey’s Clinical and Translational Research Laboratory; Arjun Rijal, M.S., from Massey’s Proteomics Shared Resource; Zackary Moore from Massey; Adolfo G. Mauro, of the Pauley Heart Center at VCU Health; Katsuhisa Horimoto, Ph.D., of SOCIUM Inc.; Lori Hazlehurst, Ph.D., and Konstantinos Sdrimas, M.D., of WVU Cancer Institute; and Liang Zhou, Ph.D., of Asklepios Biopharmaceutical, Inc.

This research was supported by multiple grants from the National Cancer Institute (P30 CA16059, 5UM1CA186644, CA205607).

Written by: Blake Belden