Acute myeloid leukemia (AML) is the deadliest form of leukemia, with a median survival of less than nine months and a 5-year survival rate of just above 30%, according to the National Cancer Institute. AML represents a disease that develops from the uncontrolled growth and survival of undifferentiated leukemia stem cells. These cells are particularly dependent for survival upon the MCL-1 protein, which plays an important role in regulating leukemia cell death. 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 – with the exception of a subset of patients eligible for bone marrow transplantation. Scientists at VCU Massey Comprehensive Cancer Center have identified an innovative drug combination that work collaboratively to effectively kill AML cells.
New research findings 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 protein tyrosine kinase to efficiently trigger cell death in AML cells. 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.
Scientists 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, they have now discovered that a class of existing drugs targeting the SRC protein tyrosine kinase (like bosutinib) 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. The research team 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.
The team, led by Dr. Grant, has investigated a parallel combination of inhibitors of the MCL-1 first cousin Bcl-2 (like venetoclax) and drugs that aim for the mTORC1/2 protein complexes. They haved spearate though complementary roles: mTORC1 is implicated in RNA translation and mTORC2, whose downstream target is protein kinase c-Akt involved in suppression of cell death (apoptosis). Since the common mTOR general inhibitor rapamycine is not fully effective in killing AML cells, Dr. Grant’s team has employed a new generation of mTORC inhibitors (AZD2014 and spanisertib) either to surpass AML resistance to venetoclax (which is already common in leukemias) and bypass consitutive activation of c-Akt that stimulates protein synthesis and cell resistance to drugs.
Another combination therapy that adds a recently approved drug to the current standard of care for newly diagnosed AML showed high rates of complete remission, in an early-phase clinical trial conducted at UNC Lineberger Comprehensive Cancer Center and 11 other sites nationwide. The trial findings have been presented at the European Hematology Association Congress in Milan, Italy, on last June 12. In this study, the investigators were looking at AML with two specific gene alterations: nucleophosmin-1 (NPM1m) or lysine methyltransferase 2A (KMT2Ar) rearrangements. NPM1m is seen in about 30% of AML patients whereas KMT2Ar is relatively rare, seen in about 5% of AML patients. Notably, both alterations share a gene expression profile that contributes to the development and progression of AML.
A new class of targeted agents known as menin inhibitors has been shown to be clinically active in patients with these alterations. Revumenib is an oral menin inhibitor that is approved for patients with relapsed AML with a KMT2Ar alteration. This phase 1 clinical trial is the first to investigate whether adding a menin inhibitor to the standard therapy is safe and effective for newly diagnosed older adults with AML The study enrolled 43 patients at 12 centers nationwide. The patients were given a combination of the current standard of care, azacitidine and venetoclax, with revumenib. The overall response rate, defined as no evidence of leukemia, was 88.4% while the complete remission rate, was 67.4%, response rates higher than expected compared to the current standard of care.
All patients responded to the treatment after one to two 28-day cycles; 84% of responders achieved remission within the first cycle. After one year on the trial, 62.9% of patients were still alive. The phase 3 trial will be led by the HOVON group, a European Cooperative Oncology Group, to make the phase 3 trial as robust as possible and hopefully provide definitive evidence of the efficacy of this drug combination.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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