Targeting metabolic reprogramming in MDS and AML stem/progenitor cells
Marina Konopleva
MD, PhDAlbert Einstein College of Medicine
Project Term: October 1, 2023 - September 30, 2026
Myelodysplastic neoplasms are malignant disorders driven by expansion of diseased hematopoietic stem cells and progression to leukemia. Our investigations have identified the important role of the transporter of amino acid glutamine SLC38A1 in sustaining metabolic demands of rapidly growing malignant stem cells. The goal of this project is to genetically target this transporter to understand its role on tumorigenesis and progression; and to develop SLC38A1 inhibitors as novel therapeutic tools.
Blood disorders commonly known as myelodysplastic syndrome (MDS) remain highly challenging to treat and are largely incurable, despite recent advances in deep molecular characterization of these malignancies, availability of novel targeted therapies and improvements in supportive care. It is now known that these tumors arise from diseased blood-forming stem cell(s) that acquired errors in DNA known as mutations, leading to the survival and proliferative advantage over time. Further, research by us and others has shown that these diseased stem cells are not eradicated with approved therapies such as hypomethylating agents (HMAs), one of the very few approved therapies in advanced disease, and over time acquire additional mutations leading to progression into highly aggressive acute myeloid leukemia (AML). The progress has been hampered by lack of our knowledge of what are the key drivers of survival and longevity of these tumor cells, and how they are different from healthy blood-forming cells, allowing tumor cells to gain advantage and dominate the diseased bone marrow.
To this end, we focused our investigations on understanding the metabolic fuels that support “fitness” of MDS stem/progenitor cells. Our investigations over the years have supported the key role of one of the most abundant amino acid glutamine, which is being avidly transported from the surrounding environment and converted into key metabolites supporting bioenergetic demands and proliferation of MDS cells, and protect these tumor cells from oxidative damage, allowing them to multiply faster and survive better than healthy hematopoietic stem cells. In the clinical trial of selective inhibitor of one of the key enzymes of this metabolic glutamine conversion we reported clinical responses in patients with high-risk MDS (including those who failed standard of care HMA therapy), associated with elimination of MDS stem cells and induction of differentiation, resulting in restoration of normal blood counts. Importantly, analysis of gene expression programs demonstrated that MDS stem cells from patients who benefited from this therapy expressed high levels of the non-canonical transporter of glutamine SLC38A1.
In this project, we will learn (1) How important is SLC38A1 in MDS stem cell proliferation, survival and in gaining pathological advantage that allows progression towards acute leukemia; (2) Understand how intracellular processes of metabolism will get altered upon genetic or pharmacological silencing of this transporter; and (3) screen and optimize novel selective small molecule inhibitors of SLC38A1 which will be tested in faithful pre-clinical models of high-risk MDS.