Advancing the therapeutic landscape for Chronic Myelomonocytic Leukemia (CMML)

Eric Padron

MD

Moffitt Cancer Center

Project Term: November 1, 2023 - October 31, 2027

Project Summary

CMML is a blood cancer characterized by increased monocytes (a type of white blood cell) in the peripheral blood and abnormal appearing cells (termed "dysplastic" cells) within the bone marrow. CMML is a universally lethal cancer, but most patients are asymptomatic when they are first diagnosed. In spite of therapeutic advances in similar blood cancers, no CMML specific therapies have been developed, including early interventional strategies. In this proposal, we will identify new therapies and repurpose existing therapies to address the unmet need for new treatments that meaningfully improve the lives of patients with CMML. In Project 1, we will focus on identifying new therapies that will prevent the worsening of disease in clinically asymptomatic CMML patients by mitigating the negative effects of acute inflammation. In Project 2, we will capitalize on a discovery that CMML cells ‘reprogram’ their non-cancerous neighboring cells to create an environment that favors CMML cell growth over normal cells. We will understand the molecular circuits responsible for this cross talk and test the ability of repurposed existing therapies and new therapies that could inhibit this malignant communication. In Project 3, we will nominate a targeted therapy that is specifically directed at CMML cells with ASXL1 gene mutations. Patients who have this mutation have worse outcomes and a lower chance of response to existing therapies. This innovative project will address this by studying whether dual targeting of key ‘epigenetic’ proteins could be leveraged to target a molecular vulnerability in ASXL1 gene mutated CMML cells in the laboratory and in the context of a clinical trial. Project 4 will study whether inhibition of a protein known as CLK is a vulnerability in another key mutation often seen in CMML cells. Mutations in the machinery that cuts RNA into its mature form are very common and an early event that occurs in most CMML patients. This project will use inhibitors of CLK that are already being tested in related diseases to preferentially destroy CMML cells that have this mutation while sparing normal cells. All of these projects will be integrated by two cores that include the administration core to ensure synergy and the sequencing core to integrate all critical genomic data. Collectively this proposal, led by international CMML experts, will result in multiple clinical trials that are poised to improve the lives of patients with this disease.