Targeting the inflammasome in CMML
Amit Verma
MBBSAlbert Einstein College of Medicine
Project Term: November 1, 2023 - October 31, 2026
Overactivation of the inflammasome is seen in CMML and leads to worsening of this condition. We will explore the potential of a new inflammasome inhibitor drug, HT-6184, in CMML patient samples and in animal models. Our preliminary results show that this drug can decrease inflammation and improve red cell development in CMML models. The new drug is approved for clinical trial use and our work will potentially lead to its use in clinical investigations in CMML.
Chronic myelomonocytic leukemia (CMML) is a blood cancer that is characterized by expansion of white blood cells known as monocytes. Monocytes in CMML patients are greatly increased in number and are also very inflamed. They have been shown to produce elevated levels of proteins that can lead to inflammation in the body. This leads to fatigue and weight loss in patients. This inflammation also leads to low levels of hemoglobin and resulting feeling of tiredness. In this proposal, we aim to reduce inflammation in CMML by targeting the central hub of this process, known as the inflammasome. The inflammasome is a complex of various proteins that triggers the production of a substance known as IL-1beta that can worsen CMML. We are using a new chemical drug known as HT-6184 in our lab to decrease the activation of inflammasome in CMML models. This drug is a potent suppressor of inflammation in CMML and MDS samples and increases the levels of red blood cells in laboratory experiments.
In the grant proposal we will first study the factors that lead to increased inflammation in CMML. We will evaluate secreted proteins, cell surface receptors and also enzymes involved in inflammation. These targets will be inhibited by antibodies and selective drugs in cell lines and blood samples. In the second aim, we will study the cellular processes that triggered by the inflammasome that worsen the state of CMML. We will use assays that can look at single cells from blood samples from CMML patients. These will tell us which secreted proteins are made by the CMML monocytes. Lastly and most importantly, we will test the effectiveness of the inflammasome drug, HT-6184, in CMML blood samples as well as in mouse models of CMML. This drug has been cleared for use in clinical trials by the FDA. We hope successful results from studies can rapidly bring this drug in CMML clinical trials.