Novel targeted therapies for acute myeloid leukaemia and multiple myeloma
Lev Kats
PhDThe University of Melbourne
Project Term: July 1, 2024 - June 30, 2029
Outcomes for acute myeloid leukemia (AML) and multiple myeloma (MM) patients remain inadequate and new treatment options to combat resistance against existing agents are urgently needed. My research aims to identify and target selective vulnerabilities of AML and MM cells. I am particularly interested in epigenetic and metabolic pathways that control self-renewal and differentiation of hematopoietic cells and that can be leveraged to modulate cell fate for therapeutic benefit.
Acute myeloid leukemia (AML) and (MM) are blood cancers that represent significant areas of unmet need globally. AML is a highly aggressive malignancy with a 5-year overall survival rate of <30%. Next generation proteasome inhibitors and immune-oncology agents have improved the outlook for MM in recent years, but it remains inadequate. A major challenge for both AML and MM, as for many cancers, is drug resistance with most patients ultimately succumbing to their disease having exhausted available therapeutic options. Hence there is a requirement to increase our treatment armament by developing new drugs.
In healthy individuals, billions of mature functional blood cells arise from a small number of stem cells through a process termed differentiation. In normal cells differentiation is carefully controlled to ensure that the appropriate types and numbers of cells are produced at a given time and is accompanied by loss of proliferative capacity with differentiated cells being unable to divide to form new cells. Blood cancer cells on the other hand can short-circuit these normal developmental pathways, acquiring the ability to self-renew indefinitely. At the molecular level cell fate decisions are regulates by proteins that interpret the genetic code (referred to as epigenetic and transcription factors) and the metabolites on which they depend to enable their function. In this fellowship I will investigate how altered activity of epigenetic and metabolic proteins affects self-renewal in AML and MM cells. This will be done by comparing normal and malignant cells in patients and modelling the differences in cells grown in culture and animal models to ascertain their functional significance. I then aim to use this information to develop new therapeutic strategies that reverse aberrant differentiation processes within AML and MM cells by engaging normal developmental pathways. I hypothesize that such treatments will be highly effective and less toxic compared with drugs that seek to directly kill cancer cells, leading to improved outcomes for patients.