Manipulation of cell fate in myeloid disease
Michael Savona
MDVanderbilt University Medical Center
Project Term: July 1, 2018 - June 30, 2023
Apoptosis is a normal cellular process of getting rid of extra cells that is co-opted by cancer cells to enhance their own survival, and we aim to better understand this process in myelodysplastic syndromes (MDS). Pevonedistat (PEV) is a novel therapy presumed to function, in part, through its effects on apoptosis. Our clinical trial will combine PEV with the standard of care therapy for MDS, azacitidine, in order to keep cancer cells from hijacking apoptosis, and we will study patient samples to match responses with molecular changes in the cancer cells. We seek to determine the suitability of this approach for MDS, and the ability to predict which patients may respond to PEV-based therapy.
Myelodysplastic syndromes (MDS) are bone marrow cancers that cause low blood counts, diminished quality of life and life expectancy, and often progress to acute myeloid leukemia (AML). Treatment options are limited, but there are many recent attempts to augment the standard therapy, 5’azacitidine (AZA) or decitabine, with novel therapy. The recent approval of venetoclax for a class of blood cancers has generated substantial interest in its use in other cancers as well. Venetoclax inhibits BCL-2, which is a regulator of programmed cell death, also known as apoptosis. Apoptosis is a normal cellular process of getting rid of extra cells that is co-opted by cancer cells to enhance their own survival. Apoptosis is precisely regulated by a variety of pro- and anti-apoptotic proteins. Venetoclax works by targeting BCL-2, an anti-apoptotic protein. Cancer cells can hijack a number of apoptotic regulators in order to survive; a goal of my research is to understand which regulators are used by MDS to aid in their own survival. We have access to a large repository of MDS patient samples, and we will experimentally inhibit a variety of anti-apoptotic proteins and evaluate the effect on cell survival. We will then use this information and mouse models to identify drug combinations that are therapeutically effective in reducing MDS. We will build on these studies by evaluating apoptosis regulators in patient samples from a clinical trial of pevonedistat (PEV) combined with AZA. PEV is presumed to function in part by dampening the effects of the anti-apoptotic protein MCL-1. Cancers primarily immortalized by MCL-1 or BCL-2 proteins are termed MCL-1-dependent or BCL-2-dependent. Our ambition is to determine if response to PEV plus AZA in MDS patients is correlated to the type of survival protein dominant in their disease. Specifically, if MDS is found to be MCL-1-dependent it follows that these MDS cells may be more sensitive to PEV/AZA, leading to greater response. Conversely, if MDS is BCL-2-dependent, PEV/AZA may have less impact. We will also determine if responses to PEV/AZA can be augmented by the addition of inhibitors of other apoptotic regulators. The overall goal of this research is to classify MDS patients according to their apoptotic regulator profile and to use this information to inform the development of clinical trials, as well as to enhance our understanding of the PEV/AZA trial that is currently open and enrolling.