The majority of people diagnosed with acute myelogenous leukemia (AML) die of their disease, despite availability of active standard chemotherapy regimens, targeted therapies, and allogeneic transplantation. We have found that we can probe mitochondrial apoptotic signaling of patient myeloblasts to identify active therapies in AML using BH3 profiling. Prior exploitation of BH3 profiling led to the FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine. Here we present an innovation, Dynamic BH3 Profiling, which we propose to use to identify active single agents as well as combinations in AML. High priority will be given to combinations with BH3 mimetic drugs. We will also include in our studies candidate small molecules that emerge from the other Projects. Promising candidates will advance to clinical trials in collaboration with Clinical Core 3. For the first time, we propose to accelerate novel clinical trials in AML by using dynamic BH3 profiling to prioritize combinations that drive high apoptotic signaling in patient myeloblasts. In prior work, we have found that BH3 profiling can predict response to induction regimens in AML. We have installed BH3 profiling in a clinical laboratory where we can now test over a hundred AML samples per year. Building on our prior work, and working with Biostatistics Core 2, we will construct predictive biomarkers based on BH3 profiling for response to standard 7+3 induction, as well as to the newer venetoclax plus azacytidine. We will test inclusion into our predictive tool information like ELN criteria, age, and pathology. The expected output is a set of predictive tools that will offer likelihood of CR/CRi for individual patients for both induction regimens. It is hoped that this tool will help guide patients to the induction therapy that is best for them. While we exploit the concept of apoptotic priming to predict clinical response and identify active regimens in AML, we know little about the molecular determinants of the apoptotic priming phenotype. We will utilize genomic, transcriptomic, and proteomic tools to investigate the differences between myeloblasts in different states of apoptotic priming. While this work will focus on AML, it is expected that it will reveal principles of molecule determination of priming that will be applicable to other cell types.

Public Health Relevance

While we have seen several exciting new drugs receive approval for treatment of acute myelogenous leukemia (AML) in the last couple of years, most patients with AML still die of their disease. We propose to expose actual patient leukemia cells to candidate drugs, and then measure which drugs cause cell death signaling, to choose active drugs for AML patients. Our overall goal is to establish a novel strategy by which a patient's AML sample can be tested to identify the best drugs with which to treat that patient.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA066996-21
Application #
9854834
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
2025-04-30
Budget Start
2020-03-15
Budget End
2021-02-28
Support Year
21
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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