# Mechanisms of venetoclax combination activity in acute myeloid leukemia

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $352,275

## Abstract

PROJECT SUMMARY/ABSTRACT
Acute myeloid leukemia (AML) is one of the most common hematologic malignancies, representing a diverse
collection of complex diseases. After 30-40 years without change of treatment strategy, the past 2 years have
seen several drug approvals, including the most recent approval for the BCL2 inhibitor, venetoclax, used in
combination with hypomethylating agents. While response rates of 60-80% with this combination are
encouraging, the 1-year survival rate is still only at 30-40%. For the past decade, we have executed a
functional genomics platform applied directly to primary samples from patients with AML and other hematologic
malignancies. Using this platform, we have collectively studied over 2,500 primary patient specimens, and we
have included a series of venetoclax combinations on this platform for the past five years. From this dataset,
we have identified several novel venetoclax combinations with better activity than venetoclax plus
hypomethylating agents, and we have started a clinical trial for one of the most promising of these
combinations, venetoclax with the JAK inhibitor ruxolitinib. For this project, our long-term goals are to
optimize and translate the most effective venetoclax drug combinations into the clinic for patients with
AML. Our immediate goals are to understand the specific biology driving venetoclax combination
synergy and identify biomarkers and mechanisms of response. Based on the central hypothesis that
venetoclax combinations exhibit patterns and mechanisms of sensitivity and resistance that are
specific to cell differentiation states and transcriptional programs. To accomplish these goals, 3 Aims are
proposed: 1) Cell differentiation state as a mechanism of drug combination sensitivity and resistance – We will
perform analytics of cell differentiation state in our large patient sample dataset as well as laboratory models of
forced differentiation in cell lines and patient samples. 2) Synthetic lethality as a guide to mechanisms of drug
combination sensitivity and resistance – Our preliminary data from genome-wide CRISPR/Cas screens point to
specific candidate genes that impact on mediators of venetoclax combination activity. These candidates will be
explored with genetic and pharmacologic perturbations. 3) Clinical validation of biomarkers and mechanisms
of sensitivity and resistance – We have opened a clinical trial testing venetoclax combined with ruxolitinib in
AML. We will have access to longitudinal specimens from patients on this trial. We will perform ex vivo drug
testing on these trial specimens coupled with transcriptional and proteomic studies to evaluate the ability of
each data type to predict clinical responses. Cumulatively, we expect these innovative analyses to have a
major impact on our understanding of AML biology, with successful clinical translation of new, more effective
drug combination strategies.

## Key facts

- **NIH application ID:** 10280901
- **Project number:** 1R01CA262758-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Stephen E Kurtz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $352,275
- **Award type:** 1
- **Project period:** 2021-06-02 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10280901

## Citation

> US National Institutes of Health, RePORTER application 10280901, Mechanisms of venetoclax combination activity in acute myeloid leukemia (1R01CA262758-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10280901. Licensed CC0.

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