# Dissecting Single-cell Response or Resistance to Novel Combination Therapy in AML using Mass Cytometry

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $146,589

## Abstract

PROJECT SUMMARY
 This application is being submitted in response to the Notice of Special Interest (NOSI) identified as
NOT-CA-21-034. Acute myeloid leukemia (AML) is among the deadliest blood cancers with over 10,000
patients dying annually in the U.S. AML displays notorious genetic heterogeneity with thousands of mutations
described across AML patient tumors to date. AML has benefited from the rise of targeted therapies although
clinical impact of individual targeted agents has been modest. In AML, impressive initial response rates of 60-
80% have been observed in elderly patients using the combination of venetoclax, a BCL2 inhibitor, and
hypomethylating agents. Yet, survival at one year is only 30-40%, suggesting more to learn about the efficacy
of this combination. Novel ex vivo drug screening platforms have identified additional venetoclax combinations.
In particular, venetoclax with ruxolitinib, a JAK tyrosine kinase inhibitor, is a promising combination therapy.
Based on this preclinical data, a novel clinical trial has been initiated for patients with relapsed or refractory
AML.
 Cancer drug combination decisions are primarily made on the basis of mutational heterogeneity, yet
evidence of non-genetic drug resistance among isogenic cells is mounting, particularly with single cell analysis.
Despite advances in single cell technologies, there are currently no strategies for making drug combination
decisions that utilize single cell platforms to explicitly address intratumoral heterogeneity. Leveraging the
strengths of CyTOF and addressing the need for analysis approaches, we developed a novel algorithm
(DRUG-NEM) that analyzes single-cell, single-drug perturbation responses on individual leukemia cells to
identify optimized drug combination strategies for the individual patient. Using mass cytometry analysis with
focus on AML phenotype, signaling and metabolism, we will determine ex vivo response to single agent
venetoclax or ruxolitinib or the combination. Using the single agent treatment data, we will use DRUG-NEM to
predict response to the combination and compare to patient samples obtained on trial after staring combination
therapy. If predictions are accurate, it provides proof of concept for using single-agent drug data to inform
combination therapy, thus a more efficient and practical approach to study future combination treatments and
will inform sensitivity or resistance to venetoclax in combination with ruxolitinib in patients with AML.

## Key facts

- **NIH application ID:** 10383056
- **Project number:** 3R01CA251858-01A1S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Kara Lynn Davis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $146,589
- **Award type:** 3
- **Project period:** 2021-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10383056

## Citation

> US National Institutes of Health, RePORTER application 10383056, Dissecting Single-cell Response or Resistance to Novel Combination Therapy in AML using Mass Cytometry (3R01CA251858-01A1S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10383056. Licensed CC0.

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