# Dissecting Single-cell Response or resistance to novel combination therapy in AML using mass cytometry

> **NIH NIH U54** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $93,333

## Abstract

Project Summary (max 30 lines)
We developed an investigator-initiated clinical trial to test the combination or ruxolitinib and venetoclax
(Rux+Ven) in relapse/refractory AML patients (NCT03874052) based upon extensive ex vivo small molecule
inhibitor screening data collected from hundreds of primary AML samples. Preliminary trial results show the
combination is well tolerated with remissions obtained in some patients after a single cycle. Our collaborative
proposal with Dr. Davis will make use of marrow and peripheral blood samples from trial patients that have been
treated ex vivo with each single agent and the drug combination along with single-cell resolution of mass
cytometry (CyTOF). While CyTOF can address intratumoral heterogeneity for drug screening at the level of the
single cell, the required analytics for the resulting complex data were not addressed. Leveraging the strengths
of CyTOF and addressing the need for analysis approaches, Dr. Plevritis’ group 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 individual patients. The CyTOF analysis will examine AML
phenotype, JAK-STAT signaling, BCL2 family proteins and cellular metabolism on individual cells from the
patients treated on study. We hypothesize that by using DRUG-NEM we can predict response to combination
treatment based on in vitro response to single agent treatment. We will compare our predicted response to the
patient’s actual response and determine cellular features associated with resistance to the combination. To
identify potential mechanisms of resistance we will perform cytokine assays on patient samples collected
throughout treatment. We hypothesize that cytokine signals emanating from the microenvironment could play a
key role in drug resistance in patients treated with Rux+Ven. If the DRUG-NEM predictions are accurate, it will
provide proof of concept for using single-agent drug data to inform combination therapy, thus, providing a more
efficient and practical approach to study future combination treatments. If specific cytokines are found to
contribute to Rux+Ven resistance, approaches to overcome the resistance can be elucidated. Overall, our
proposed supplement project makes use of our combined strengths to predict drug response and further
understand mechanisms of drug resistance in AML patients. This application is being submitted to request
a supplemental budget for the Drug Resistance and Sensitivity Center (DRSC) to perform the
collaborative work as proposed in Dr. Kara Davis’ administrative supplement application titled
"Dissecting Single-Cell Response or Resistance to Novel Combination Therapy in AML Using Mass
Cytometry ” in response to NOT-CA-21-034 “Notice of Special Interest (NOSI): Administrative
Supplements to Support Collaborations with the NCI-supported Drug Resistance and Sensitivity
Network (DRSN).

## Key facts

- **NIH application ID:** 10411840
- **Project number:** 3U54CA224019-04S1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** BRIAN J DRUKER
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $93,333
- **Award type:** 3
- **Project period:** 2017-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10411840

## Citation

> US National Institutes of Health, RePORTER application 10411840, Dissecting Single-cell Response or resistance to novel combination therapy in AML using mass cytometry (3U54CA224019-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10411840. Licensed CC0.

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