# Functional Genomic Discovery of Pathway Targeted and Immune Modulatory Therapeutic Combinations in Hematologic Malignancies

> **NIH NIH U01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $1,004,844

## Abstract

PROJECT SUMMARY
Targeted therapies have been a recent focus of drug development for acute myeloid leukemia (AML) and
chronic lymphocytic leukemia (CLL), but the majority of patients eventually develop resistance even to these
new drugs. There is thus an urgent need to better understand the pathways underlying drug resistance to
identify novel drugs or combinations of drugs that can effectively inhibit these pathways. Through our
leadership of the Beat AML program as well as other programs in our laboratories oriented towards CLL, we
are amassing a large cohort of patient samples with corresponding genomic, functional, clinical and immune
annotation. We are developing novel computational tools to extract useful conclusions from these large
datasets. The overall goals of this proposal are to leverage our existing cohorts, high-throughput screening
tools, and datasets for prediction and pre-clinical testing of novel drug combinations that will eventually be
translated into clinical trials. The specific aims of this project are to: (1) use genome-wide CRISPR screening
and mass cytometry to create a discovery resource of genomic and immune profiles of 500 primary samples
from leukemia patients; (2) develop an integrated computational framework (called PRECEPTS) to infer the
cellular processes driving resistance to perturbagens and predict combination targets that can overcome
resistance; (3) identify synergistic drug combinations by combining ex vivo testing of single drugs with
CRISPR/Cas synthetic lethality screening with genes prioritized by computational prediction, and identify
resistance pathways by using RNAseq to profile any residual resistant cells; and (4) use the data from (3) to
identify and test drug combinations. This proposed project will contribute to all 3 areas of research interest for
the CTD2 by improving our understanding of the molecular processes underlying drug sensitivity and
resistance in leukemias, developing algorithms to predict markers and targets in these processes, and
identifying drugs and/or combinations that will maximize drug sensitivity and minimize resistance. The
proposed studies have direct translational relevance in selecting novel treatment strategies for clinical trials,
and will benefit the CTD2 by generating large-scale data sets and providing novel computational tools that can
be applied to future studies and expanded beyond leukemias.

## Key facts

- **NIH application ID:** 10238859
- **Project number:** 5U01CA217862-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** BRIAN J DRUKER
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,004,844
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10238859

## Citation

> US National Institutes of Health, RePORTER application 10238859, Functional Genomic Discovery of Pathway Targeted and Immune Modulatory Therapeutic Combinations in Hematologic Malignancies (5U01CA217862-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10238859. Licensed CC0.

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