# Studying drug resistance in AML and PDAC using a novel heterotypic 3D organoid model

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $125,000

## Abstract

PROJECT SUMMARY
This application is being submitted in response to the Notice of Special Interest (NOSI) identified as
NOT-CA-20-020. The work will initiate a unique collaboration between research groups at OHSU (Agarwal
Lab) and WUSTL (Lim Lab) to identify the mechanisms by which the tumor microenvironment (TME) contribute
to the drug resistance in cancer using a 3D multicellular tumor organoid model. The bi-directional communication
between cancer cells and microenvironment is much more complex than initially perceived. In general, the tumor
microenvironment provides nutrient supplies and survival signals to cancer cells, resulting in tumor development,
metastasis, and therapy resistance. Therefore, cutting off these resources represents an effective anti-cancer
strategy. Most of the traditional in vitro drug screening approaches does not mimic the components of tumor
microenvironment, thereby may account for high failure rates of the resultant regimens in clinical trials. Here we
propose to develop a novel in vitro 3D multicellular tumor organoid model that will closely recapitulate the in vivo
tumor microenvironment to improve our understanding of cancer cell-microenvironment interactions. We will use
this model to study pancreatic ductal adenocarcinoma (PDAC) and acute myeloid leukemia (AML), where
treatment resistance is a major challenge. Preliminary data from both labs show that the secreted factors from
microenvironment play an important role in conferring drug resistance to MAPK pathway inhibitors in both AML
and PDAC. In patient-derived xenograft (PDX) models of PDAC, in vitro drug sensitivity to MAPK pathway
inhibitor differs greatly between monolayer culture and when grown in mice, strongly suggesting the TME as an
essential component that is missing in the current culture system. Therefore, the Lim lab developed a novel 3D
heterotopic models comprising of cancer-associated fibroblasts (CAFs) and tumor cells. In this proposal, we will
adopt this 3D organoid model to perform functional drug screening and understand the mechanisms of drug
response in AML and PDAC. We will test the hypothesis that heterotypic 3D organoid model will better mimic
therapy response for AML and PDAC cells in their native environment. Specifically, we will utilize primary AML
cells and cell lines from the OHSU group and cells derived from PDAC PDX model to perform drug testing in 96
well plate format for trametinib (CTEP drug) as single agent and as combination with FDA approved drugs. We
will test the effect of these inhibitors on cell viability, cellular composition, differentiation, and target inhibition
using multi-parametric flow cytometry and immunofluorescence analysis. We will identify the secreted cytokine
landscape in microenvironment and impact of these on the growth and survival of tumors cells. The data
integration and pathway analysis will be performed to identify unique therapeutic targets. Perturbing the
supporting cells of the microenvironmen...

## Key facts

- **NIH application ID:** 10141772
- **Project number:** 3R01CA229875-02S1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Anupriya Agarwal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $125,000
- **Award type:** 3
- **Project period:** 2020-07-01 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10141772

## Citation

> US National Institutes of Health, RePORTER application 10141772, Studying drug resistance in AML and PDAC using a novel heterotypic 3D organoid model (3R01CA229875-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10141772. Licensed CC0.

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