# In search of synergistic drug interactions in cancer

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $205,740

## Abstract

PROJECT SUMMARY
Colorectal cancer (CRC) is the third most prevalent cancer worldwide, killing over 850,000 people every year,
50,000 of these in the US. Only a handful of small molecule drugs are approved for patient treatment. Small
molecule drugs are often easy to formulate and more convenient for patients than antibody-based drugs, and
combination therapies have proved quite effective – FOLFOX (folinic acid, 5FU and oxaliplatin) being the prime
example in CRC. A recent study evaluated 2,025 clinically-relevant two-drug combinations on 125 tumor cell
lines representing breast, colon and pancreas and noted that “synergy overall was rare…” We wondered whether
this lack of drug-drug interaction might be a product of the simple and non-physiologic setting in which these
tumor cells were grown – monolayer cultures on tissue culture plastic – and whether a more physiologic setting
of 3-dimensional culture in the presence of a complex stroma might yield a different result. Our guiding
hypothesis for this study, therefore, is that a more complex and physiological model of human tumors will reveal
potentially clinically-relevant drug synergies.
In this study we propose to use our well-characterized human cell-based Vascularized Micro-Tumor (VMT) model
to test multiple drug combinations for potential synergies on colon cancer cells (both lines and patient-derived),
exploring the idea that drugs may target pathways and combinations of pathways that are not necessarily active
in 2D cultures, or may target tumor-stroma interactions that are just not present in monocultures. Indeed, we
have already identified a drug that blocks tumor growth only in the VMT, and not in monolayer culture or in
spheroids. The VMT platform comprises perfused living capillary beds in vitro that supply nutrients to the
surrounding tissue in much the same way they do in vivo. Microtumors, comprised of tumor cells and stromal
cells, embedded in extracellular matrix (ECM) are grown in the tissue chambers and these are surrounded and
penetrated by the micro-vessels, which support their growth. This is a flexible and powerful platform, and one
that is ideal for studying tumor biology, where remodeling of the vascular and stromal components is key to
tumor progression.
Our hypothesis is that: the VMT platform can reveal positive drug interactions not seen in simple 2D,
monocultures. To test this hypothesis we will challenge five tumor lines, representing the 5 CRIS categories of
colon cancer, against 25 drugs, representing most of the major signaling pathways, in all pairwise combinations.
We will then repeat this study with 5 patient-derived tumor lines. Our Aims are: 1. Establish dose-response
curves for each drug in the VMT. 2. Test all 2-way combinations of drugs in the VMT. 3. Compare drug
responses in tumor lines versus patient-derived tumors in the VMT.

## Key facts

- **NIH application ID:** 10651215
- **Project number:** 1R21CA280567-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** CHRISTOPHER C. W. HUGHES
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $205,740
- **Award type:** 1
- **Project period:** 2023-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10651215

## Citation

> US National Institutes of Health, RePORTER application 10651215, In search of synergistic drug interactions in cancer (1R21CA280567-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10651215. Licensed CC0.

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