# Project 3: Targeting Vulnerabilities in the Fibrotic Extracellular Matrix (ECM) of Lung Cancers

> **NIH NIH P50** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $282,686

## Abstract

Project 3 Project Summary/Abstract
Substantial therapeutic advances have been made in the treatment of non-small cell lung cancer (NSCLC) based
on the incorporation of immune checkpoint inhibitors of the PD-1/PD-L1 axis. Unfortunately, the majority of
patients do not benefit from this single-agent approach, either due to primary or acquired resistance
mechanisms. There is a knowledge gap about the interplay between the tumor-infiltrating immune cells and the
dynamic changes in the extracellular matrix and tumor microenvironment that may drive an immunosuppressive
microenvironment, which translates into a major unmet therapeutic need. The members of our multidisciplinary
team (Gibbons, Kurie, Cascone, Yamauchi, Dalby, Wistuba, and Wang) have a track record of productivity in
studying tumor matrix dynamics and immune factors in the microenvironment during lung cancer progression
and in response to immune therapy. The investigators bring expertise in mouse modeling of human lung cancer,
clinical oncology, immunotherapy, molecular pathology of lung cancer, drug development and
bioinformatics/biostatistics. We have developed preliminary data from analysis of human lung cancer specimens
and preclinical genetically engineered mouse models (GEMMs) of NSCLC that the deposition and crosslinking
of the collagen matrix suppresses intratumoral surveillance by immune cells. Based on these findings, we
hypothesize that extracellular matrix deposition and collagen crosslinking in the tumor microenvironment
suppress tumor-infiltrating immune cells, facilitating tumor invasion and metastasis. Through parallel study of
pre-clinical models and assessment of patient samples, we will address this hypothesis and explore clinical
translational opportunities by: 1. evaluating the role of collagen crosslinking enzymes and a fibrotic extracellular
matrix on the immune cell profile of murine and human lung tumors; 2. determining how treatment with immune
checkpoint inhibitors (ICI, e.g. anti-PD-(L)1 and/or anti-CTLA-4) alters extracellular matrix composition and
crosslinking in murine and patient tumors; and 3. testing the efficacy of agents that block fibrotic collagen
crosslinking or collagen-mediated T cell suppression, with or without immune checkpoint inhibitors to reverse
the suppression of a productive intratumoral immune response in preclinical models. The Human Endpoint is
demonstrated in our analysis of key ECM features in: A. SPORE tumor samples; B. 150 paired surgical
tumor/normal samples and >500 blood samples from previously untreated patients with stage IB-IIIA NSCLC
from the MDACC ImmunogenomiC prOfiling of NSCLC (ICON) study; C. 44 paired tumor/normal samples from
patients treated on the MDACC NEOSTAR study of neoadjuvant ICI for resectable stage I-IIIA NSCLC; and D.
tumors from patients after treatment with the multi-kinase inhibitor nintedanib.

## Key facts

- **NIH application ID:** 10489264
- **Project number:** 5P50CA070907-23
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** JOHN D. MINNA
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $282,686
- **Award type:** 5
- **Project period:** 1997-09-05 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10489264

## Citation

> US National Institutes of Health, RePORTER application 10489264, Project 3: Targeting Vulnerabilities in the Fibrotic Extracellular Matrix (ECM) of Lung Cancers (5P50CA070907-23). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10489264. Licensed CC0.

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