# Overcoming stromal barriers to therapeutics in pancreas cancer

> **NIH NIH R01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $513,401

## Abstract

PROJECT SUMMARY
Pancreatic ductal adenocarcinomas (PDA) are unrivaled in their lethality. PDAs have the highest 1-
year, 5-year, and 10-year mortalities of any cancer and are expected to become the second-leading
cause of cancer-related death by 2030. An invasive PDA represents the coordinated evolution of cell-
intrinsic and extrinsic processes and capabilities that subvert and repurpose the dictums of normal
tissue composition, architecture, and physiology to foster unbridled growth and colonization. This new
organizational entity is constructed at the behest of the mutated epithelial cell. The resulting PDA neo-
organ contains a minority of tumor epithelial cells amidst a heterogeneous sea of non-epithelial cells; a
complex interstitial stew of proteins, proteoglycans and glycosaminoglycans, together with both freely
mobile and complexed water; and a paucity of vessels that otherwise resemble a normal vasculature in
lacking fenestrae or interendothelial junctions, but that are collapsed under intense interstitial fluid
pressures. We have undertaken a systematic exploration of the cell autonomous and non-cell
autonomous processes that drive PDA pathogenesis and resistance. We have developed genetically
engineered animal models that faithfully recapitulate the clinical syndrome, metastatic behavior,
histopathology and molecular features of the human disease as primary platforms to both uncover
critical principles of disease biology and to rigorously test strategies to overcome them. Through such
investigations we have identified unusually high concentrations of intratumoral hyaluronan (HA) as the
primary culprit in the extraordinarily elevated interstitial fluid pressures (IFP) in PDA that, in turn, cause
the vascular collapse and hypoperfusion characteristic of this disease. The stromal barrier to perfusion
also serves as a primary mechanism of drug resistance in limiting the tumor penetration of systemically
delivered agents. We have additionally identified multiple mechanisms of immune suppression that
prevent the development of an endogenous effector T cell response. Collectively, these unique
aspects of stromal biology in PDA conspire to create a drug- and immune-privileged sanctuary for
unimpeded growth of the pancreas cancer cell. Very recently, we have elaborated strategies to
overcome critical aspects of these physical and immunological barriers to therapy revealing a perhaps
unexpected degree of vulnerability once the barriers are breached. We describe a series of continuing
investigations into this strategy of stromal re-engineering to expand upon the significant inroads made
in the hopes of radically transforming the approach and prognosis for this formidable disease.

## Key facts

- **NIH application ID:** 9980300
- **Project number:** 5R01CA161112-10
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Sunil R Hingorani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $513,401
- **Award type:** 5
- **Project period:** 2011-09-22 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980300

## Citation

> US National Institutes of Health, RePORTER application 9980300, Overcoming stromal barriers to therapeutics in pancreas cancer (5R01CA161112-10). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9980300. Licensed CC0.

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