# Overcoming stromal barriers to therapeutics in pancreas cancer

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2022 · $265,568

## 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 largely 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 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 pressures 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 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 overarching strategy of stromal re-engineering to build upon
the significant inroads made – and the important lessons learned – in the hopes of radically
transforming the approach and prognosis for this formidable disease.

## Key facts

- **NIH application ID:** 10467650
- **Project number:** 2R01CA161112-12A1
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Sunil R Hingorani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $265,568
- **Award type:** 2
- **Project period:** 2011-09-22 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467650

## Citation

> US National Institutes of Health, RePORTER application 10467650, Overcoming stromal barriers to therapeutics in pancreas cancer (2R01CA161112-12A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10467650. Licensed CC0.

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