# Reprogramme the stroma rather than remove it: second-generation stromal trials with a stromal biomarker and a survival endpoint

Source: https://onco.cc/ideas/idea-pdac-stromal-reprogramming-not-depletion/  
OnCo record `idea-pdac-stromal-reprogramming-not-depletion` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Pancreatic tumours are mostly scar tissue. The first attempt to dissolve it, an enzyme given with chemotherapy to nearly 500 patients, shrank more tumours but did not lengthen life, and mouse work showed that stripping out the scar-forming cells made cancers worse. The proposal is to test drugs that change what the stroma does rather than remove it, in trials measured on survival.

## Summary

HALO-301 (2020) selected hyaluronan-high patients, added pegvorhyaluronidase alfa to gemcitabine and nab-paclitaxel and produced a higher response rate (47 versus 36 percent) with identical survival (11.2 versus 11.5 months); development stopped. Özdemir (2014) had shown that deleting alpha-SMA myofibroblasts in mice produced undifferentiated, hypoxic, immunosuppressed tumours and shorter survival, reversible by anti-CTLA4 but not gemcitabine, and that fewer myofibroblasts in human tumours also meant worse survival. Moffitt (2015) showed the stroma itself has prognostic subtypes (normal versus activated). The lesson is that the stroma is heterogeneous and partly restraining, so the target is its activated, immunosuppressive state rather than its mass: candidate approaches include FAP-directed agents (imaging and radioligands exist), TGF-beta pathway modulation and vitamin D receptor or other fibroblast-reprogramming agents, combined with RAS inhibition or chemotherapy. The design requirement is a stromal biomarker at entry and on treatment (activated stroma signature or FAP PET), randomisation against the same backbone, and overall survival rather than response as the endpoint, because response without survival is the failure mode this field has already seen.

## Fields

- Kind: Idea
- Last checked: 2026-09-24
- Tags: pancreatic-evidence
- Hypothesis: In activated-stroma pancreatic cancer, a fibroblast-reprogramming agent added to a RAS inhibitor or chemotherapy backbone improves overall survival (hazard ratio 0.75 or better) where matrix depletion did not, and the benefit tracks conversion of the stromal signature on treatment.
- Rationale: Depletion failed and can harm; the stroma's prognostic subtypes show it has states that can be measured and, in models, shifted; RAS inhibition now gives a backbone active enough for a stromal partner to matter.
- Proposed test: Randomised phase 2 with mandatory paired biopsies or FAP PET, stromal signature as a stratification factor, overall survival as primary endpoint; go or no-go on survival, not response.
- Maturity: preclinical-evidence
- Actor: research

## Sources

- HALO 109-301 (JCO 2020): https://europepmc.org/article/MED/32706635
- Özdemir et al.: fibroblast depletion accelerates pancreas cancer (Cancer Cell 2014): https://europepmc.org/article/MED/24856586

## Connected records

- ideas: [FAP theranostics as a pan-cancer stromal strategy](https://onco.cc/ideas/idea-fap-theranostics-pancancer/)
- cancers: [Metastatic pancreatic ductal adenocarcinoma](https://onco.cc/cancers/metastatic-pdac/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- technologies: [FAPI PET](https://onco.cc/technologies/fapi-pet/)
- targets: [FAP](https://onco.cc/targets/fap/)
- pathways: [Epithelial-mesenchymal transition & drug efflux](https://onco.cc/pathways/emt/), [TGF-β signalling](https://onco.cc/pathways/tgf-beta/)
- terms: [Cancer-associated fibroblasts (CAFs)](https://onco.cc/terms/cancer-associated-fibroblasts/), [Desmoplasia (tumour stroma)](https://onco.cc/terms/desmoplasia/), [Hot vs cold tumours](https://onco.cc/terms/cold-vs-hot/), [Stroma-rich and desmoplastic tumours in molecular data](https://onco.cc/terms/desmoplastic-stroma-rich/)
- bottlenecks: [Cold tumours and the immunosuppressive microenvironment](https://onco.cc/bottlenecks/b-tme-immunosuppression/), [Failures are hidden](https://onco.cc/bottlenecks/b-negative-results/), [Lab models that fail to predict what happens in patients](https://onco.cc/bottlenecks/b-preclinical-models/)
- key papers: [Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival](https://onco.cc/key-papers/paper-ozdemir-caf-depletion-accelerates-pancreatic-cancer-cancer-cell-2014/), [Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma](https://onco.cc/key-papers/paper-halo-301-pegvorhyaluronidase-jco-2020/), [Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma](https://onco.cc/key-papers/paper-moffitt-virtual-microdissection-subtypes-nat-genet-2015/)
- roadmaps: [Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question](https://onco.cc/roadmaps/pancreatic-roadmap/)

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