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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.
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.
The definitive negative result for first-generation stromal targeting: a biomarker-selected population, a drug that did what it was designed to do to the matrix, and no survival benefit; the stroma ideas on this page start from here.
The classical versus basal-like split, later tied to GATA6 expression and to chemotherapy response, is the subtype scheme most likely to reach the clinic; the stromal subtypes are why the desmoplastic stroma is treated as a partner in the disease rather than inert scar.
Together with the negative HALO-301 trial of hyaluronidase this ended the first, blunt version of stromal targeting; second-generation ideas aim to reprogramme rather than remove the stroma.
Shares Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma, TGF-β signalling, Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question, Pancreatic ductal adenocarcinoma and the tag pancreatic-evidence.
Shares Hot vs cold tumours, Cold tumours and the immunosuppressive microenvironment, Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question, Pancreatic ductal adenocarcinoma and the tag pancreatic-evidence.
Shares Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question, Pancreatic ductal adenocarcinoma and the tag pancreatic-evidence.
Shares Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question, Pancreatic ductal adenocarcinoma and the tag pancreatic-evidence.
Shares Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question, Metastatic pancreatic ductal adenocarcinoma, Pancreatic ductal adenocarcinoma and the tag pancreatic-evidence.
Shares Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question, Metastatic pancreatic ductal adenocarcinoma, Pancreatic ductal adenocarcinoma and the tag pancreatic-evidence.
Shares Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question, Pancreatic ductal adenocarcinoma and the tag pancreatic-evidence.
Shares Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question, Pancreatic ductal adenocarcinoma and the tag pancreatic-evidence.