Abstract

Desmoplastic solid tumours carry a dense, collagen-rich stroma that raises interstitial fluid pressure and collapses intratumoral microvasculature, impeding delivery of systemically administered drugs. In the one human measurement available, CuET — the cytotoxic copper complex of disulfiram's dithiocarbamate metabolite, and an inhibitor of the p97/NPL4 segregase — was detected in the plasma of glioblastoma patients but not in resected tumour tissue. Separately, vitamin D receptor agonism has been shown in a randomised human trial to reprogram pancreatic tumour stroma, reducing the alpha-SMA fibroblast fraction and increasing CD8 T cell infiltration on paired biopsy. This disclosure proposes that the first can be used to fix the second: that a sustained 60-to-90-day VDR agonist window, timed to the kinetics of collagen turnover and fibroblast phenotypic reversion rather than to a one- or two-week run-in, opens desmoplastic tissue sufficiently for CuET generated in situ from an oral disulfiram substrate pool and a low-milligram systemic copper lever to reach tumour cells without a nanocarrier. The hypothesis is falsified if sequenced administration does not outperform simultaneous, if interstitial pressure does not fall under sustained VDR agonism, if intratumoral CuET does not rise with matrix opening, or if the combination index does not fall below 1. Executable 3D spheroid and orthotopic protocols are specified. No experiment has been performed. No evidence of safety or efficacy exists. The document is published, with a full enumeration of agents, doses, ratios, schedules, routes and indications, to place the subject matter permanently in the public domain. No patent protection is sought or claimed. CCA 4.0.

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This work is licensed under a Creative Commons Attribution 4.0 License.

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