1945P - Stroma-derived bIgH3 (βigH3/TGFBI) is the local mediator of pathological TGFβ activity in pancreatic cancer and a target to treat in patients with high fibrotic activity

Background

Fibroblast activities are important in the tumor microenvironment and for survival outcomes. Fibroblast activity results in collagen formation leading to tumor fibrosis. The pro-peptide fragment of type III collagen (PRO-C3) is a circulating prognostic biomarker that can identify cancer patients with active fibrosis. Consequently, modifiers of PRO-C3 expression are potential anti-fibrotic targets for patients with cancer. The aim was to identify genetic variants associated with circulating PRO-C3 levels and explore their relevance as pharmacological targets for treatment of fibrotic cancers.

Methods

The Prospective-Epidemiology Risk Factors (PERF) cohort study (n=4968) was used to investigate genetic variants (GWAS) associated with PRO-C3. PRO-C3 was correlated to the identified protein in 178 patients with advanced (stage III+IV) pancreatic ductal adenocarcinoma (PDAC) (NCT03311776). Exposure of pancreatic fibroblasts in vitro was used to explore whether the protein was also an inducer of PRO-C3 with or without the presence of transforming growth factor receptor β (TGF-β) and function blocking antibody (18B3).

Results

GWAS unveiled a notable association between PRO-C3 and Beta-Ig H3 (BigH3/TGFBI). Investigating BigH3 and PRO-C3 in serum from patients with PDAC revealed a positive correlation (Spearman r=0.665, p<0.0001). Furthermore, PRO-C3 was associated with poor OS (log rank p-value 0.0074). Both TGF-β and BigH3 induced PRO-C3 in pancreas fibroblasts in vitro, and for both inducers, PRO-C3 was attenuated by 18B3 but not with an isotype control antibody.

Conclusions

An association between BigH3 and PRO-C3 was found by GWAS and in vitro, and the proteins correlated in PDAC. The data illustrate a novel pathological cascade in tumor fibrosis with TGF-β inducing BigH3, which subsequently activate fibroblasts to become fibrotic, resulting in elevated levels of PRO-C3, which in turn can be modulated by an anti-BigH3 antibody. This highlights the potential for treatment of tumor fibrosis by inhibiting BigH3 in cancer patients with elevated PRO-C3 levels.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Nordic Bioscience.

Funding

KeyBioscience.

Disclosure

M.A. Karsdal, N. Willumsen, C. Bager, N.I. Nissen, A. Teo Hansen Selnø, R.S. Pedersen: Financial Interests, Institutional, Full or part-time Employment: Nordic Bioscience. K.E. Mohamed, K. Henriksen: Financial Interests, Institutional, Full or part-time Employment: KeyBioscience. All other authors have declared no conflicts of interest.