Inhibition of FGF/FGFR autocrine signaling in mesothelioma with the FGF ligand trap, FP-1039/GSK3052230

Our plain-English summary of Inhibition of FGF/FGFR autocrine signaling in mesothelioma with the FGF ligand trap, FP-1039/GSK3052230, by C. Blackwell, C. Sherk, M. Fricko, et al (Oncotarget, 2016).

The study

• Authors: C. Blackwell, C. Sherk, M. Fricko, G. Ganji, M. Barnette, B. Hoang, J. Tunstead, T. Skedzielewski, H. Alsaid, B.M. Jucker, E. Minthorn, R. Kumar, M.P. DeYoung
• Journal: Oncotarget
• Published: 2016;7(26):39861-39871
• Cited by: 36 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Fibroblast growth factor (FGF) ligand-dependent signaling has a fundamental role in cancer development and tumor maintenance. GSK3052230 (also known as FP-1039) is a soluble decoy receptor that sequesters FGFs and inhibits FGFR signaling. Herein, the efficacy of this molecule was tested in models of mesothelioma, a tumor type shown to express high levels of FGF2 and FGFR1. GSK3052230 demonstrated antiproliferative activity across a panel of mesothelioma cell lines and inhibited growth of tumor xenografts in mice. High expression of FGF2 and FGFR1 correlated well with response to FGF pathway inhibition. GSK3052230 inhibited MAPK signaling as evidenced by decreased phospho-ERK and phospho-S6 levels in vitro and in vivo. Additionally, dose-dependent and statistically-significant reductions in tumor vessel density were observed in GSK3052230-treated tumors compared to vehicle-treated tumors. These data support the role of GSK3052230 in effectively targeting FGF-FGFR autocrine signaling in mesothelioma, demonstrate its impact on tumor growth and angiogenesis, and provide a rationale for the current clinical evaluation of this molecule in mesothelioma patients.

In plain English

This laboratory study tested an experimental drug, GSK3052230 (also called FP-1039), in mesothelioma and lung cancer cell lines and in mice carrying implanted human mesothelioma tumors. No patients received the drug, and asbestos exposure was not studied. The drug is designed to trap growth signals called FGFs. Both this drug and a second FGF-blocking compound, NVP-BGJ398, slowed growth of 6 of 8 mesothelioma cell lines and 4 of 15 lung cancer cell lines. Cell lines with high levels of FGF2 and FGFR1 tended to respond. In mice with NCI-H226 tumors, the two higher doses inhibited tumor growth by 57% and 78% compared with vehicle-treated mice. In MSTO-211H tumors, growth inhibition versus vehicle was 20% at 5.12 mg/kg (not statistically significant) and 50% at the highest dose, 25.6 mg/kg. Treated NCI-H226 tumors had lower blood-vessel density in the outer region and the whole tumor. Imaging of these tumors showed no change in blood flow. The authors concluded that the data support clinical testing of the drug in mesothelioma patients. They noted that other FGFs the drug does not block well might still drive tumor signaling.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical laboratory study: experiments in cancer cell lines and in mice carrying human tumor xenografts
• Who was studied: A panel of 23 cancer cell lines (8 mesothelioma, 15 lung cancer), plus female CB-17 SCID mice with implanted NCI-H226 tumors (n = 8 per group) or MSTO-211H tumors (n = 10 per group). No patients received the drug. The authors also referred to human tumor expression data from The Cancer Genome Atlas, shown in a supplementary figure.
• Exposure: No asbestos exposure was studied. The exposure was treatment with the FGF ligand trap GSK3052230. In cells it was compared with the FGFR kinase inhibitor NVP-BGJ398. Mice received vehicle or GSK3052230 at 1.024, 5.12 or 25.6 mg/kg three times per week for 4 weeks.
• Main results:
  • Both FGF pathway inhibitors showed antiproliferative activity in 6 of 8 mesothelioma cell lines and in 4 of 15 lung cancer cell lines.
  • Across the cell lines, high levels of FGF2 and FGFR1 correlated well with response to both compounds.
  • In mice with NCI-H226 mesothelioma xenografts, GSK3052230 at 5.12 and 25.6 mg/kg caused significant tumor growth inhibition of 57% and 78%, respectively, compared with vehicle.
  • In mice with MSTO-211H xenografts, 5.12 mg/kg did not significantly inhibit tumor growth (20% TGI). The highest dose (25.6 mg/kg) caused 50% TGI compared with vehicle.
  • In NCI-H226 tumors, reductions in phospho-ERK and phospho-S6 with the two highest doses were not statistically significant.
  • In MSTO-211H tumors, phospho-ERK was reduced by about 50% with 25.6 mg/kg at 3 days after the last dose. It rebounded to vehicle levels by 14 days.
  • In NCI-H226 tumors, blood vessel density (vessels per area) was significantly lower in the GSK3052230-treated group than in the vehicle group for the outer region and the whole tumor. There was no difference in the inner region.
  • Dynamic contrast-enhanced MRI showed no effect of GSK3052230 on tumor blood flow and perfusion in NCI-H226 tumors.
• The authors' conclusion: The authors concluded that the data support the ongoing clinical evaluation of GSK3052230 in previously untreated mesothelioma patients.
• Limitations the authors state:
  • Other FGFs that GSK3052230 does not inhibit, or inhibits only weakly, could be secreted by the tumor or nearby cells and contribute to signaling.
  • One mesothelioma cell line with high FGF2 (NCI-H2052) did not respond to either drug, for reasons the authors do not know.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Fibroblast, Angiogenesis.

Related studies

• A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma — E.M.J. van Brummelen, E. Levchenko, et al. (2020)
• Nonamplified FGFR1 is a growth driver in malignant pleural mesothelioma — L.A. Marek, T.K. Hinz, et al. (2014)
• The inhibition of FGF receptor 1 activity mediates sorafenib antiproliferative effects in human malignant pleural mesothelioma tumor-initiating cells — A. Pattarozzi, E. Carra, et al. (2017)
• Absence of amplification of the FGFR1-gene in human malignant mesothelioma of the pleura: a pilot study — T. Plönes, F. Beckers, et al. (2014)
• Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy — K. Schelch, M.A. Hoda, et al. (2014)
• Autocrine CSF-1R signaling drives mesothelioma chemoresistance via AKT activation — M. Cioce, C. Canino, et al. (2014)

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