Ligands to FGF receptor 2-IIIb induce proliferation, motility, protection from cell death and cytoskeletal rearrangements in epithelial ovarian cancer cell lines

Epithelial ovarian cancer (EOC) is the most common and lethal form of gynecological malignancy. These cancers are thought to be derived from the ovarian surface epithelium (OSE). We have previously reported that the epithelial-specific FGF receptor 2 splice variant IIIb is not expressed in normal OSE, but is expressed in approximately 80% of EOCs. We have examined the phenotypic effects of ligands to FGF receptor 2-IIIb, namely FGFs 1,7 and 10, on a panel of EOC cell lines. We show that these ligands increase cell viability, induce DNA synthesis, motility and chemotaxis and protect from spontaneous cell death when EOC cells are maintained in serum free medium. A blocking antiserum to FGF-7 reduces viability of 41-M EOC cells, and abrogates the ability of ascitic fluid containing FGF-7 to induce DNA synthesis in these cells. Finally, we show that FGF-7 can induce a reorganization of the actin cytoskeleton in SK-OV-3 ovarian cancer cells. It is suggested that ligands to FGF receptor 2-IIIb affect a range of phenotypes important in the neoplastic growth of EOCs

Netazepide, a Gastrin Receptor Antagonist, Normalises Tumour Biomarkers and Causes Regression of Type 1 Gastric Neuroendocrine Tumours in a Nonrandomised Trial of Patients with Chronic Atrophic Gastritis

<div><p>Introduction</p><p>Autoimmune chronic atrophic gastritis (CAG) causes hypochlorhydria and hypergastrinaemia, which can lead to enterochromaffin-like (ECL) cell hyperplasia and gastric neuroendocrine tumours (type 1 gastric NETs). Most behave indolently, but some larger tumours metastasise. Antrectomy, which removes the source of the hypergastrinaemia, usually causes tumour regression. Non-clinical and healthy-subject studies have shown that netazepide (YF476) is a potent, highly selective and orally-active gastrin/CCK-2 receptor antagonist. Also, it is effective in animal models of ECL-cell tumours induced by hypergastrinaemia.</p> <p>Aim</p><p>To assess the effect of netazepide on tumour biomarkers, number and size in patients with type I gastric NETs.</p> <p>Methods</p><p>We studied 8 patients with multiple tumours and raised circulating gastrin and chromogranin A (CgA) concentrations in an open trial of oral netazepide for 12 weeks, with follow-up 12 weeks later. At 0, 6, 12 and 24 weeks, we carried out gastroscopy, counted and measured tumours, and took biopsies to assess abundances of several ECL-cell constituents. At 0, 3, 6, 9, 12 and 24 weeks, we measured circulating gastrin and CgA and assessed safety and tolerability.</p> <p>Results</p><p>Netazepide was safe and well tolerated. Abundances of CgA (p<0.05), histidine decarboxylase (p<0.05) and matrix metalloproteinase-7(p<0.10) were reduced at 6 and 12 weeks, but were raised again at follow-up. Likewise, plasma CgA was reduced at 3 weeks (p<0.01), remained so until 12 weeks, but was raised again at follow-up. Tumours were fewer and the size of the largest one was smaller (p<0.05) at 12 weeks, and remained so at follow-up. Serum gastrin was unaffected.</p> <p>Conclusion</p><p>The reduction in abundances, plasma CgA, and tumour number and size by netazepide show that type 1 NETs are gastrin-dependent tumours. Failure of netazepide to increase serum gastrin further is consistent with achlorhydria. Netazepide is a potential new treatment for type 1 NETs. Longer, controlled trials are justified.</p> <p>Trial Registration</p><p>European Union EudraCT database 2007-002916-24 <a href="https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-002916-24" target="_blank"><u>https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-002916-24</u></a><a href="http://clinicaltrials.gov" target="_blank">ClinicalTrials.gov</a> NCT01339169 <a href="http://clinicaltrials.gov/ct2/show/nct01339169?term=yf476&rank=5" target="_blank"><u>http://clinicaltrials.gov/ct2/show/NCT01339169?term=yf476&rank=5</u></a></p> </div

Endoscopic photographs from the same area of the stomach in patients 1 (a, b) and 2 (c, d) at baseline (a, c) and after 12 weeks of netazepide (b, d).

<p>Endoscopic photographs from the same area of the stomach in patients 1 (a, b) and 2 (c, d) at baseline (a, c) and after 12 weeks of netazepide (b, d).</p

Fasting (a) plasma chromogranin A (U/L) and (b) serum gastrin (pmol/L) concentrations at baseline, after 3, 6, 9 and 12 weeks’ netazepide treatment, and at follow-up at 24 weeks, 12 weeks after end of treatment.

<p>Fasting (a) plasma chromogranin A (U/L) and (b) serum gastrin (pmol/L) concentrations at baseline, after 3, 6, 9 and 12 weeks’ netazepide treatment, and at follow-up at 24 weeks, 12 weeks after end of treatment.</p

Endoscopic tumour characteristics: (a) number of tumours; (b) size of largest tumour, and (c,d) % change from baseline after 6 and 12 weeks’ netazepide treatment, and at follow-up at 24 weeks, 12 weeks after end of treatment.

<p>Endoscopic tumour characteristics: (a) number of tumours; (b) size of largest tumour, and (c,d) % change from baseline after 6 and 12 weeks’ netazepide treatment, and at follow-up at 24 weeks, 12 weeks after end of treatment.</p

Gastric corpus mucosal mRNA abundance of CgA (a), HDC (b), MMP-7 (c), PAI-1 (d) and PAI-2 (e) normalised to mRNA abundance of the housekeeper gene GAPDH.

<p>Mean ± standard deviation of each biomarker after 6 and 12 weeks of netazepide treatment, and at follow-up at 24 weeks, 12 weeks after end of treatment (f). *p<0.05.</p