ABSTRACT
PURPOSE: In REFLECT, lenvatinib demonstrated an effect on overall survival (OS) by confirmation of noninferiority to sorafenib in unresectable hepatocellular carcinoma. This analysis assessed correlations between serum or tissue biomarkers and efficacy outcomes from REFLECT. EXPERIMENTAL DESIGN: Serum biomarkers (VEGF, ANG2, FGF19, FGF21, and FGF23) were measured by ELISA. Gene expression in tumor tissues was measured by the nCounter PanCancer Pathways Panel. Pharmacodynamic changes in serum biomarker levels from baseline, and associations of clinical outcomes with baseline biomarker levels, were evaluated. RESULTS: Four hundred and seven patients were included in the serum analysis set (lenvatinib n = 279, sorafenib n = 128); 58 patients were included in the gene-expression analysis set (lenvatinib n = 34, sorafenib n = 24). Both treatments were associated with increases in VEGF; only lenvatinib was associated with increases in FGF19 and FGF23 at all time points. Lenvatinib-treated responders had greater increases in FGF19 and FGF23 versus nonresponders at cycle 4, day 1 (FGF19: 55.2% vs. 18.3%, P = 0.014; FGF23: 48.4% vs. 16.4%, P = 0.0022, respectively). Higher baseline VEGF, ANG2, and FGF21 correlated with shorter OS in both treatment groups. OS was longer for lenvatinib than sorafenib [median, 10.9 vs. 6.8 months, respectively; HR, 0.53; 95% confidence interval (CI), 0.33-0.85; P-interaction = 0.0397] with higher baseline FGF21. In tumor tissue biomarker analysis, VEGF/FGF-enriched groups showed improved OS with lenvatinib versus the intermediate VEGF/FGF group (HR, 0.39; 95% CI, 0.16-0.91; P = 0.0253). CONCLUSIONS: Higher baseline levels of VEGF, FGF21, and ANG2 may be prognostic for shorter OS. Higher baseline FGF21 may be predictive for longer OS with lenvatinib compared with sorafenib, but this needs confirmation.
Subject(s)
Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/analysis , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/mortality , Liver Neoplasms/drug therapy , Liver Neoplasms/mortality , Phenylurea Compounds/therapeutic use , Quinolines/therapeutic use , Sorafenib/therapeutic use , Biomarkers, Tumor/pharmacokinetics , Carcinoma, Hepatocellular/blood , Carcinoma, Hepatocellular/chemistry , Humans , Liver Neoplasms/blood , Liver Neoplasms/chemistry , Predictive Value of Tests , Survival RateSubject(s)
Angiogenesis Inhibitors , Biomarkers, Tumor , Molecular Targeted Therapy , Neoplasms/blood supply , Neoplasms/drug therapy , Phenylurea Compounds , Quinolines , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Animals , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Melanoma/drug therapy , Mutation , Neoplasms/genetics , PTEN Phosphohydrolase/genetics , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Phenylurea Compounds/therapeutic use , Precision Medicine , Proto-Oncogene Proteins B-raf/genetics , Quinolines/chemistry , Quinolines/pharmacology , Quinolines/therapeutic use , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Skin Neoplasms/drug therapy , Translational Research, Biomedical/trendsABSTRACT
In the continuing study of antifeedant compounds in Protium javanicum Burm. f. against Coptotermes formosanus Shiraki, 6-desacetylnimbin (1), quercitrin (2) and myricitrin (3) were isolated from P. javanicum extract. All compounds were characterised by NMR and MS. Furthermore, the structure of 6-desacetylnimbin was confirmed by X-ray crystallography. The antifeedant activity was evaluated with no-choice feeding tests. At a dose of 0.5 mg, 6-desacetylnimbin exhibited the highest antifeedant activity among the isolates.
Subject(s)
Burseraceae/chemistry , Insecticides/chemistry , Insecticides/pharmacology , Isoptera/drug effects , Plant Extracts/chemistry , Plant Extracts/pharmacology , Animals , Crystallography, X-Ray , Diterpenes/chemistry , Diterpenes/pharmacology , Feeding Behavior/drug effects , Flavonoids/chemistry , Flavonoids/pharmacology , Isoptera/physiology , Quercetin/analogs & derivatives , Quercetin/chemistry , Quercetin/pharmacologyABSTRACT
Infertility technologies often employ exogenous gonadotropin therapy to increase antral follicle production. In an effort to enhance ovarian response, several long-acting FSH therapies have been developed including an FSH-C-terminal peptide (CTP), where the FSH subunits are linked by the CTP moiety from human chorionic gonadotropin, which is responsible for the increased half-life of human chorionic gonadotropin. We found that administration of FSH-CTP for ovarian hyperstimulation in rats blunted ovarian follicle vascular development. In women, reduced ovarian vasculature has been associated with lower pregnancy rates. We were interested in determining whether vascular endothelial growth factor (VEGF) therapy could enhance ovarian angiogenesis in FSH-CTP-treated rats. Coadministration of systemic FSH-CTP plus recombinant VEGF was compared with treatment with a novel, single-chain bifunctional VEGF-FSH-CTP (VFC) analog. For VFC, the FSH portion targets the protein to the ovary and stimulates follicle growth, whereas VEGF enhances local vascular development. Both in vitro and in vivo studies confirm the dual FSH and VEGF action of the VFC protein. Evaluation of ovarian follicle development demonstrates that administration of combination therapy using VEGF and FSH-CTP failed to increase follicle vasculature above levels seen with FSH-CTP monotherapy. However, treatment with VFC significantly increased follicle vascular development while concurrently increasing the number of large antral follicles produced. In conclusion, we report the production and characterization of a long-acting, bifunctional VEGF-FSH-CTP protein that is superior to combination therapy for enhancing VEGF activity in the ovary and stimulating follicular angiogenesis in rats.