RESUMEN
The FGFR4/FGF19 signaling axis is overactivated in 20% of liver tumors and currently represents a promising targetable signaling mechanism in this cancer type. However, blocking FGFR4 or FGF19 has proven challenging due to its physiological role in suppressing bile acid synthesis which leads to increased toxic bile acid plasma levels upon FGFR4 inhibition. An FGFR4-targeting antibody, U3-1784, was generated in order to investigate its suitability as a cancer treatment without major side effects.U3-1784 is a high-affinity fully human antibody that was obtained by phage display technology and specifically binds to FGFR4. The antibody inhibits cell signaling by competing with various FGFs for their FGFR4 binding site thereby inhibiting receptor activation and downstream signaling via FRS2 and Erk. The inhibitory effect on tumor growth was investigated in 10 different liver cancer models in vivo The antibody specifically slowed tumor growth of models overexpressing FGF19 by up to 90% whereas tumor growth of models not expressing FGF19 was unaffected. In cynomolgus monkeys, intravenous injection of U3-1784 caused elevated serum bile acid and liver enzyme levels indicating potential liver damage. These effects could be completely prevented by the concomitant oral treatment with the bile acid sequestrant colestyramine, which binds and eliminates bile acids in the gut. These results offer a new biomarker-driven treatment modality in liver cancer without toxicity and they suggest a general strategy for avoiding adverse events with FGFR4 inhibitors.
Asunto(s)
Anticuerpos Monoclonales/toxicidad , Anticuerpos Monoclonales/uso terapéutico , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/inmunología , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Resina de Colestiramina/farmacología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Íleon/efectos de los fármacos , Íleon/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Ratones Endogámicos BALB C , Células 3T3 NIH , Transducción de Señal/efectos de los fármacos , Sorafenib/farmacologíaRESUMEN
The anti-tumour activity of the novel thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARgamma) agonist CS-7017 was investigated. CS-7017 activated PPARgamma-mediated luciferase expression with an EC(50) of 0.20 nM. In addition, CS-7017 was shown to be highly selective for PPARgamma amongst other PPAR subfamilies. CS-7017 inhibited the proliferation of the human anaplastic thyroid tumour cell line DRO and the pancreatic tumour cell line AsPC-1 in vitro at concentrations as low as 10 nM. In xenograft studies, CS-7017 inhibited the growth of the human colorectal tumour cell line HT-29 in nude mice as well as DRO in nude rats in a dose-dependent manner. At the same dose, an increase in the levels of adiponectin, a surrogate marker for PPARgamma activation, was also observed. CS-7017 prolonged the survival of mice inoculated with murine colorectal tumour Colon 38 with marginal tumour growth inhibition. These preclinical results support the potential utility of CS-7017 in a clinical setting.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , PPAR gamma/agonistas , Tiazolidinedionas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Luciferasas/metabolismo , Ratones , Ratones Desnudos , Tiazolidinedionas/metabolismo , Neoplasias de la Tiroides/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The potent chemopreventive activity of cyclooxygenase-2 (COX-2) inhibitors has been demonstrated in a number of preclinical studies, but their potency in antitumor activity is still in dispute. In this report, we demonstrate the potent antitumor activity of a novel COX-2 inhibitor, CS-706 in mouse colorectal adenocarcinoma colon 26 tumor-bearing mice treated with or without antitumor chemotherapeutic agents. Daily oral administration of CS-706 at doses of 3-100 mg/kg from the day of tumor inoculation (Day 0) inhibited tumor growth dose-dependently, and the maximal inhibition was 67% at a dose of 100 mg/kg. In contrast, celecoxib, a well-known COX-2 inhibitor, did not inhibit tumor growth at doses up to 100 mg/kg. Furthermore, CS-706 at a dose of 1 mg/kg or above markedly prolonged the survival time of tumor-bearing mice. Administration of 30 mg/kg CS-706 from Day 7 combined with a single intravenous treatment of 10 mg/kg cisplatin on Day 7 completely regressed the tumors in all tumor-bearing mice examined, whereas only in 1 of 10 mice tumor was regressed with cisplatin treatment. Similar combination effects were observed with 10 mg/kg CS-706 and 60 mg/kg 5-fluorouracil (5-FU). Moreover, 10 mg/kg CS-706 significantly inhibited angiogenesis induced by implanted chambers with colon 26 cells in a dorsal air sac assay in mice. Collectively, these results suggest that CS-706 is a potent antitumor agent, especially in combination with conventional chemotherapeutic agents, and that the anti-angiogenic activity of CS-706 may contribute at least in part to its marked antitumor activity.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Pirroles/uso terapéutico , Sulfonamidas/uso terapéutico , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Línea Celular Tumoral , Cisplatino/uso terapéutico , Ensayos de Selección de Medicamentos Antitumorales , Fluorouracilo/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Factor A de Crecimiento Endotelial Vascular/biosíntesisRESUMEN
Biliary tract cancer is still challenging to treat and manage due to its poor sensitivity to conventional therapies and the inability to prevent or detect the early tumor formation. The most well known risk factor for gallbladder cancer is the presence of chronic inflammation, usually related to gallstones. It has been suggested that cyclooxygenase-2 (COX-2) plays a variety of roles in the gastrointestinal tract, including pathogenic processes such as neoplasia. Recently, we have generated transgenic mice that overexpress rat ErbB-2 under the control of bovine keratin 5 promoter (BK5.ErbB-2 mice). Homozygous BK5.ErbB-2 mice develop adenocarcinoma of gallbladder with an approximately 90% incidence. In addition to the activation of ErbB-2 and epidermal growth factor receptor, mRNA and protein levels of COX-2 were up-regulated in the gallbladder carcinomas that developed in these transgenic mice. The aim of this study was to examine the effects of a COX-2 inhibitor, CS-706, on the development of gallbladder carcinomas using the BK5.ErbB-2 mouse model. Ultrasound image analysis as well as histologic evaluation revealed a significant therapeutic effect of CS-706 on the gallbladder tumors, either as reversion to a milder phenotype or inhibition of tumor progression. The antitumor effect was associated with inhibition of prostaglandin E(2) synthesis. CS-706 treatment also down-regulated the activation of ErbB-2 and epidermal growth factor receptor, resulting in decreased levels of phosphorylated Akt and COX-2 in gallbladder cancers of BK5.ErbB-2 mice. Based on our results, targeting COX-2 could provide a potentially new and effective therapy alone or in combination with other therapeutic agents for patients with biliary tract cancer.