title: The tyrosine kinase inhibitor E-3810 combined with paclitaxel inhibits the growth of advanced-stage triple-negative breast cancer xenografts.
abstract: E-3810 is a novel small molecule that inhibits VEGF receptor-1, -2, and -3 and fibroblast growth factor receptor-1 tyrosine kinases at nmol/L concentrations currently in phase clinical II. In preclinical studies, it had a broad spectrum of antitumor activity when used as monotherapy in a variety of human xenografts. We here investigated the activity of E-3810 combined with different cytotoxic agents in a MDA-MB-231 triple-negative breast cancer xenograft model. The molecule could be safely administered with 5-fluorouracil, cisplatin, and paclitaxel. The E-3810-paclitaxel combination showed a striking activity with complete, lasting tumor regressions; the antitumor activity of the combination was also confirmed in another triple-negative breast xenograft, MX-1. The activity was superior to that of the combinations paclitaxel+brivanib and paclitaxel+sunitinib. Pharmacokinetics studies suggest that the extra antitumor activity of the combination is not due to higher paclitaxel tumor levels, which in fact were lower in mice pretreated with all three kinase inhibitors, and the paclitaxel plasma levels excluded reduced drug availability. Pharmacodynamic studies showed that E-3810, brivanib, and sunitinib given as single agents or in combination with paclitaxel reduced the number of vessels, but did not modify vessel maturation. Reduced tumor collagen IV and increased plasma collagen IV, associated with increased matrix metalloproteinases (MMP), particularly host MMP-9, indicate a proteolytic remodeling of the extracellular matrix caused by E-3810 that in conjunction with the cytotoxic effect of paclitaxel on the tumor cells (caspase-3/7 activity) may contribute to the striking activity of their combination. These data support the therapeutic potential of combining E-3810 with conventional chemotherapy.
authors.affiliation: Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Ezia
authors.initials: E
authors.lastname: Bello
authors.forename: Giulia
authors.initials: G
authors.lastname: Taraboletti
authors.forename: Gennaro
authors.initials: G
authors.lastname: Colella
authors.forename: Massimo
authors.initials: M
authors.lastname: Zucchetti
authors.forename: Daniele
authors.initials: D
authors.lastname: Forestieri
authors.forename: Simonetta A
authors.initials: SA
authors.lastname: Licandro
authors.forename: Alexander
authors.initials: A
authors.lastname: Berndt
authors.forename: Petra
authors.initials: P
authors.lastname: Richter
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Ennio
authors.initials: E
authors.lastname: Cavalletti
authors.forename: Raffaella
authors.initials: R
authors.lastname: Giavazzi
authors.forename: Gabriella
authors.initials: G
authors.lastname: Camboni
authors.forename: Giovanna
authors.initials: G
authors.lastname: Damia
mesh_terms: D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage; D064750:Rabeprazole / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011897:Random Allocation; D000077210:Sunitinib; D014227:Triazines / Q000008:administration & dosage; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D014227:Triazines; D064750:Rabeprazole; C509922:brivanib; D000409:Alanine; D017239:Paclitaxel; D000077210:Sunitinib