Sunitinib and PF-562,271 (FAK/Pyk2 inhibitor) effectively block  growth and recovery of human hepatocellular carcinoma in a rat  xenograft model.
METHODS
To investigate the antitumor effect of sunitinib and FAK/Pyk2 tyrosine kinase inhibitor (PF-562,271)combination therapy in vivo, utilizing human hepatocellular carcinoma (HCC) cells Huh7.5. Nude rats were inoculated subcutaneously with Huh7.5 hepatoma cells. Dosing for Phase 1 was initiated on day 5 post tumor inoculations with Vehicle(Group 1), sunitinib (25 mg/kg/day; Group 2) and sunitinib plus PF-562,271 combination (15 mg/kg/day; Group 3). Phase 2 of the study started on day 26, and each of the three original groups was divided in two subgroups; half of the rats remained on original therapy (Groups 1A and 2A) with the exception of Group 3A that was euthanized after Phase 1. The other half of the rats were switched to sunitinib and PF-562,271 combination (Group 1B) or vehicle (Groups 2B and 3B). Tumor volume and weight, serum alpha feto-protein (AFP), contrast-enhanced ultrasound imaging (CEUS) and tumor histology were used to evaluate effects of treatment on tumor growth.


RESULTS
The results from this study indicate that the combination of sunitinib and PF-562,271 TKI has the potential to target different aspects of angiogenesis and tumor aggressiveness and may have significantly greater effect than relevant single agent, blocking not only tumor growth, but also impacting the ability of the tumor to recover upon withdrawal of the therapy.
Bagi
Cedo M
CM
Global Science & Technology, PGRD, Pfizer, Inc., Groton, CT 06340, USA. cedo.bagi@pfizer.com
Christensen
James
J
Cohen
Darrel P
DP
Roberts
Walter G
WG
Wilkie
Dean
D
Swanson
Terri
T
Tuthill
Theresa
T
Andresen
Catharine J
CJ
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011923:Rats, Nude; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays
D007211:Indoles; C527797:N-methyl-N-(3-((2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl)-pyridin-2-yl)-methanesulfonamide; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D013449:Sulfonamides; D051418:Focal Adhesion Kinase 2; D000077210:Sunitinib