Bioluminescent imaging study: FAK inhibitor, PF-562,271, preclinical study in PC3M-luc-C6 local implant and metastasis xenograft models.
Focal adhesion kinase (FAK) is essential in regulating integrin signaling pathways responsible for cell survival and proliferation, as well as motility, making FAK a distinctive target in the field of anticancer drug development, especially with regards to metastatic disease.(1) Our objective was to demonstrate tumor growth inhibition by PF-562,271, a selective inhibitor of FAK and FAK2, or Pyk2,(2) in mouse xenograft models, both subcutaneous and metastatic, employing the human prostate cancer cell line PC3M-luc-C6, a modified PC3M cell line that expresses luciferase. After 2 weeks of treatment with PF-562,271, 25 mg/kg PO BID 5x/wk, the subcutaneous model showed a 62% tumor growth inhibition compared to control based on tumor measurements (p < 0.05), with a 88% vs. a 490% increase in bioluminescent signal for treatment and control respectively (p < 0.05). In the metastasis model, the percent change from baseline, after 18 days of treatment, of the treatment group was 2,854 vs. 14,190% for the vehicle (p < 0.01). These results show that PF-562,271 has a potent effect on metastatic prostate cancer growth in vivo.
Sun
Haihao
H
Molecular Pharmacology Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Pisle
Stephen
S
Gardner
Erin R
ER
Figg
William D
WD
D000818:Animals; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008163:Luminescent Measurements; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology*; D015996:Survival Rate; 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; D013449:Sulfonamides; D051416:Focal Adhesion Protein-Tyrosine Kinases