Dual focal adhesion kinase/Pyk2 inhibitor has positive effects on bone tumors: implications for bone metastases.
BACKGROUND
Lytic bone metastases occur frequently in cancer patients and present major clinical issues including lack of effective therapies. The mechanism of lytic bone metastases involves interactions between tumor cells, bone matrix, and bone cells. Both focal adhesion kinase (FAK) and Pyk2 are implicated in the biology and physiology of bone and cancer.


METHODS
The efficacy of PF-562,271 was evaluated using MDA-MB-231 cells implanted in the tibia of nude rats. The drug was administered orally at a dose of 5 mg/kg, 7 days per week for 28 days. Serum and urine biomarkers, imaging, and histologic techniques were deployed to monitor tumor take rate, disease progression, and response to therapy.


RESULTS
The compound was well tolerated. Both compound-treated groups demonstrated significant and similar increases in osteocalcin and cancellous bone parameters. Radiographic evaluation of tumor-bearing tibiae revealed tumor expansion in nontreated rats compared with a decrease in tumor growth and signs of bone healing in rats treated with PF-562,271. Tartrate-resistant acid phosphatase and fluorescent in situ hybridization analysis revealed that the majority of bone resorption at the tumor site was performed by osteoclasts of rat origin.


CONCLUSIONS
The oral administration of PF-562,271 at a dose of 5 mg/kg suppressed the growth and local spread of intratibial tumors and restored tumor-induced bone loss. The unique ability of PF-562,271 to both curb tumor growth and safely increase bone formation may be an effective therapy for many cancer patients with bone metastases and cancer-associated osteoporosis.
Bagi
Cedo M
CM
Pfizer Inc., PGRD, World Wide Comparative Medicine, Groton, Connecticut 06340, USA. cedo.bagi@pfizer.com
Roberts
Gregory W
GW
Andresen
Catharine J
CJ
D000284:Administration, Oral; D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000556:secondary; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007211:Indoles / Q000627:therapeutic use*; D010012:Osteogenesis / Q000187:drug effects; D051381:Rats; D011923:Rats, Nude; D013449:Sulfonamides / Q000627:therapeutic use*
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; D051418:Focal Adhesion Kinase 2; D051416:Focal Adhesion Protein-Tyrosine Kinases