In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. LB-230-LB-230
Abstract:
Focal adhesion kinase (FAK) represents a central point of convergence for many signaling pathways implicated in cancer progression and metastasis. Pazopanib is a pan-VEGFR and PDGFR inhibitor. In the present study, we examined whether pazopanib treatment would result in greater anti-tumor activity in combination with the novel FAK-inhibitor, GSK2256098. The in vitro effects of GSK2256098 on invasion and migration were examined using the HeyA8 and SKOV3-IP1 human ovarian cancer cell lines. In vivo effects of pazopanib with and without GSK2256098 were then assessed using an orthotopic mouse model of human ovarian cancer. GSK2256098 resulted in reduced levels of FAK phosphorylation at Y397 (pFAKY397) at 1μM concentration in SKOV3-IP1 cells. GSK2256098 resulted in a reduced invasion (p & lt;0.001) and decreased migration (p & lt;0.001) in SKOV3-ip1 cells. Dose-finding studies performed in vivo demonstrated that a 75 mg/kg dose resulted in a significant reduction in pFAKY397. Monotherapy with GSK2256098 resulted in a 58% decrease in mean tumor weight compared to control (p = 0.038). The combination of GSK2256098 with pazopanib resulted in a 71% decrease in mean tumor weight compared to pazopanib monotherapy (p = 0.04). We also tested treatment combinations including traditional cytotoxic chemotherapy. The combination of GSK2256098 with docetaxel resulted in a 44% decrease in mean tumor weight compared to docetaxel monotherapy (p = 0.17). The triplet combination of GSK2256098 with pazopanib and docetaxel resulted in the greatest overall decrease mean tumor weight, 99% compared to control and 92% compared to the doublet alone (p = 0.001). Similar trends were noted with mean number of tumor nodules and ascites volume. On the basis of our recent findings that FAK is highly phosphorylated in platelets in cancer-bearing mice, we also examined FAK phosphorylation in the platelets of treated and untreated mice. Phosphorylation of platelet FAK (pFAKY397) was inhibited by 68% at 4 hours after treatment compared to control (p = 0.07). Treatment with pazopanib decreased MVD by 49% (p & lt; 0.01), which was further enhanced in combination with GSK2256098 (p & lt; 0.01). In summary, FAK inhibition results in substantial anti-angiogenic and anti-tumor effects in combination with pazopanib and represents a viable strategy for further development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-230. doi:10.1158/1538-7445.AM2011-LB-230
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-LB-230
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
