Bioluminescent imaging study

Sun, Haiming; Pisle, Stephen T; Gardner, Erin R.; Figg, William D.

doi:10.4161/cbt.10.1.11993

Cited by 33 publications

(19 citation statements)

References 16 publications

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“…Like TAE226, PF-562,271 blocks the ATP binding site of FAK and of Pyk2 (protein-rich tyrosine kinase 2), another nonreceptor tyrosine kinase known to bind and activate src [146, 147]. PF-562,271 inhibited in vivo breast cancer cell growth and metastasis in a murine model, and decreased the in vivo growth of prostate cancer cells and in vitro growth of lung cancer cells [146, 148–150]. It also has exhibited synergy with sunitinib in the inhibition of hepatocellular tumor growth in vivo [151].…”

Section: Fak Inhibitorsmentioning

confidence: 99%

Evolving Therapies and FAK Inhibitors for the Treatment of Cancer

Dunn

Heffler²,

Golubovskaya³

2010

ACAMC

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Despite advances in medical and surgical therapy, cancer kills more than half a million people in the United States annually, and the majority of these patients succumb to metastatic disease. The traditional approach to treating systemic disease has been the use of cytotoxic chemotherapy. However, chemotherapy is rarely curative and toxicity is often dose limiting. In addition, the effects of chemotherapy are nonspecific, targeting both malignant and normal tissues. As a result, recent efforts increasingly have focused on developing agents that target specific molecules in tumor cells in order to both improve efficacy and limit toxicity. This review summarizes the history and current use of targeted molecular therapy for cancer, with a special emphasis on recently developed inhibitors of Focal Adhesion Kinase (FAK).

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Section: Fak Inhibitorsmentioning

confidence: 99%

Evolving Therapies and FAK Inhibitors for the Treatment of Cancer

Dunn

Heffler²,

Golubovskaya³

2010

ACAMC

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“…Completed Phase I human studies of PF-562,271 (PF-271) are encouraging as oral administration of this FAK inhibitor is tolerable and was associated with prolonged stable disease by 12% of patients [25]. Studies in human xenograft or syngeneic mouse tumor models have associated PF-271 administration with the inhibition of breast [26,27], liver [28], prostate [29,30], pancreatic [31], and squamous cell [32] tumor progression. However, the proposed mechanism(s) of action associated with FAK inhibition are varied and may also involve alterations in the tumor microenvironment [33].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression

Ward

Tancioni

Lawson

et al. 2012

Clin Exp Metastasis

102

127

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Recurrence and spread of ovarian cancer is the 5th leading cause of death for women in the United States. Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase located on chromosome 8q24.3 (gene is Ptk2), a site commonly amplified in serous ovarian cancer. Elevated FAK mRNA levels in serous ovarian carcinoma are associated with decreased (logrank P = 0.0007, hazard ratio 1.43) patient overall survival, but how FAK functions in tumor progression remains undefined. We have isolated aggressive ovarian carcinoma cells termed ID8-IP after intraperitoneal (IP) growth of murine ID8 cells in C57Bl6 mice. Upon orthotopic implantation within the periovarian bursa space, ID8-IP cells exhibit greater tumor growth, local and distant metastasis, and elevated numbers of ascites-associated cells compared to parental ID8 cells. ID8-IP cells exhibit enhanced growth under non-adherent conditions with elevated FAK and c-Src tyrosine kinase activation compared to parental ID8 cells. In vitro, the small molecule FAK inhibitor (Pfizer, PF562,271, PF-271) at 0.1 uM selectively prevented anchorage-independent ID8-IP cell growth with the inhibition of FAK tyrosine (Y)397 but not c-Src Y416 phosphorylation. Oral PF-271 administration (30 mg/kg, twice daily) blocked FAK but not c-Src tyrosine phosphorylation in ID8-IP tumors. This was associated with decreased tumor size, prevention of peritoneal metastasis, reduced tumor-associated endothelial cell number, and increased tumor cell-associated apoptosis. FAK knockdown and re-expression assays showed that FAK activity selectively promoted anchorage-independent ID8-IP cell survival. These results support the continued evaluation of FAK inhibitors as a promising clinical treatment for ovarian cancer.

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“…Ten Alb-cre ERT2 and ten Alb-cre ERT2; Fak flox/flox mice were injected hydrodynamically with MET/CAT and, 4 weeks later, with 33 mg/kg PF-562271 (dissolved in 12.5% DMSO and 12.5% PEG400) 20 daily for 3 weeks.…”

Section: Methodsmentioning

confidence: 99%

FAK Kinase Activity Is Required for the Progression of c-MET/β-Catenin-Driven Hepataocellular Carcinoma

Shang

Arteaga²,

Zaidi³

et al. 2016

gene expr

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Background & Aims There is an urgent need to develop new and more effective therapeutic strategies and agents to treat hepatocellular carcinoma (HCC). We have recently found that deletion of Fak in hepatocytes before tumors form inhibits tumor development and prolongs survival of animals in a c-Met (MET)/β-catenin (CAT)-driven HCC mouse model. However, it has yet to be determined whether FAK expression in hepatocytes promotes MET/CAT-induced HCC progression after tumor initiation. In addition, it remains unclear whether FAK promotes HCC development through its kinase activity. Methods We generated hepatocyte-specific inducible Fak-deficient mice (Alb-creERT2; Fakflox/flox) to examine the role of FAK in HCC progression. We re-expressed wild-type and mutant FAK in Fak-deficient mice to determine FAK’s kinase activity in HCC development. We also examined the efficacy of a FAK kinase inhibitor PF-562271 on HCC inhibition. Results We found that deletion of Fak after tumors form significantly repressed MET/CAT-induced tumor progression. Ectopic FAK expression restored HCC formation in hepatocyte-specific Fak-deficient mice. However, overexpression of a FAK kinase-dead mutant led to reduced tumor load compared to mice which express wild-type FAK. Furthermore, PF-562271 significantly suppressed progression of MET/CAT-induced HCC. Conclusion Fak kinase activity is important for MET/CAT-induced HCC progression. Inhibiting FAK kinase activity provides a potential therapeutic strategy to treat HCC.

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Bioluminescent imaging study

Cited by 33 publications

References 16 publications

Evolving Therapies and FAK Inhibitors for the Treatment of Cancer

Evolving Therapies and FAK Inhibitors for the Treatment of Cancer

Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression

FAK Kinase Activity Is Required for the Progression of c-MET/β-Catenin-Driven Hepataocellular Carcinoma

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