501 - Preclinical data investigating the use of saracatinib in renal cell carcinoma
|Date||28 September 2012|
|Event||ESMO Congress 2012|
|Topics|| Drug Development
Renal Cell Cancer
K. Sharpe1, Y. Lu2, D. Berney3, C. Rofe2, T.B. Powles4
SRC, a non-receptor tyrosine kinase, has been shown to effect pathways implicated in anti-VEGF drug resistance. Anti-VEGF drugs provide standard of care in renal cell carcinoma (RCC) and therefore we investigated the potential of the SRC inhibitor saracatinib in preclinical models of RCC.Methods and results
In vitro MTS assays were performed on a panel of RCC cell lines which demonstrated saracatinib significantly reduced cell viability in all RCC cell lines tested in a dose-dependent manner. Follow-up experiments performed using two separate isogenic cell lines confirmed that mutation of the VHL gene impaired saracatinib's ability to reduce cell viability. In vitro migration assays confirmed saracatinib's ability to reduce motility and migration and this effect did not correlate with VHL status. Using the VHL-null 786-O xenograft model we investigated the impact of saracatinib in vivo. Saracatinib (25 mg/kg) significantly slowed tumour growth compared to vehicle-treated tumours. Furthermore, when combined with the anti-VEGF drug cediranib, combination therapy (25 mg/kg + 3mg/kg) significantly slowed tumour growth when compared to cediranib monotherapy (3mg/kg). Combination therapy significantly reduced vessel density (as measured by CD31 immunohistochemistry [IHC]) and increased the percentage of apoptotic cells (cleaved-caspase 3 IHC) compared to vehicle-treated tumours. Moreover, combination therapy increased the percentage of apoptotic cells compared to cediranib monotherapy but this result did not reach statistical significance. IHC analysis showed that saracatinib (25mg/kg) significantly reduced tumour phospho-STAT3 levels.Conclusions
These data demonstrate saracatinib's potential to reduce RCC cell viability and motility in vitro and slow tumour growth in vivo both as monotherapy and in combination with an anti-VEGF agent. A randomised phase II trial is ongoing to investigate the potential of combining saracatinib and cediranib in VEGF TKI refractory RCC.Disclosure
K. Sharpe: Kevin Sharpe receives an MRC CASE stipend which AstraZeneca contributes towards.
T. Powles: Thomas Powles has participated in advisory boards for Pfizer and GSK and has received research funding from these institutions.
All other authors have declared no conflicts of interest.