CDX Models Research Articles

Abstract 1877: Predictive marker discovery for Sorafenib using patient derived xenograft models of hepatocellular carcinoma

Abstract Sorafenib, a multikinase inhibitor targeting vascular endothelial growth factor (VEGF)- mediated angiogenesis and blocking the RAF/extracellular signal regulated kinase (ERK) kinase (MEK)/ERK cascade, is the first drug found to prolong survival of patients with advanced hepatocellular carcinoma (HCC). Although it is only used in treating advanced renal cell carcinoma and unresectable HCC, many patients with other malignant diseases as well as patient with resectable HCC may also benefit from this treatment. There is a clear need for predictive markers of Sorafenib to help selecting the patient population that may benefit the most. We set out to discover the predictive markers using patient derived xenograft (PDX) models of HCC. The response to Sorafenib was investigated in 20 PDX subcutaneous models and 6 orthotopic cell line (MHCC97H, HUH-1, HepG2, Hep3B, SK-Hep-1 and PLC/PRF/5) derived xenogrft (CDX) models. 11 out of 20 PDX models (55%), and 4 out of 6 CDX models (67%) achieved significant tumor growth inhibition by the treatment of Sorafenib at the dose range from 25-50 mg/kg in nude mice. Gene expression profile, hotspot mutation detection and copy number variations were analyzed to sift out the molecular signatures that may be predictive of the response to Sorafenib. Genes and pathways such as VEGF, PDGF, FGF, Raf/MAPK/ERK, PTEN/ PI3K/AKT/mTOR, TGF-beta/Wnt, EGFR, IGF and HGF/c-MET, were investigated using methods such as IHC analysis of pretreatment xenograft tissues. Our results indicate that more than half of the resectable HCC may be responsive to Sorafenib treatment, and markers other than the usual targets of Sorafenib may be predictive of this response. This study may shed light on the predictive markers of Sorafenib and help patients that may be mostly benefited from this drug. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1877. doi:1538-7445.AM2012-1877