Abstract 1322: Autocrine c-met/HGF HCC patient derived xenograft (PDX) models for evaluating c-met inhibitors

Abstract

Abstract c-Met is a receptor tyrosine kinase that interacts with its ligand, HGF, secreted from surrounding stroma (paracrine signaling). This interaction is involved in cell growth, invasion, metastases and angiogenesis of a number of solid tumors. c-met gene amplification and increased gene expression have been frequently associated with these tumors. c-met is thus considered as an important cancer target for therapy of the cancers that their growth depends on activated c-met/HGF signaling1, including many HCC. As for any investigational c-met inhibitors, a highly relevant c-met/HGF experimental cancer model is critical to evaluate its efficacy and associated changes in biomarkers for predicting the likely responders. While patient derived xenograft (PDX) models, without any in vitro manipulation, mirror patients’ histopathological and genetic profiles2,3, the successfully engrafted PDX models usually lost its human stroma in mice and thus its c-met dependency. This is due to the lack of paracrine c-met/HGF mechanism in mice (no cross reactivity between mouse and human), and the tumors with such c-met/HGF paracrine dependency are selected against. The engrafted models might have changed its properties from the original human tumors by relying on other signaling pathways for survival, and thus not suitable for evaluating c-met inhibitors. Apparently, neither of these scenarios can be adequately used to evaluate c-met inhibitors. One alternative to this is engraftment of primary human tumor into HGF-transgenic immunocompromised mice, which would support the growth of c-met dependent PDX via paracrine mechanism. We recently screened a number of PDX HCC models using a c-met inhibitor and identified two responders, indicating their reliance on c-met/HGF signaling for growth, among many non-responders. The non-responders likely grow by relying on signaling pathway other than c-met/HGF. The two responders, on the other hand, likely grow through c-met/HGF autocrine mechanism. To further investigate this, we performed genomic profiling and IHC analysis of c-met and HGF on these two responders and other non-responders. Our results demonstrated that these two responders have amplification of HGF gene and express high levels of both c-met and HGF in both mRNA and protein (IHC). This is in contrast to no gene amplification and low level expression of both genes for non-responders. All these are consistent with that these two responders grow in mice via c-met/HGF autocrine mechanism. In conclusion, these two HCC models could be very useful models for evaluating c-met inhibitors. 1. Nat Rev Drug Discov 7, 504-516 (2008). 2. Nature 464, 999-1005 (2010). 3. Clin Cancer Res 13, 3989-3998 (2007). 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 1322. doi:1538-7445.AM2012-1322