Although no HER3-targeting therapy was approved for cancer treatment nowadays, new drugs targeting HER3 demonstrated the promising application potential, especially the report of U3-1402 in 2019 ASCO annual meeting.ĬAN017, also known as AV-203, is a humanized antibody that plays its role via blocking both ligand-dependent and ligand-independent HER3 signalings. It was reported that HER3 frequently expressed in several cancers including ESCC and its overexpression was correlated with poor prognosis, as well as the close correlation between NRG1 upregulation with HER3 activation and poor prognosis. Also, as a ligand of HER3, neuregulin 1 (NRG1) is very important to promote the heterodimerization of HER3 and other HER family members and is identified as a predictive biomarker for HER3 targeting therapy in multiple solid tumors. As one of the members of HER family, HER3 has its unique biological characteristics such as lacking intrinsic tyrosine kinase activity and forming heterodimer with HER2 rather than forming homodimers followed by the activation of downstream signals. Therefore, it’s urgent to develop new drugs to improve the prognosis of ESCC.įor several years, targeted HER (human epidermal receptor) family drugs have been the focus of new drug research and development. For patients with advanced ESCC, systematic treatment based on drug therapy is still the main strategy, but almost all new targeted drugs developed for ESCC have been failed except for the newly approved Pembrolizumab for second-line therapy. Moreover, due to the low proportion of patients with early diagnosis and treatment, most of the ESCC patients were diagnosed at a later stage with poor prognosis. The morbidity of esophageal cancer in China is very high with more than half of the global cases (53%), however, it’s greatly different from the western countries that more than 95% Chinese cases are histopathologically diagnosed as esophageal squamous cell carcinoma (ESCC). In our study, HER3-targeting therapy was first demonstrated to have potency in inhibiting ESCC tumor growth, and NRG1 served as a predictive biomarker to screen patients in future clinical trials. These results were also validated in PDX models of cohort 2 indicated as the powerful anti-tumor activity of CAN017 in PDX models with NRG1 high expression. Furthermore, the efficacy of CAN017 was positively correlated with NRG1 expression and the response rates in cohort 1 were 73% (8/11) versus 0% (0/13) in NRG1 high and low expression models, respectively. In cohort 1, all PDX models showed good tolerance to CAN017 and 8 out of 24 (33.3%) PDX models responded to CAN017 with tumor growth inhibition (TGI) ≥70% compared to controls. Two separate cohorts of ESCC patient-derived xenograft (PDX) models including 24 (cohort 1 as training models, from Crown Bioscience Inc.) and 22 (cohort 2 as validating models, from Peking University Cancer Hospital) models, respectively, were used to study the efficacy and safety of CAN017, as well as the correlation of NRG1 expression to the response of CAN017. The aim of this study was to further investigated the efficacy and possible responsive biomarkers of CAN017 in esophageal squamous cell carcinoma (ESCC) with Chinese characteristics. CAN017 (AV-203), a novel anti-HER3 antibody, exerts very promising anti-tumor activities in several human tumor models.
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