HGF/MET-directed therapeutics in gastroesophageal cancer: a review of clinical and biomarker development

Abstract

Aberrant activation of the HGF/MET signaling axis has been strongly implicated in the malignant transformation and progression of gastroesophageal cancer (GEC). MET receptor overexpression in tumor samples from GEC patients has been consistently correlated with an aggressive metastatic phenotype and poor prognosis. In preclinical GEC models, abrogation of HGF/MET signaling has been shown to induce tumor regression as well as inhibition of metastatic dissemination. Promising clinical results in patient subsets in which MET is overexpressed have spurned several randomized studies of HGF/MET-directed agents, including two pivotal global Phase III trials. Available data highlight the need for predictive biomarkers in order to select patients most likely to benefit from HGF/MET inhibition. In this review, we discuss the current knowledge of mechanisms of MET activation in GEC, the current status of the clinical evaluation of MET-targeted therapies in GEC, characteristics of ongoing randomized GEC trials and the associated efforts to identify and validate biomarkers. We also discuss the considerations and challenges for HGF/MET inhibitor drug development in the GEC setting.

Depletion of FOXM1 via MET Targeting Underlies Establishment of a DNA Damage–Induced Senescence Program in Gastric Cancer

“…Complete resection of localized tumors is the mainstay of treatment, but patients newly diagnosed with gastric cancer tend to present with advanced and often incurable disease (42). The MET RTK is frequently dysregulated and strongly implicated in the malignant transformation and progression of this disease (43).…”

Evaluation of serum HGF and CK18 levels in patients with esophageal cancer

“…It has been suggested that inactivating HGF using antibodies and/or inhibiting the HGF/c-Met signaling pathway may be a potential therapeutic approach for regulating the angiogenesis and metastasis of tumorigenic tissues (Grugan et al, 2010). There are promising targeted therapy strategies that have demonstrated favorable results in both completed and ongoing preclinical studies (Hack et al, 2014). The results of these studies reveal the need for biomarkers that are not only used for diagnosis and prognosis, but also for determining patients who are more prone to benefit from targeted therapies.…”

Expression of the c-MET, HGF and VEGF biomarkers in intestinal and diffuse gastric cancer in the Brazilian population: a pilot study for the standardization of the quantitative PCR technique

“…In contrast to qPCR, most studies that performed the IHQ methodology do not have a consensus on the score criteria to test c-Met [15]. Furthermore, this technique has several variables involved, such as: the use of heterogeneous samples, with different tissue sections and sizes; variation between observers; a large range of primary and secondary antibodies and their particularities; staining protocols; methods used for the score; differences in the samples' processing or handling; and storage conditions.…”

“…Furthermore, this technique has several variables involved, such as: the use of heterogeneous samples, with different tissue sections and sizes; variation between observers; a large range of primary and secondary antibodies and their particularities; staining protocols; methods used for the score; differences in the samples' processing or handling; and storage conditions. Besides, the used IHC reagents often vary their specificity and sensitivity [15]. All these factors have implications for the use of c-Met and its ligand in the IHC method, which made us to opt for the qPCR technique for the pilot study, instead of using the IHQ that was also an option, considering our small sampling and poor amount of tissue in the paraffin blocks to standardize more than one procedure.…”

“…MET is a proto-oncogene, located at the chromosome 7, which encodes the receptor tyrosine kinase c-MET. The Hepatocyte Growth Factor (HGF) is the only known ligand for the c-MET receptor [12][13][14][15].…”