ABSTRACT
BACKGROUND: Cancer associated cachexia affects the majority of cancer patients during the course of the disease and thought to be directly responsible for about a quarter of all cancer deaths. Current evidence suggests that a pro-inflammatory state may be associated with this syndrome although the molecular mechanisms responsible for the development of cachexia are poorly understood. The purpose of this work was the identification of key drivers of cancer cachexia that could provide a potential point of intervention for the treatment and/or prevention of this syndrome. METHODS: Genetically engineered and xenograft tumour models were used to dissect the molecular mechanisms driving cancer cachexia. Cytokine profiling from the plasma of cachectic and non-cachectic cancer patients and mouse models was utilized to correlate circulating cytokine levels with the cachexia phenotype. RESULTS: Utilizing engineered tumour models we identified MAP3K11/GDF15 pathway activation as a potent inducer of cancer cachexia. Increased expression and high circulating levels of GDF15 acted as a key mediator of this process. In animal models, tumour-produced GDF15 was sufficient to trigger the cachexia phenotype. Elevated GDF15 circulating levels correlated with the onset and progression of cachexia in animal models and in patients with cancer. Inhibition of GDF15 biological activity with a specific antibody reversed body weight loss and restored muscle and fat tissue mass in several cachectic animal models regardless of their complex secreted cytokine profile. CONCLUSIONS: The combination of correlative observations, gain of function, and loss of function experiments validated GDF15 as a key driver of cancer cachexia and as a potential therapeutic target for the treatment and/or prevention of this syndrome.
ABSTRACT
PURPOSE: ERBB3 is overexpressed in a broad spectrum of human cancers, and its aberrant activation is associated with tumor pathogenesis and therapeutic resistance to various anticancer agents. Neuregulin 1 (NRG1) is the predominant ligand for ERBB3 and can promote the heterodimerization of ERBB3 with other ERBB family members, resulting in activation of multiple intracellular signaling pathways. AV-203 is a humanized IgG1/κ ERBB3 inhibitory antibody that completed a first-in-human phase I clinical trial in patients with advanced solid tumors. The purpose of this preclinical study was to identify potential biomarker(s) that may predict response to AV-203 treatment in the clinic. EXPERIMENTAL DESIGN: We conducted in vivo efficacy studies using a broad panel of xenograft models representing a wide variety of human cancers. To identify biomarkers that can predict response to AV-203, the relationship between tumor growth inhibition (TGI) by AV-203 and the expression levels of ERBB3 and NRG1 were evaluated in these tumor models. RESULTS: A significant correlation was observed between the levels of NRG1 expression and TGI by AV-203. In contrast, TGI was not correlated with ERBB3 expression. The correlation between the levels of NRG1 expression in tumors and their response to ERBB3 inhibition by AV-203 was further validated using patient-derived tumor explant models. CONCLUSIONS: NRG1 is a promising biomarker that can predict response to ERBB3 inhibition by AV-203 in preclinical human cancer models. NRG1 warrants further clinical evaluation and validation as a potential predictive biomarker of response to AV-203.
Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Gene Expression , Neoplasms/genetics , Neuregulin-1/genetics , Receptor, ErbB-3/antagonists & inhibitors , Animals , Antibodies, Monoclonal, Humanized/administration & dosage , Area Under Curve , Biomarkers , Cell Line, Tumor , Disease Models, Animal , Drug Resistance, Neoplasm/genetics , Female , Humans , Ligands , Mice , Mutation , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Neuregulin-1/metabolism , Prognosis , Protein Binding , Receptor, ErbB-3/genetics , Receptor, ErbB-3/metabolism , Reproducibility of Results , Xenograft Model Antitumor AssaysABSTRACT
Dysregulated fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of human cancers. Aberrant activation of FGF receptor 2 (FGFR2) signaling, through overexpression of FGFR2 and/or its ligands, mutations, and receptor amplification, has been found in a variety of human tumors. We generated monoclonal antibodies against the extracellular ligand-binding domain of FGFR2 to address the role of FGFR2 in tumorigenesis and to explore the potential of FGFR2 as a novel therapeutic target. We surveyed a broad panel of human cancer cell lines for the dysregulation of FGFR2 signaling and discovered that breast and gastric cancer cell lines harboring FGFR2 amplification predominantly express the IIIb isoform of the receptor. Therefore, we used an FGFR2-IIIb-specific antibody, GP369, to investigate the importance of FGFR2 signaling in vitro and in vivo. GP369 specifically and potently suppressed ligand-induced phosphorylation of FGFR2-IIIb and downstream signaling, as well as FGFR2-driven proliferation in vitro. The administration of GP369 in mice significantly inhibited the growth of human cancer xenografts harboring activated FGFR2 signaling. Our findings support the hypothesis that dysregulated FGFR2 signaling is one of the critical oncogenic pathways involved in the initiation and/or maintenance of tumors. Cancer patients with aberrantly activated/amplified FGFR2 signaling could potentially benefit from therapeutic intervention with FGFR2-targeting antibodies.
