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Neuregulin 1 expression is a predictive biomarker for response to AV-203, an ERBB3 inhibitory antibody, in human
Kristan Meetze1, Sylvie Vincent1, Steven Tyler1
1AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts.
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.
Insights
Neuregulin 1 (NRG1) expression predicts response to ERBB3-targeted therapy AV-203 in preclinical cancer models. NRG1 is a promising biomarker for predicting treatment efficacy in patients with advanced solid tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- ErbB3 (ERBB3) overexpression is common in human cancers, driving tumor growth and resistance to therapies.
- Neuregulin 1 (NRG1) is the primary ligand for ErbB3, activating downstream signaling pathways.
- AV-203 is an investigational antibody targeting ErbB3, which has undergone Phase I clinical trials.
Purpose of the Study:
- To identify predictive biomarkers for response to AV-203 therapy.
- To investigate the relationship between ERBB3 and NRG1 expression and tumor response.
Main Methods:
- In vivo efficacy studies using diverse human cancer xenograft models.
- Correlation analysis between AV-203's tumor growth inhibition (TGI) and ERBB3/NRG1 expression levels.
- Validation using patient-derived tumor explant models.
Main Results:
- Tumor growth inhibition by AV-203 significantly correlated with NRG1 expression levels.
- No correlation was found between TGI and ERBB3 expression.
- NRG1's predictive value was confirmed in patient-derived models.
Conclusions:
- NRG1 is a potential predictive biomarker for AV-203 efficacy in preclinical cancer models.
- NRG1 warrants further clinical investigation as a biomarker for AV-203 treatment response.
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