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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Role of MAPK in oncolytic herpes viral therapy in triple-negative breast cancer
1Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Abstract:
Triple-negative breast cancers (TNBCs) have poor clinical outcomes owing to a lack of targeted therapies. Activation of the MEK/MAPK pathway in TNBC has been associated with resistance to conventional chemotherapy and biologic agents and has a significant role in poor clinical outcomes. NV1066, a replication-competent herpes virus, infected, replicated in and killed all TNBC cell lines (MDA-MB-231, HCC1806, HCC38, HCC1937, HCC1143) tested. Greater than 90% cell kill was achieved in more-sensitive lines (MDA-MB-231, HCC1806, HCC38) by day 6 at a multiplicity of infection (MOI) of 0.1. In less-sensitive lines (HCC1937, HCC1143), NV1066 still achieved >70% cell kill by day 7 (MOI 1.0). In vivo, mean volume of flank tumors 14 days after treatment with NV1066 was 57 versus 438 mm(3) in controls (P=0.002). NV1066 significantly downregulated p-MAPK activation by 48 h in all cell lines in vitro and in MDA-MB-231 xenografts in vivo. NV1066 demonstrated synergistic effects with a MEK inhibitor, PD98059 in vitro. We demonstrate that oncolytic viral therapy (NV1066) effectively treats TNBC with correlation to decreased MEK/MAPK signaling. These findings merit future studies investigating the potential role of NV1066 as a sensitizing agent for conventional chemotherapeutic and biologic agents by downregulating the MAPK signaling pathway.
Insights
NV1066, an oncolytic virus, effectively kills triple-negative breast cancer (TNBC) cells by targeting the MEK/MAPK pathway. This therapy shows promise in reducing tumor growth and could enhance conventional treatments for TNBC.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) presents significant clinical challenges due to limited targeted therapies.
- The MEK/MAPK pathway is frequently activated in TNBC, contributing to treatment resistance and poor outcomes.
Purpose of the Study:
- To evaluate the efficacy of NV1066, a replication-competent oncolytic herpes virus, against TNBC.
- To investigate the impact of NV1066 on MEK/MAPK signaling in TNBC.
- To explore the potential of NV1066 as a sensitizing agent for conventional therapies.
Main Methods:
- In vitro assessment of NV1066's cytolytic activity against multiple TNBC cell lines.
- In vivo evaluation of NV1066 efficacy in a TNBC xenograft model.
- Analysis of p-MAPK signaling pathway modulation by NV1066.
- Investigation of synergistic effects between NV1066 and a MEK inhibitor (PD98059).
Main Results:
- NV1066 demonstrated significant cell kill across all tested TNBC cell lines in vitro.
- In vivo studies showed substantial reduction in tumor volume following NV1066 treatment.
- NV1066 treatment led to significant downregulation of p-MAPK activation both in vitro and in vivo.
- Synergistic anti-cancer effects were observed when NV1066 was combined with a MEK inhibitor.
Conclusions:
- Oncolytic viral therapy with NV1066 is an effective treatment for TNBC, correlating with reduced MEK/MAPK signaling.
- NV1066 exhibits potent anti-tumor activity and warrants further investigation as a sensitizer for existing TNBC therapies.
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