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Published on: September 13, 2018
Selective tropism of Seneca Valley virus for variant subtype small cell lung cancer
J T Poirier1, Irina Dobromilskaya, Whei F Moriarty
1Sidney Kimmel Compre hensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.
Abstract:
We assessed the efficacy of Seneca Valley virus (SVV-001), a neuroendocrine cancer-selective oncolytic picornavirus, in primary heterotransplant mouse models of small cell lung cancer (SCLC), including three lines each of classic and variant SCLC. Half-maximal effective concentrations for cell lines derived from three variant heterotransplants ranged from 1.6×10(-3) (95% confidence interval [CI] = 1×10(-3) to 2.5×10(-3)) to 3.9×10(-3) (95% CI = 2.8×10(-3) to 5.5×10(-3)). Sustained tumor growth inhibition in vivo was only observed in variant lines (two-sided Student t test, P < .005 for each). Doses of 10(14) vp/kg were able to completely and durably eradicate tumors in a variant SCLC heterotransplant model in two of six mice. Gene expression profiling revealed that permissive lines are typified by lower expression of the early neurogenic transcription factor ASCL1 and, conversely, by higher expression of the late neurogenic transcription factor NEUROD1. This classifier demonstrates a sensitivity of .89, specificity of .92, and accuracy of .91. The NEUROD1 to ASCL1 ratio may serve as a predictive biomarker of SVV-001 efficacy.
Insights
Seneca Valley virus (SVV-001) shows efficacy against variant small cell lung cancer (SCLC) models. Gene expression analysis identified a NEUROD1 to ASCL1 ratio as a potential biomarker for predicting treatment response.
Area of Science:
- Oncolytic virology
- Cancer biology
- Genomics
Background:
- Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with limited treatment options.
- Seneca Valley virus (SVV-001) is an oncolytic picornavirus with selectivity for neuroendocrine tumors.
- Developing effective therapies for SCLC remains a significant clinical challenge.
Purpose of the Study:
- To evaluate the efficacy of Seneca Valley virus (SVV-001) in preclinical models of small cell lung cancer (SCLC).
- To identify potential biomarkers that predict response to SVV-001 treatment in SCLC.
Main Methods:
- Assessment of SVV-001 efficacy in primary heterotransplant mouse models of classic and variant SCLC.
- Determination of half-maximal effective concentrations (EC50) for SVV-001 in SCLC cell lines.
- Gene expression profiling of SCLC lines to identify molecular correlates of viral permissiveness.
Main Results:
- SVV-001 demonstrated significant tumor growth inhibition in variant SCLC models.
- Complete and durable tumor eradication was observed in a subset of variant SCLC models at a dose of 10(14) viral particles/kg.
- Permissive SCLC lines exhibited lower ASCL1 and higher NEUROD1 expression.
- A classifier based on the NEUROD1 to ASCL1 ratio achieved high sensitivity (0.89), specificity (0.92), and accuracy (0.91).
Conclusions:
- SVV-001 exhibits therapeutic potential against variant SCLC.
- The NEUROD1 to ASCL1 expression ratio serves as a predictive biomarker for SVV-001 efficacy in SCLC.
- Further investigation into SVV-001 as a treatment for SCLC is warranted.
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