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Tepilamide Fumarate as a Novel Potentiator of Virus-Based Therapy
Akram Alwithenani1,2,3, Rozanne Arulanandam1, Boaz Wong1,2
1Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
Abstract:
Oncolytic virotherapy, using viruses such as vesicular stomatitis virus (VSVΔ51) and Herpes Simplex Virus-1 (HSV-1) to selectively attack cancer cells, faces challenges such as cellular resistance mediated by the interferon (IFN) response. Dimethyl fumarate (DMF) is used in the treatment of multiple sclerosis and psoriasis and is recognized for its anti-cancer properties and has been shown to enhance both VSVΔ51 and HSV-1 oncolytic activity. Tepilamide fumarate (TPF) is a DMF analog currently undergoing clinical trials for the treatment of moderate-to-severe plaque psoriasis. The aim of this study was to evaluate the potential of TPF in enhancing the effectiveness of oncolytic viruses. In vitro, TPF treatment rendered 786-0 carcinoma cells more susceptible to VSVΔ51 infection, leading to increased viral replication. It outperformed DMF in both increasing viral infection and increasing the killing of these resistant cancer cells and other cancer cell lines tested. Ex vivo studies demonstrated TPF's selective boosting of oncolytic virus infection in cancer cells without affecting healthy tissues. Effectiveness was notably high in pancreatic and ovarian tumor samples. Our study further indicates that TPF can downregulate the IFN pathway through a similar mechanism to DMF, making resistant cancer cells more vulnerable to viral infection. Furthermore, TPF's impact on gene therapy was assessed, revealing its ability to enhance the transduction efficiency of vectors such as lentivirus, adenovirus type 5, and adeno-associated virus type 2 across various cell lines. This data underscore TPF's potential role in not only oncolytic virotherapy but also in the broader application of gene therapy. Collectively, these findings position TPF as a promising agent in oncolytic virotherapy, warranting further exploration of its therapeutic potential.
Insights
Tepilamide fumarate (TPF) enhances oncolytic virotherapy by increasing viral infection and cancer cell killing, outperforming dimethyl fumarate (DMF). TPF also boosts gene therapy vector efficiency, showing broad therapeutic potential.
Area of Science:
- Oncology
- Virology
- Immunology
- Gene Therapy
Background:
- Oncolytic virotherapy uses viruses to target cancer cells but faces challenges like interferon-mediated cellular resistance.
- Dimethyl fumarate (DMF) shows anti-cancer properties and enhances oncolytic virus activity.
- Tepilamide fumarate (TPF), a DMF analog, is being tested for psoriasis and its potential in virotherapy is unexplored.
Purpose of the Study:
- To evaluate Tepilamide fumarate (TPF) as an agent to enhance oncolytic virotherapy effectiveness.
- To compare TPF's efficacy against dimethyl fumarate (DMF) in improving viral infection and cancer cell lysis.
- To investigate TPF's impact on the interferon (IFN) pathway and its potential in gene therapy.
Main Methods:
- In vitro studies using 786-0 carcinoma cells and other cancer cell lines with VSVΔ51 and HSV-1 viruses.
- Ex vivo analysis on pancreatic and ovarian tumor samples.
- Assessment of TPF's effect on the IFN pathway and gene therapy vector transduction efficiency (lentivirus, adenovirus type 5, AAV2).
Main Results:
- TPF treatment increased cancer cell susceptibility to VSVΔ51 infection and viral replication.
- TPF outperformed DMF in enhancing viral infection and cancer cell killing across tested cell lines.
- TPF selectively boosted oncolytic virus infection in cancer cells, notably in pancreatic and ovarian tumors, without affecting healthy tissues.
- TPF downregulated the IFN pathway, increasing cancer cell vulnerability to viral infection.
- TPF enhanced transduction efficiency of lentivirus, adenovirus type 5, and AAV2 vectors.
Conclusions:
- TPF is a potent enhancer of oncolytic virotherapy, demonstrating superior efficacy to DMF.
- TPF's ability to overcome IFN-mediated resistance and enhance viral activity makes it a promising therapeutic agent.
- TPF shows significant potential in improving gene therapy vector delivery and efficacy.
- TPF warrants further investigation for its broad therapeutic applications in cancer treatment and gene therapy.
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