National Cancer Institute 1R15CA290568-01

Harnessing the potential of pharmacological small molecules to amplify VSV-based oncolytic viral therapy

This award funds research to enhance VSV-based oncolytic viral therapy for melanoma by using pharmacological small molecules to inhibit the PI3K/AKT/mTOR pathway, improving virus spread and cancer cell death, with the goal of developing effective melanoma treatments.

Description

Malignant cutaneous melanoma is the most lethal form of all skin cancers causing 10,000 deaths annually in the United States and 200,000 globally and remains a major oncological problem. Oncolytic viruses (OVs) can selectively infect, replicate and eradicate cancer cells with defective type I interferons (IFNs) mechanisms, a major antiviral pathway. The PI3K/AKT/mTOR signaling pathway is a crucial survival regulator of cellular stress and helps balance protein synthesis, cell cycle, and apoptosis to ensure the survival of resilient tumor cells. Vesicular stomatitis virus (VSV) is a non-pathogenic, enveloped, negative-strand RNA Rhabdovirus with a potent vaccine and oncolytic potential across multiple human cancer. VSV is highly sensitive to type-I interferons (IFNs); therefore, it cannot initiate a productive infection in healthy cells due to IFNs mediated antiviral response. Dysregulated IFNs and PI3K/Akt/mTOR signaling cooperate in tumorigenesis related to many cancer types, including melanoma. Moreover, PI3K or AKT inhibition diminishes cells' IFN-Is signatures. Therefore, the hypothesis is that local inhibition of the PI3K/AKT/mTOR pathway in tumors will facilitate VSV spread and cancer cell death, delaying tumor growth and extending survival in a mouse melanoma model. The project involves engineering a hybrid VSV virus (VSV-MORV-G [VMG]) to improve safety and potency, and using fisetin, a natural compound, to inhibit mTOR and S6K1 kinase, enhancing oncolytic virus sensitivity. The research aims to inform melanoma development and develop practical control solutions.

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