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

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, we hypothesize that local inhibition of
the PI3K/AKT/mTOR signaling pathway in the tumors will create a needful condition for the
intratumoral spread of VSV and virus-induced cancer cell death resulting in tumor growth delay
and extension in survival in a mouse model of melanoma. Because of the adverse effects
associated with VSVs, we have engineered a novel hybrid VSV virus (VSV-MORV-G [VMG]),
where the VSV envelops protein G and is replaced with that of Morreton virus to improve their
safety and potency. We recently identified fisetin, a natural compound, and two of its potent
derivatives, F019, F040 and F142, as inhibitors that competitively bind mTOR and S6K1 kinase
to inhibit the mTOR/AKT/IFN pathway. Furthermore, our preliminary data show increased
sensitivity and cytotoxicity of melanoma cells to oncolytic virus upon pre-therapy with fisetin
while sparing normal cells. Thus, we expect that locally turning off the type I IFN response and
mTOR can serve as a novel pharmacovirotherapy for advanced localized melanoma. Novel
outcomes stemming from the proposed investigations will inform the role of local turning off of
target pathways in the development/progression of melanoma, and will serve as a catalyst to
develop practical solutions for melanoma control and possibly other cancers with significant
public health burdens. Our aims are designed to test this innovative hypothesis in cell lines and
preclinical animal models of melanoma. Funding of this current application will enhance
biomedical research, student training, education and infrastructure at the SUBR College of
Sciences and Engineering and College of Nursing and Allied Health. The proposed work will
directly involve students majoring in biomedical-related fields, selected to reflect the broader
composition of the student body.

Grant Number: 1R15CA290568-01
NIH Institute/Center: NIH
Principal Investigator: Jean Christopher Chamcheu