Advancing Oncolytic Virotherapy: The Role of Chemical Sensitizers in Enhancing Viral Oncolysis in Resistant Cancers

Abstract

Oncolytic virotherapy, leveraging viruses to target cancer selectively, has shown promise with the FDA-approved oncolytic herpes simplex virus-1 (HSV-1) for melanoma treatment. However, the efficacy of oncolytic viruses (OVs) varies across cancer types, highlighting the need for strategies to sensitize resistant tumors. This thesis investigates the potential of Dimethyl fumarate (DMF), its analog Tepilamide Fumarate (TPF), and novel synthetic small molecules identified from a high-throughput screen to enhance OV effectiveness in cancer therapy. DMF, approved for multiple sclerosis and psoriasis, and TPF, under trial for psoriasis, were evaluated for their ability to boost HSV-1 and vesicular stomatitis virus (VSVΔ51) activity against cancer cells. Our findings reveal that pre-treatment with DMF or TPF significantly increases HSV-1 and VSVΔ51 replication in various cancer cell lines, including melanoma, and improves viral oncolysis. Notably, both DMF and TPF enhance OV infection in mouse-derived tumor cores and human tumor samples, while TPF exhibits a remarkable capacity to heighten VSVΔ51 infection and cell killing, outperforming DMF in vitro. Both compounds achieve these effects by downregulating the interferon (IFN) pathway, rendering cancer cells more susceptible to viral infection. Additionally, we demonstrate the ability of DMF and TPF to boost gene therapy vectors' transduction efficiency, which points to the broader utility of these drugs in gene therapy. Further exploration through a high-throughput screen identified several small molecules that sensitize human renal carcinoma cells to HSV-1 and VSVΔ51, highlighting potential new avenues for overcoming tumor resistance to OVs. These compounds enhance viral replication and oncolysis, presenting a promising path for future oncolytic virotherapy research and development. The synergistic potential of combining approved therapies like DMF with OVs, the promising effects of TPF, and newly identified small molecule sensitizers underscore the feasibility of enhancing OV efficacy in resistant cancers. This study not only broadens our understanding of how small molecules can potentiate oncolytic virotherapy but also sets the stage for clinical evaluation and the development of more effective, personalized cancer treatment strategies. Collectively, these findings advocate for further investigation into DMF, TPF, and other sensitizing compounds to unlock their full therapeutic potential in oncolytic virotherapy.