Development of natural and synthetic compounds as novel potentiators of HSV-1 VC2-GMCSF-based oncolytic viral therapy in Breast Cancer

Breast cancer (BC) is the most commonly diagnosed cancer in women, a leading cause of cancer related death in the United States and remains a major oncological problem global. Triple-negative BC (TNBC), is a more aggressive clinical subtype with high incidence rate and mortality, and dampened response to chemotherapies. Oncolytic viruses (OVs) can selectively infect, replicate and eradicate cancer cells with defective type I interferons (IFNs) mechanisms, a major antiviral pathway. Herpes-based OVs epitomize a hopeful and innovative anti-cancer strategy and a substantial benefit of HSV-1 is its large genome size (~152kbp), having modifiable accessory genes that allow for genes to be deletion or insertion with the goal to enhance antitumor immune responses.

Therefore, it can be engineered to not initiate a productive infection in healthy cells. In cancer, dysregulated IFNs and signaling pathway like the PI3K/Akt/mTOR cooperate in tumorigenesis related to many cancer types, including BC. 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. Moreover, PI3K or AKT inhibition diminishes cells' IFN-Is signatures.

Therefore, we hypothesize that local inhibition of the cancer molecular targets and PI3K/AKT/mTOR signaling pathway in the tumors will create a conducive environment for the intratumoral replication and spread of oncolytic HSV-1 and virus-induced cancer cell death resulting in tumor growth delay and extended survival in a stage four metastatic mouse model of BC.

Grant Number: 5P20GM135000-05
NIH Institute/Center: NIH
Principal Investigator: Jean Christopher Chamcheu