溶瘤麻疹病毒抗乳腺癌治療之開發研究(3/3)

Breast cancer is among the leading causes of female cancer deaths worldwide including Taiwan and its incidence in the Taiwanese female population has substantially increased over the past decade. Conventional treatments include combinations of surgery, radiation, chemotherapy, or hormonal therapies depending on the tumor type. Oncolytic virotherapy using viruses that preferentially target and kill cancer cells represents a novel therapy for the management of breast cancer. Recent discoveries that attenuated strains of measles virus (MV) possess oncolytic properties and can be used to destroy tumor cells have kindled an interest in this virus as a gene therapy agent. More importantly, the newly discovered ability of certain MV strains to preferentially target adenocarcinomas, which account for over 90 % of breast tumor cases, underscores its potential as an effective and highly specific therapy against breast cancer. Taking advantage of this targeting specificity, in this 3-year study, we propose to develop and evaluate novel recombinant MV vectors as a potential therapeutic agent against breast adenocarcinoma in vitro and in vivo. In Year 1, the aim is to build attenuated MV vector platforms that preferentially target adenocarcinoma using reverse genetics and examine its in vitro infectivity against various breast cancer cell lines. Experiments include reverse genetic cloning, fluorescent marker tagging, analysis of viral infection kinetics, and screening of breast cancer cells for permissive infection. In Year 2, we will evaluate the efficacy of MV-induced oncolysis in the breast cancer lines to determine the effective dose requirement and investigate the influence of combinatorial treatment with chemotherapeutics and small molecules. Specifically, the ability of these agents to synergistically enhance MV’s tumor-killing efficiency, bypass host immune response for boosting MV infection, and control MV spread as means of augmenting treatment safety will be explored. Subsequently in Year 3, we wish to validate the in vivo oncolytic potency of MV for treating breast adenocarcinomas in a xenotropic mouse model. The experiments will be performed using bioluminescence method with reporter-tagged MV vector in immunocompromised mice subcutaneously grafted with breast cancer cells. Results from these studies will help develop attenuated MV vectors as potent anticancer agents for highly targeted and efficacious therapy against breast cancer, and present a novel avenue for the treatment of this disease.