Abstract
The burden of cancer on patient care and public health systems continues to grow, in part due to the aging population. Effective treatment for cancer is often not available, though new and improved approaches are being developed. Gene therapy has been in clinical use for over 25 years and its use for the treatment of cancer has shown several successes, including recent approval by the FDA for one such modality. Cancer gene therapy efforts in Brazil are well underway, but will require considerable investment in research and infrastructure in order to reach clinical application. The Viral Vector Laboratory (VVL, ICESP, FMUSP) has developed an immunotherapy for melanoma based on adenoviral vectors encoding p19Arf and interferon-beta, while the Gene Therapy Laboratory (GTL, ICB-USP) has developed a gene therapy approach for lung cancer involving adenoviral transfer of CDKN2a and p53. These adenovirus-mediated cancer gene therapy approaches have been shown to retard tumor progression, induce cell death and promote an important anti-tumor immune response when using in vitro and in vivo models. However promising, these approaches must pass through rigorous pre-clinical testing before application in patients can be considered. With this proposal, we aim to pave the way for such pre-clinical assays by implementing three strategies. First, production of adenovirus with adequate quantity and quality for in vivo assays with pre-clinical relevance will be established. Second, the mechanisms behind the cellular and immune responses after tumor treatment with the adenoviral vectors will be explored in mouse and human cell lines in tissue culture and in vivo. Third, clinically relevant animal models, including conditional mouse models and PDX (Patient Derived Xenografts), will be employed in order to show the merit of our approaches. This project will ensure that the VVL and GTL are positioned to cross the frontier between basic and clinical research in the near future. (AU)
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