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    Research Grants Awarded

    Characterization of Oncolytic Adenovirus Deleted Core Protein V Gene Regulated by Novel Distinct Pathways in Breast Cancer Model

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    Breast cancer is the second most common cause of cancer death in women in the United States. Although local therapies (surgery and radiation therapy) and systemic therapies (chemotherapy, hormone therapy, and immunotherapy) have greatly reduced the mortality rate associated with the disease, the current survival statistics of breast cancer warrants development of new therapeutic agents for this disease. The recent cancer research focuses on virotherapy using oncolytic viruses as a potential treatment. These viruses are genetically designed to selectively replicate in cancer cells, kill the cancer cells by a natural lytic mechanism called "oncolysis". Oncolytic adenoviruses as ONYX-015 and Delta-24 have been evaluated in numbers of cancer diseases by researches of cancer gene therapy and rapidly translated to human clinical trials. However, the genetic designs of the existing oncolytic adenoviruses indicate the limitation of oncolytic potency in tumor cells and the cytotoxity in normal cells. Recent evidence suggests that the nucleolar localization of adenoviral core protein V (pV) is redistributed nucleolin/C23 and nucleophosmin/B23 from the nucleolus to the cytoplasm. Interestingly, B23 was recently reported to physically interact and regulate p53 as well as p14/ARF, human mdm2 (HDM2) and retinoblastoma (Rb) protein in the nucleolus of cells. Based on the observation of the interconnecting between the pV signal and the pathways of p53 and Rb, we hypothesize that the deletion of pV gene from adenoviral genome could restrict viral replication in normal cells with intact p53 and Rb pathways but allow the adenovirus deleted pV gene to selectively replicate in cancer cells with the defective pathways. Therefore, we intensely developed a novel mutant of adenovirus deleted core protein V gene as a new promising agent for cancer treatment. Our studies as a result of the initial experiments revealed that the pV-deleted adenovirus replicated in and kills cancer cells much efficiently in vitro and strictly restricted the replication in normal cells as compared to wild type adenovirus type 5. Consequently, in this research proposal we aim at evaluating oncolytic properties of the pV-deleted adenovirus in breast cancer cell lines in vitro (Aim I) and assess its therapeutic efficacy in murine breast cancer model (Aim II). In addition we propose to validate the proposed molecular mechanism to achieve the replication specificity of pV-deleted adenovirus in cancer cells and address how normal cells restrict the replication in comparison to Ad5 (Aim III). These studies will significantly advance our understanding of oncolytic mechanism and could lead to the development of medicine based on evidence for gene therapy of breast cancer.

    Lay Abstract:
    Breast cancer is the second most common cause of cancer death in women in the United States. Although breast cancer therapies (surgery, radiation therapy and chemotherapy etc.) have greatly reduced the mortality rate associated with the disease, the current survival statistics of breast cancer warrants development of new therapeutic agents for this disease. The recent research of the disease focuses on virotherapy using oncolytic viruses as a potential treatment because the viruses, which are genetically designed to selectively replicate in cancer cells, kill the cancer cells by a natural lytic mechanism called "oncolysis". Oncolytic adenoviruses such as ONYX-015 and Delta-24 have been evaluated in a number of cancer diseases and rapidly translated to the human clinical context. However, the genetic designs of the existing oncolytic adenoviruses indicate the limitation of oncolytic potency in cancer cells and the cytotoxity in normal cells. Recent evidence suggests that adenoviral core protein V (pV) may modulate p53 and Rb signaling pathways in viral infected cell. In this regard, we speculate that the deletion of pV gene from adenoviral genome could restrict viral replication in normal cells but allow the pV-deleted adenovirus to selectively replicate in a variety of cancer cells with defective p53 and Rb pathways. Based on the observation of the interconnecting between a signal by pV and the pathways, we developed a novel mutant of adenovirus deleted pV gene as a new promising agent for cancer treatment. Our initial experiments revealed that the pV-deleted adenovirus possessed oncolytic potency in a variety of cancer cells. The overall goal of this research proposal is to evaluate oncolytic properties of the pV-deleted adenovirus in breast cancer cell lines in vitro (Aim I) and assess the therapeutic efficacy in murine breast cancer model (Aim II). In addition, we propose to validate the proposed molecular mechanisms to achieve the replication specificity of pV-deleted adenovirus in cancer cells and address how infected normal cells restrict the viral replication in comparison to Ad5 (Aim III). This research project could lead to the development of a new, clinically efficacious medicine against breast cancer which could be translated to the human clinical context in a very short time frame, and we also hope that this research provides us with more data relevant to oncolytic mechanism of the virus.