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    Research Grants Awarded

    Targeted Gene Therapy for Breast Cancer Growth and Metastasis

    Study Section:
    Treatment

    Scientific Abstract:
    Background: Breast cancer growth and metastasis are the result of a complex process that involves cell migration, tumor vascularization, interaction with the microenvironment, intravasation, and survival at distant sites. Transforming growth factor (TGF)- b is a multifunctional cytokine, which plays an important role in these processes. Overexpression of TGF- b in breast cancer tissue has been well documented. Downregulation of TGF- b has been reported to promote tumor cell apoptosis. Thus, identifying key targets of TGF- b , which promote aggressive phenotype of breast cancer, and development of novel means to neutralize TGF- b in breast cancer tissue in situ would provide better insight to control the growth and metastasis. Such a strategy can also be used as an adjuvant therapy to increase survival. Objective/Hypothesis: The objective of the proposed study is to develop clonal derivatives of human metastatic breast cancer cell lines containing transcriptionally regulated small-interference (si) RNA vector targeting TGF- b and identify molecular alterations associated with TGF- b overexpression during stages of aggressive growth and metastasis, and to develop and validate a therapeutic recombinant adeno-associated virus (rAAV) producing TGF- b inhibitory siRNA to achieve targeted gene therapy for breast cancer growth and metastasis in a preclinical mouse model. Specific Aims: The above hypothesis will be tested in two specific aims to: 1) Determine stage-specific changes in key pathways of TGF- b upregulation for therapeutic intervention of breast cancer and 2) Determine the therapeutic effects of rAAV containing TGF- b inhibitory siRNA in breast cancer growth and metastasis either as a standalone therapy or as an adjuvant therapy. Study Design: The proposal will be tested in a mouse model of metastatic breast cancer. In the first step, key changes associated with TGF- b downregulation at specific stages of breast cancer growth and metastatic transformation will be identified using a clonal derivative of human breast cancer cell lines. Next, a non-pathogenic rAAV, stably expressing siRNA targeted to TGF- b will be administered either alone or in combination with vectors encoding anti-angiogenic factors in established tumors. Effects of this therapy in long-term survival will be determined. Potential Outcomes and Benefits of the Research: A positive outcome of these studies will provide new leads towards developing targeted therapies for breast cancer.

    Lay Abstract:
    Background: The major cause of morbidity and mortality in breast cancer is due to the transformation of benign tumor into aggressive phenotype. A key molecule that promotes the metastatic conversion and helps in tumor cell escape of immunological surveillance is the transforming growth factor (TGF)- b . Although the role and association of TGF- b in phenotypic changes of breast cancer are well known, the mechanisms for resistance to TGF- b growth inhibition and stage-specific events associated with such changes are not known. Thus, identification of molecular events associated with TGF- b upregulation at defined stages of breast cancer growth and metastasis in vivo and development of novel means to neutralize TGF- b in breast cancer tissue in situ would provide newer therapeutic interventions. Objective/Hypothesis: The objective of the proposed study is to identify specific stages and pathways TGF- b that promote aggressive phenotypic changes and test a gene therapy approach using recombinant adeno-associated virus vector (rAAV) producing inhibitory small-interfering (si)RNA molecules for neutralizing TGF- b in breast cancer cells in vivo . The central hypothesis is that targeted inhibition of TGF- b can minimize the rate of tumor growth and metastasis and may prove as an adjuvant therapy overcoming limitations due to upregulated TGF- b levels. Specific Aims: The above hypothesis will be tested in two major specific aims to: 1) Determine stage-specific changes in key pathways of TGF- b signaling for therapeutic intervention of breast cancer, and 2) Determine the therapeutic effects of rAAV containing TGF- b inhibitory siRNA in breast cancer growth and metastasis either as a standalone therapy or as an adjuvant therapy. Study Design: The proposal will be tested in a preclinical mouse model of metastatic breast cancer in two steps. In the first step, key changes associated with TGF- b downregulation and specific stage of breast cancer growth and metastasis promoting the transformation will be identified in a xenograft mouse. Next, a non-pathogenic recombinant adeno-associated virus, stably expressing si-RNA targeted to TGF- b will be administered either alone or in combination with vectors encoding anti-angiogenic factors. The effects of the therapy in long-term survival will be determined. Potential Outcomes and Benefits of the Research: A positive outcome of these studies will provide new leads towards developing targeted therapies for breast cancer.