Perhaps the wave of the future for her2 bc tx with hMtd gene therapy.
Mien-Chie Hung, PhD
http://www.bcrfcure.org/images/spacer.gifhttp://www.bcrfcure.org/images/spacer.gif
Professor & Chair, Department of Molecular and Cellular Oncology
Director, Breast Cancer Basic Research Program
The University of Texas
MD Anderson Cancer Center
Houston, TX
2005-2006 BCRF Project:
Co-investigator: Gabriel Hortobagyi, MD, MD Anderson Cancer Center The researchers’ work may provide a strategy to develop a novel therapy by combination of AIM2 gene therapy and TNF-α therapy, as a non-toxic low dose of TNF-α may be sufficient to kill breast cancer cells while AIM2 gene is also introduced into breast cancer cells. They will test the potential synergistic effects of the combination of TNF-α and AIM2 gene therapy. Most breast cancers are associated with a mutation in the p53 gene or overexpression of the HER-2 gene. Both defects are associated with poor survival and resistance to certain chemotherapy drugs. With support from BCRF, the Hortobagyi-Hung team has recently identified a gene, hMtd, that kills breast cancer cells in the laboratory, including those in which HER-2 is overexpressed or p53 is mutated. They have also developed a super-activated form of hMtd that is even more effective at killing breast cancer cells. Over the past year, they demonstrated that hMtd induces apoptosis (cell death) and suppresses growth of breast cancer cells. To develop an effective gene therapy using hMtd for breast cancer treatment, they have constructed a breast cancer-specific vector that is able to drive a therapeutic gene to be selectively expressed in breast cancer cells in culture and in mammary tumors in a laboratory model. Continued success of these laboratory studies may lead to the development of clinical trials to evaluate this gene therapy approach in breast cancer patients
AIM2 suppresses human breast cancer cell proliferation in vitro and mammary tumor growth in a mouse model.
I-Fen Chen, Fu Ou-Yang, Jen-Yu Hung, Jaw-Ching Liu, Hongying Wang, Shao-Chun Wang, Ming-Feng Hou, Gabriel N Hortobagyi, Mien-Chie Hung
IFN-inducible proteins are known to mediate IFN-directed antitumor effects. The human IFN-inducible protein absent in melanoma 2 (AIM2) gene encodes a 39-kDa protein, which contains a 200-amino-acid repeat as a signature of HIN-200 family (hematopoietic IFN-inducible nuclear proteins). Although AIM2 is known to inhibit fibroblast cell growth in vitro, its antitumor activity has not been shown. Here, we showed that AIM2 expression suppressed the proliferation and tumorigenicity of human breast cancer cells, and that AIM2 gene therapy inhibited mammary tumor growth in an orthotopic tumor model. We further showed that AIM2 significantly increased sub-G(1) phase cell population, indicating that AIM2 could induce tumor cell apoptosis. Moreover, AIM2 expression greatly suppressed nuclear factor-kappaB transcriptional activity and desensitized tumor necrosis factor-alpha-mediated nuclear factor-kappaB activation. Together, these results suggest that AIM2 associates with tumor suppression activity and may serve as a potential therapeutic gene for future development of AIM2-based gene therapy for human breast cancer. [Mol Cancer Ther 2006;5(1):1-7].
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