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Paul L. Hermonat, PhD Professor of Obstetrics and Gynecology Director of the Gene Therapy Program Mehta/Stebbins Chair in Medicine |
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Doctoral DegreeUniversity of Florida, Gainesville, Medical Microbiology & Immunology Postdoctoral Training University of Florida, Gainesville, Pathology National Instititutes of Health, NCI, LTVB Research Interests Adeno-associated virus Rep78 protein as an antioncogene Human papillomavirus as a causative agent for breast cancer Adeno-associated virus as a gene therapy vector
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| Research Details: | ||
| Dr. Yong Liu and a host of valuable colleagues collaborate with me on the following projects in molecular oncology.
1) Adeno-associated virus (AAV) Rep78 as an antioncogene. We identified the AAV-encoded Rep78 as an “anti-oncogene” in 1989 by its ability to inhibit oncogenic transformation by bovine papillomavirus. Subsequently we (and others) have demonstrated that Rep78 is able to inhibit a wide variety of oncogenes (human papillomavirus type 16 [HPV-16], c-H-ras, c-myc, c-fos, c-jun), while a few others are resistant (v-fos, c-sis). Rep78 has several mechanisms of action, largely on the level of transcription, through binding Sp1, AP-1 and others. These major activities have been confirmed by other labs. 2) Human papillomavirus causal association with breast cancer. HPV is famous for causing cervical cancer. Now we find that HPV DNA is present in many breast cancers. This finding has resulted in US Patent 6,884,603 (2005). In fact in some breast cancers HPV DNA is present at such high levels that we believe that HPV is actually replicating in the mammary ducts. Our findings have been confirmed by Dr. zur Hausen’s group, the top HPV group in the world. Recently we have found that HPV will replicate in primary mammary ductal epithelial cells in culture, suggesting a pathway for high HPV levels. We have also identified HPV variants, possibly breast-tropic HPV types, at high frequency in breast cancers. 3) AAV as a gene therapy vector for modifying dendritic cells and mounting an anti-cancer immune response. In 1983 I was the first to conceive of a method to generate rAAV and demonstrate gene transfer by rAAV (US Patent 5,139,941 (1992)). Now there is a gene therapy industry based on this seminal work. We now find that AAV is excellent at delivering antigen genes into dendritic cells (DC), professional antigen presenting cells, achieving over 90% transduction efficiency in vitro. Important DC markers are also up-regulated, in particular CD80. We find that these AAV/antigen-modified DC stimulate MHC Class I-restricted, antigen specific cytotoxic T lymphocytes (CTL) better than all other techniques known, stimulating significant CTL in only one stimulation in only one week. No other technique can match this. Our hope is develop this technology as a type of anti-cancer “vaccine” for the treatment of cancer and infectious disease. | ||
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