The human papillomavirus (HPV) is a significant etiologic agent in lower female genital tract neoplasia. Novel interactions with other co-carcinogens and/or immuno-deficiency lead to tumorigenesis and cancer progression. However, both the lack of adequate animal models and prospective clinical trials are impediments to the development of effective anti-HPV therapies and prevent a thorough understanding of human interactions with this virus. The objective of this proposal is to support the career development of Bradley J. Monk, M.D. Under the direction of Dr. Luis P. Villarreal, Ph.D., Dr. Monk will evaluate co-carcinogens and anti-viral agents in a recently described severe combined immunodeficiency mouse model using implanted human HPV infected epithelium, cervical intraepithelial neoplasia (CIN). Dr. Monk proposes to study the neoplastic transformation as well as the progression or regression of these cervical tissue implants. The influence of specific promoters or genotoxic compounds (e.g. hormones, nicotine) as well as novel anti-HPV agents (e.g. stimulated immune cells, anti-sense oncogenes) and nutritional supplements (e.g. indole 3-carbinol or I3C) will be studied. In addition, under the direction of Philip J. DiSaia, M.D., a Gynecologic Oncologist; Frank L. Meyskens, M.D., a Medical Oncologist with expertise in Chemoprevention; and Jeffrey S. Weber, M.D., Ph.D., a Medical Oncologist with expertise in Immunology, Dr. Monk will conduct two prospective clinical trials of novel HPV therapies. First, I3C, a compound found in cruciferous vegetables and effective in HPV related laryngeal papillomatosis, will be evaluated in patients with HPV induced genital warts in a randomized phase II trial. Second, a phase I and II study of a DNA plasmid vaccine encoding an immunogenic portion of the HPV type 16 E7 protein is planned among women with CIN. Dr. Monk will focus his career on translational research in the area of anti-HPVmodalities specifically related to female lower genital tract neoplasia. Mentors in Virology, Chemoprevention, Immunology and Gynecologic Oncology will allow Dr. Monk to investigate unique anti-viral agents both in the laboratory and in clinical settings with an emphasis on HPV immunity. This path will develop Dr. Monk into an independent investigator able to study anti-HPV therapies first in animals then in human chemoprevention trials. It is expected that Dr. Monk will have obtained extramural funding for both his laboratory and clinical studies by the end of the period of support requested.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23CA087558-05
Application #
6876651
Study Section
Subcommittee G - Education (NCI)
Program Officer
Gorelic, Lester S
Project Start
2001-08-29
Project End
2006-06-30
Budget Start
2005-03-21
Budget End
2005-12-31
Support Year
5
Fiscal Year
2005
Total Cost
$127,170
Indirect Cost
Name
University of California Irvine
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Luevano, Martha; Bernard, Hans-Ulrich; Barrera-Saldana, Hugo A et al. (2010) High-throughput profiling of the humoral immune responses against thirteen human papillomavirus types by proteome microarrays. Virology 405:31-40
Monk, Bradley J; Sill, Michael W; McMeekin, D Scott et al. (2009) Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 27:4649-55
Randall, Leslie M; Monk, Bradley J; Darcy, Kathleen M et al. (2009) Markers of angiogenesis in high-risk, early-stage cervical cancer: A Gynecologic Oncology Group study. Gynecol Oncol 112:583-9
Camacho, Luis H; Antonia, Scott; Sosman, Jeffrey et al. (2009) Phase I/II trial of tremelimumab in patients with metastatic melanoma. J Clin Oncol 27:1075-81
Monk, Bradley J; Sill, Michael W; Burger, Robert A et al. (2009) Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol 27:1069-74
Monk, Bradley J; Tian, Chunqiao; Rose, Peter G et al. (2007) Which clinical/pathologic factors matter in the era of chemoradiation as treatment for locally advanced cervical carcinoma? Analysis of two Gynecologic Oncology Group (GOG) trials. Gynecol Oncol 105:427-33
Long 3rd, Harry J; Monk, Bradley J; Huang, Helen Q et al. (2006) Clinical results and quality of life analysis for the MVAC combination (methotrexate, vinblastine, doxorubicin, and cisplatin) in carcinoma of the uterine cervix: A Gynecologic Oncology Group study. Gynecol Oncol 100:537-43
Tewari, Devansu; Monk, Bradley J; Al-Ghazi, Muthana S et al. (2005) Gene expression profiling of in vitro radiation resistance in cervical carcinoma: a feasibility study. Gynecol Oncol 99:84-91
Monk, Bradley J; Wang, Jianmin; Im, Samuel et al. (2005) Rethinking the use of radiation and chemotherapy after radical hysterectomy: a clinical-pathologic analysis of a Gynecologic Oncology Group/Southwest Oncology Group/Radiation Therapy Oncology Group trial. Gynecol Oncol 96:721-8
Monk, Bradley J; Huang, Helen Q; Cella, David et al. (2005) Quality of life outcomes from a randomized phase III trial of cisplatin with or without topotecan in advanced carcinoma of the cervix: a Gynecologic Oncology Group Study. J Clin Oncol 23:4617-25

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