Dr. Ie-Ming Shih
Molecular genetic basis in the development of ovarian cancer and application of new biomarkers for early detection of cancer
Professor of Pathology and Oncology
M.D., Medicine, Taipei Medical University Ph.D., Pathology, University of Pennsylvania
Intern, McKay Memorial Hosptial, Taipei, Taiwan
Resident, Department of Pathology, Johns Hopkins Hospital, Baltimore, MD
Fellow, Division of Gynecologic Pathology, Johns Hopkins Hospital, Baltimore, MD
American Board of Pathology - Anatomic Pathology
Pathology of gynecological lesions, especially ovarian epithelial neoplasms and gestational trophoblastic diseases.
Dr. Shih’s research team focuses on the molecular pathology of ovarian cancer, the most lethal malignant tumor among gynecological neoplasms. The long-term objectives of his research team are:
A. to understand the molecular etiology in the development of human cancer, and
B. to identify and characterize cancer molecules for cancer detection, diagnosis, and therapy.
Dr. Shih’s team use ovarian carcinoma as a disease model because it is one of the most aggressive neoplastic diseases in women. For the first research direction, they aim to identify and characterize the molecular alterations during initiation and progression of ovarian carcinomas. Previous genome-wide analyses from his team have identified molecular alterations in several new cancer-associated genes including Rsf-1, NAC1, and fatty acid synthase among several others. The investigators have demonstrated the essential roles of these gene products in sustaining tumor growth and survival. Current projects are focusing on elucidating the mechanisms by which these genes function in cancer cells and delineating the cross-talks between those genes and other signaling pathways.
Specifically, they are identifying their downstream targets and pathways, and are determining their roles in maintaining cancer stem cell-like features, invasion and drug resistance. The second research direction is a translation-based study. The team is assessing the clinical significance of an array of new cancer-associated genes in predicting clinical outcome and in the developing potential target-based therapy in mouse preclinical models.
They are also establishing innovative assays for cancer detection and diagnosis by identifying new tumor-associated genetic and protein biomarkers through serial analysis of gene expression, gene expression arrays, proteomics and methylation profiling. The purpose is to develop new tools in detecting human cancer using body fluid samples. In collaboration with several investigators, they are integrating new technologic platforms such as microfluidics, nanotechnology and systems biology in their studies. More details of Dr.Shih’s research can be found at http://pathology2.jhu.edu/shihlab/index.cfm.
Selected Recent Journal Citations
Shih IM, Torrance C, Sokoll L, Chan DW, Kinzler KW, Vogelstein B. Assessing tumors in living animals through measurement of urinary beta-human chorionic gonadotropin. Nature Med, 6:711-714, 2000.
Shih IM, Wang TL, Traverso G, Romans K, Hamilton SR, Kinzler KW, Vogelstein B. Top-down morphogenesis of colorectal tumors. Proc Natl Acad Sci USA, 98:2640-2645, 2001.
Chang H-W, Singer G, Cho SR, Sokoll L, Montz F, Roden R, Zhang Z, Chan DW, Kurman RJ, Shih IM. Detection of allelic imbalance by counting alleles in plasma as a diagnostic tool for cancer. J Natl Can Inst, 94:1697-1703, 2002.
Singer G, Oldt R, Cohen Y, Wang B, Sidransky D, Kurman RJ, Shih IM. Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Can Inst, 95:484-486, 2003.
Wang BG, Huang H-Y, Chen Y-C, Bristow RE, Kassauei K, Cheng C-C, Roden R, Sokoll LJ, Chan DW, Shih IM. Increased plasma DNA integrity in cancer patients. Cancer Res, 63:3966-3968, 2003
Buckhaults P, Zhang Z, Chen Y-C, Wang T-L, St. Croix B, Saha S, Bardelli A, Morin PJ, Polyak K, Hruban RH, Velculescu VE, Shih IM. Identifying tumor origin using a gene expression based classification map. Cancer Res, 63:4144-4149, 2003.
Ho C-L, Kurman RJ, Dehari R, Wang T-L, Shih IM. Mutations of BRAF and KRAS precede the development of ovarian serous borderline tumors. Cancer Res, 64:6915-6918, 2004.
Chen Y-C, Pohl G, Wang TL, Morin PJ, Risberg B, Christesen GB, Yu A, Davidson B, Shih IM. Apolipoprotein E is required for cell proliferation and survival in ovarian cancer. Cancer Res, 65:331-7, 2005
Pohl G, Ho C-L, Kurman RJ, Bristow R, Wang T-L, Shih IM. Inactivation of the MAPK pathway as a potential target-based therapy in ovarian serous tumors with KRAS or BRAF mutations. Cancer Res, 65:1994-2000, 2005.
Shih IM, Sheu J, Santillan A, Nakayama K, Yen MJ, Bristow RE, Vang R, Parmigiani G, Kurman RJ, Trope CG, Davidson B and Wang T-L. Amplification of a chromatin remodeling gene, Rsf-1/HBXAP, in ovarian carcinoma. Proc Natl Acad Sci USA, 102:14004-14009, 2005.
Davidson B, Trope G, Wang T-L, Shih IM. Expression of the chromatin remodeling factor, Rsf-1, in effusions is a novel predictor of poor survival in ovarian carcinoma. Gyn Oncol, 103:814-819, 2006.
Davidson B, Kleinberg L, Forences VA, Zhang Z, Wang TL, Shih IM. Gene expression signatures differentiate ovarian/peritoneal serous carcinoma from diffuse peritoneal malignant mesothelioma. Clin Cancer Res, 12:5944-5950, 2006.
Nakayama K, Nakayama N, Davidson B, Sheu J, Natini Jinawath, Santillan A, Salani R, Bristow RE, Morin PJ, Kurman RJ, Wang TL, Shih IM. A BTB/POZ protein, NAC-1, is related to tumor recurrence and is essential for tumor growth and survival. Proc Natl Acad Sci USA, 103:18739-18744, 2006.
Shih IM, Wang TL. Notch signaling, gamma secretase inhibitors and cancer therapy. Cancer Res, 67:1879-1882, 2007.
Shih IM. Gestational trophoblastic neoplasms- pathogenesis and target-based therapy. Lancet Oncology, 8:642-650, 2007.
Nakayama K, Nakayama N, Wang TL, Shih IM. NAC-1 controls cell growth and survival by repressing transcription of Gadd45GIP1, a candidate tumor suppressor. Cancer Res, 67: 8058-8064, 2007.
Kurman RJ, Visvanathan K, Roden R, Wu TC, Shih IM. Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis. Am J Obst Gyn, 198:351-356, 2008.
Sheu J, Choi JH, Lin A, Yyldyz I, Tsai F-J, Shaul Y, Wang TL, Shih IM. The roles of hSNF2H in the tumor-promoting functions of Rsf-1. Cancer Res, 68:4050-4057, 2008.
Cho K, Shih IM. Ovarian cancer (review). Annual Review Pathol, 4:287-313, 2009.
Choi JH, Sheu J, Guan B, Jinawath N, Markowski P, Wang TL, Shih IM. Functional analysis of 11q13.5 amplicon identifies Rsf-1 (HBXAP) as a gene involved in paclitaxel resistance in ovarian cancer. Cancer Res, 69:1407-1415, 2009
Kuo KT, Mao TL, Jones S, Veras E, Ayhan A, Wang TL, Glas R, Slamon D, Velculescu VE, Kurman RJ, Shih IM. Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma. Am J Pathol, 174:1597-1601, 2009.
Jinawath N. Nakayama K, Yap K, Thiaville M, Wang TL, Shih IM. NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathway. Oncogene, 28: 1941-1948, 2009.