DEVELOPMENTAL RESEARCH PROGRAM

发展研究计划

基本信息

批准号：
7300581
负责人：
DAVID SIDRANSKY
金额：
$ 16.4万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7300581
关键词：
AQP1 gene Address Advertisements Advertising Advisory Committees Affect African American Age American Cancer Society Anchorage-Independent Growth Appointment Area Arthritis Award Azacitidine BRAF gene Baltimore Behavior Behavioral Sciences Benign Biological Assay Biological Markers Biology Biophysics Biopsy Specimen Breeding Bronchoalveolar Lavage CALCA gene CDH1 gene California Canada Cancer Center Cancer Control Cancer Patient Cancer Vaccine Related Development Cancer cell line Cancerous Caring Categories Cell Line Cell Proliferation Center Core Grants Cervical Cervix Uteri Chairperson Characteristics Chinese People Chromatin Clinical Clinical Trials Collaborations Committee Members Communities Consultations Country Cytopathology D Aspartate DNA DNA Sequence Rearrangement DNA Vaccines Detection Development Diagnostic Differentiation Antigens Disabled Persons Doctor of Medicine Doctor of Philosophy Dose Early Diagnosis Electronic Mail Elevation Endocrine Endocrinologist Endocrinology Environment Epidemiologist Epidemiology Epigallocatechin Gallate Epigenetic Process Ethnic Origin Etiology Evaluation Event Excision Exhibits Faculty Fellowship Female Fine needle aspiration biopsy Fostering Funding Gastrointestinal tract structure Gender Gene Expression Gene Expression Regulation Gene Mutation Gene Silencing Genes Genetic Genetic Polymorphism Goals Grant Growth Guidelines Hand Head Head and Neck Cancer Head and Neck Surgery Head and neck structure Health Policy Hematology Histones Hormones Hospitals Human Human Genetics Human Papillomavirus Hypermethylation Hyperplasia Immunologics Immunology Individual Industry Institution Interdisciplinary Study International Intervention Interview Investigation Investments Iodides Job Description K-Series Research Career Programs Koreans Laboratories Lead Lesion Letters Lung MAP Kinase Activation Pathway MEKs Malignant Neoplasms Malignant neoplasm of esophagus Malignant neoplasm of lung Malignant neoplasm of thyroid Medical Medical Oncologist Medical Residency Medical center Medicine Mentors Methylation Micronutrients Minority Mitochondria Mitogen-Activated Protein Kinases Modeling Modification Molecular Molecular Biology Molecular Genetics Molecular Profiling Moon Morbidity - disease rate Morus Mutation NIH 3T3 Cells Neoplasms Operating Rooms Operative Surgical Procedures Organ Otolaryngology Outcome Papillary thyroid carcinoma Pathogenesis Pathology Pathway interactions Patient Care Patients Physicians Physiology Play Population Positioning Attribute Principal Investigator Private Practice Process Program Description Program Development Progress Reports Protein Overexpression Protocols documentation Public Health Public Health Schools Publications Qualifying Race Radiation Radiation Oncology Radiology Specialty Rate Recording of previous events Records Recruitment Activity Regulation Relative (related person)Reproduction spores Request for Applications Research Research Personnel Research Project Grants Resources Reverse Transcriptase Polymerase Chain Reaction Review Committee Rheumatism Risk Role Running Salivary Gland Neoplasms Sample Size Science Scientist Screening procedure Selection Criteria Serum Services Specimen Structural Genes Surgeon Surgical Oncology TIMP3 gene Techniques Telefacsimile Telephone Testing Thyroid Diseases Thyroid Gland Thyroid carcinoma Thyrotropin Receptor Time Tissues Tobacco Tobacco use Training Transforming Growth Factor beta Translating Translational Research Translations Tumor Markers Tumor Suppressor Genes Ultrasonography United States National Institutes of Health Universities University Hospitals Veterans Vietnam Vitamin A Voting Wages Woman Work Writing Youth adenoma anticancer research aspartate receptor base cancer cell cancer prevention cancer research center director cancer risk career cigarette smoking clinical application cohort desire disability experience gene therapy interest male medical schools member mutant novel novel diagnostics oncology outcome forecast post-doctoral training preference professor progesterone 11-hemisuccinate-(2-iodohistamine)programs promoter prospective research and development response skin cancer prevention stem success therapeutic target thyroid neoplasm tool translational approach translational clinical trial trend tumor tumor immunology tumor progression tumorigenesis water channel

项目摘要

Principal Investigator/Program Director (Last, First, Middle): Sidransky, David Career Development Program Description 1. Describe the process for selecting candidates and how the program will place special emphasis on recruiting qualified women and minorities. The candidate selection process has been in place since the initiation of the program in 2002. Our mechanism for selection of candidates is based on merit with further consideration based on diversity of race, gender, and age among the applicant pool. The Program is administered by the SPORE Director, Dr. David Sidransky. The emphasis is on recruitment of young or less established investigators from the talented pool throughout the Johns Hopkins Medical Institutions to direct their research career focus upon translational progress in head and neck cancer. The positions are advertised in official Johns Hopkins University and Hospital publications and in memoranda to department and division heads. Moreover, we use informal networking among the faculty throughout the institution which is also emphasized. The advertisements consist of the following: A. A description of the position (career development of new or established investigators that wish to redirect their efforts specifically in the area of translational research into head and neck or thyroid cancer) B. A statement that two-three positions are available, each offer approximately $50,000/year of salary support C. A statement that candidates will be selected by the Career Development Committee with approval by the SPORE Steering Committee. D. A list of selection criteria and of the Committee members (see below). E. Applications are due by a set date each February, for starting dates of the following July 1. This distribution of dates has encouraged departments to cooperation with the SPORE to plan ahead, in order to protect the research time of the awardee and maximize their translational career F. Inquiries should be made to David Sidransky MD, Professor of Oncology, Otolaryngology, and Pathology, CRB II 5N.03, The Johns Hopkins Univ. School of Medicine, 1550 Orleans Street, Baltimore, MD 21231; Phone 410-502-5155, Fax 410-614-1411, email dsidrans@jhmi.edu G. The Johns Hopkins University is an Equal Opportunity, Affirmative Action Employer. Minorities, women, Vietnam-era veterans, disabled veterans, and individuals with disabilities are encouraged to apply. In addition to the advertisement, a letter including the advertisement is sent to each of the department chairpersons in the Johns Hopkins University School of Medicine and School of Public Health as part of our recruiting approach to identify candidates. Recruitment of qualified women and minorities is a high priority of the Program, and such prospective candidates are approached and encouraged to apply. Such candidates are sought by annual inquiry of department/Division chairs from Medicine, Oncology, Otolaryngology, Pathology, Radiation Oncology, Endocrinology, and Public Health and from personal contacts of the Career Development Committee and Steering Committee. For example, in the history of the program, of nine award recipients, two female and seven males were selected, representing (in terms of country/ethnicity of their youth) Korean, Canadian, and Chinese origin. In each selection process, the best candidates based on merit have been the award recipients, a testament to the comparable quality of minority applicants. We have added Dr Jean Ford from the school of public health to help us to continue to build the program and to recruit additional minority applicants. Additional resources have always been made available due to the flexible funding of the SPORE, as in the current year, to expand the program to include additional highly attractive candidates. Often, the primary department contributes heavily to the recruitment and start up of these investigators. However, it s often SPORE funding that encourages these researchers into Hopkins and the translational HNwork. Prospective candidates are requested to submit a Biographical Sketch on NIH PHS form 398, and a one to one and a half page description of their career goals and interests in translational research, past experience, and a Biographical Sketch of the proposed mentor. The submitted materials are reviewed by the Career Development Committee. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 371 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Sidransky, David Career Development Member David Sidransky,MD Arlene Forastiere, MD Martin Abeloff, MD Charles Rudin, MD PhD William Westra, MD PhD Jean Ford MD, MPH Career Development Committee Position Major Perspective PI, Career Develop. PI, Project 4 PI, Cancer Center Core Grant Co PI UAD program PI, TissueCore Bloomberg School of Public Health SPORE Director CO Director SPORE Cancer Center Director Translational clinical trials Translational laboratory science Health Policy, minority recruitment The criteria for selection of individuals for supportare: A. Potential for independent investigation B. Feasibility and quality of the proposedarea of research C. Translational importanceof the proposedresearch D. Experience of the mentor E. Interactions with other SPORE investigators F. Time commitment to research The Committee members rate the applicants in each of the six categories as: A. Outstanding (1.0-1.5) B. Excellent (1.6-2.0) C. Very good (2.1 -3.0) D. Good (3.1-4.0) E. Acceptable (4.1-5.0) F. Not responsive to Program guidelines In addition, Committee members rank the applicants in overall order of preference for funding. The mean rating and mean rank of each applicant are calculated and the Committee then meets to discuss the applicants. The two individuals selected must be approved by unanimous vote of the Career Development Committee. The successful applicants and their chairmen are notified in writing. Careful records of the proceedings are maintained to document the search process with the assumption that the Committee may need to defend the final decision. Notes on telephone contacts with candidates or the outside reviewer are made and filed. The genderand race/ethnicity of the applicant pool is always formally discussed in relationship to the candidates who areselected. We are aware that the quality of the proposed science is not necessarily the only predictor of the relative benefit to be conveyed by our Career Development program. We also recognize, however, that modern institutions do not readily invest in even the most selective candidates and that the most attractive candidates are often lost to private practice and industry, andthus we maintain the quality of the science as our main criterion. As discussed below, the absence of significant independent funding is also an indication that a candidate represents a productive use of Career Development investment, and is used in the decision process. The potential for growth within the program and for interactions within the translational environment are additional major considerations. The Evaluation of Progress is conducted yearly for each awardee. The Career Development Program-funded individuals submit a yearly progress report that isformally reviewed by the Committee. In addition, the mentor is interviewed to discuss the progress of the individual. The Program's success is convincingly shown when these individuals achieve independent funding fortheir translational research. In some cases, successful PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 372 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Sidransky, David Career Development career growth occurs when an awardee is successfully recruited to an attractive outside position, a sharing of the translational research cultures among institutions. Changes in Candidates may be necessitated because of progress to significant independent funding status. Poor progress is also possible, but unlikely due to the stringency of the selection process. As part of the yearly progress evaluation, the Committee will consider the current status of each candidate. Candidates will be able to request a change in status, expected to be made in consultation with their mentor. Changes in the status will be made by a four-sixths vote of the Career Development Committee with unanimous approval of the SPORE Steering Committee. A Requirement for Full-Time Research was part of Request for Application that led to the initiation of this Program. Although we have selected full-time research faculty for receipt of the $44-50,000 in Career Development support, we have been flexible to address the disparity between required effort and available salary support, and to allow clinical activities that foster translational science. We do not now follow a strict requirement for full-time research. For example, Dr. Moon began his faculty appointment in Otolaryngology as a research-only position, but later added occasional oncology services as part of his translational research, a feature that took advantage of his being a board-certified medical Oncologist. Indicate the prospective mentors/consultants who have experience in translational research and who will interact directly with career development candidates. Our prospective mentors are drawn primarily from our Internal Advisory Committee, Steering Committee, and all Project Principal Investigators. For many of these prospective mentors, details of their research interests are best gleamed from the Research Projects described in other pages of this application and their biosketches. However, Dr Sidransky is always involved in the development of each candidate and meets formally with them every quarter to assess their progress, relationship with the main mentor, and to discuss immediate and longer term career plans. Dr Sidransky is eminently qualified to lead this program as an international leader in translational research, well versed in both clinical and basic career advancement. 2. Describe any candidates that have already been selected for support under this program and the rationale for these selections (this cycle) PATRICK HA, M.D. Dr. Ha will start on his career development award and as an Assistant Professor of the Department of Otolaryngology - Head and Neck Surgery andOncology at the Johns Hopkins School of Medicine this summer. His career goals stem from a desire to treat patients suffering from head and neck cancer by all means possible. Surgery is clearly one aspect of treatment, but he understands that we may have reached our limits of therapy by simple extirpation. Although a combination of medical and radiation treatment has greatly expanded treatment options and sometimes offers a better chance of survival with less functional morbidity, much remains to be done. As a young clinician-scientist, he is dedicated to not only treating patients in the office and operating room, but also to the laboratory. He intends to examine the basic biology of head and neck cancers including salivary gland tumors and make special efforts to understand the epigenetic progression of these cancers. Form these studies he will identify cancer-specific promoter methylation events and generate new biomarkers of cancer. He will focus on translating these discoveries into efforts aimed at the early detection, molecular progression, and targeted therapy of head and neck cancer.As a practicing surgeon, he will play a unique role in these discoveries and possess the ability to implement these new techniques into the care of his patients. He will be mentored by Drs Califano and Sidransky. Rationale: Talented surgeon with several years of molecular biology experience under Joseph Califano. A rare breed that needs to be cultivated in this environment more than ever. Sara Isabel Pai, MDPhD Dr. Pai is trained in Otolaryngology/Head and Neck Surgery. She obtained doctoral training in tumor immunology, molecular biology, gene therapy, and cancer vaccine development in the MD/PhD program at the Johns Hopkins University School of Medicine. Her mentors were Drs. Drew Pardoll. T.-C. Wu, Robert Siliciano and David Sidransky. She also received fellowship training at the National Institutes of Health in the molecular biology/immunology laboratory of Dr. Paul Plotz, Chief of Arthritis and Rheumatism Branch. During her PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 373 Continuation Format Page Principal Investigator/ProgramDirector (Last, First, Middle): Sidransky, David Career Development graduate training, she was a principal investigator in a clinical trial evaluating HPV specific immunologic responses in patients with HPV-associated pre-cancerous lesions within the cervix. She also worked with the Rapid Access to Interventional Development (RAID) program of NCI in the development of the pNGVL4a- Sig/E7/LAMP-1 and pNGVL4a-E7/HSP70 DNA vaccines that are currently being used in several ongoing clinical trials at the Johns Hopkins Hospital. Dr. Pai is a principal investigator in a clinical trial evaluating HPV specific immunologic responses in HPV-associated head and neck cancers at the Greater Baltimore Medical Center. She is also a co-investigator in the HPV clinical trial in Project 3 of the previous Head and Neck SPORE program. She currently participates in the Clinical Trials Working Group at the Johns Hopkins Hospital headed by Dr. Elizabeth Jaffee. She will be an Assistant Professor in the Department of Otolaryngology/Head and Neck Surgery and will be a co-principal investigator with Dr. T.-C. Wu in the HPV clinical trial in Project 3 of the current SPORE application. Rationale: Practicing surgeon with a PhD in immunology under TC Wu and Drew Pardoll. Also a woman with a strong desire to compete and succeed. As above, a rare breed that needs to be cultivated in this environment more than ever. 3. For competing renewal applications, list all of the individuals supported by this program during the past term of the grant, how the SPORE has contributed to their careers in translational research, and the process by which a career development project has been promoted or incorporated into the full translational research projects within the SPORE. Seven candidates have or will receive $44-50,000 awards from the Career Development Program since 2000. One of our Career Development awardees at Hopkins became the leader of a Research Project (Califano from the Lung SPORE), Two are CO-PIs of a SPORE clinical supplemental grant (Califano and Gibson), and one was elevated to status of investigator in a Core (Xing). Elevation to the status of Research Project occurs when a budgetary opportunity occasions a solicitation for new Research Project(s) in the SPORE; thus, the awardee's proposal is required to out-compete all other alternative projects if it is to become a Research Project. In other words, a successful career development award can be a means to prepare an application for the SPORE, and the Career Development Program remains keenly aware that a successful awardee can be a useful addition to the SPORE even beyond the award period. Chul-So Moon MD PhD received his career development award form 2002-2005. He is currently an Assistant Professor in the Department of Otolaryngology - Head and Neck Surgery and Oncology at the Johns Hopkins School of Medicine. In 1991, he came to Johns Hopkins Medical School for the human genetics Ph.D. program. At Hopkins, he discovered the human AQP structural gene and stayed in Peter Agre's lab to further study gene expression regulation. After finishing his medicine training, he went to MD Anderson for a Hematology-Oncology fellowship where he finished under the tutelage of Dr. W Hong and Dr. Li Mao. At the end of his fellowship training at MD Anderson, Dr. Moon was recruited to the Head and Neck Cancer Research Center at the Johns Hopkins University Oncology Center where he is involved in the care of upper aero- digestive tract cancer patients. Presently, his research interests are focused on the biology and translational approaches for head and neck and lung cancer including functional studies on the aquaporins and the search new methylation markers in lung and head and neck cancers. He was recently mentored by Drs Agre and Sidransky. His studies have been funded in part by a pilot grant form this SPORE and are the basis of an RO1 submission on aquaporin biology. ¿ Kim MS, Yamashita K. Baek JH, Park HL. Carvalho AL, Osada M, Hoque MO. Upadhvav S. Mori M. Moon C, Sidransky D.N-methyl-D-aspartate receptor type 2B is epigenetically inactivated and exhibits tumor-suppressive activity in human esophageal cancer. Cancer Res. 2006 Apr 1; 66(7):3409-18. ¿ Hoque MO. Soria JC, Woo J. Lee T. Lee J, Jang SJ, Upadhvav S, Trink B, Monitto C, Desmaze C. Mao L. Sidranskv D, Moon C. Aquaporin 1 is overexpressed in lung cancer and stimulates NIH-3T3 cell proliferation and anchorage-independent growth. Am J Pathol. 2006 Apr; 168(4):1345-53. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 374 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): SJdransky, David Career Development ¿ Topaloqlu O. Hoque MO, Tokumaru Y, Lee J. Ratovitski E, Sidransky D, Moon CS. Detection of promoter hypermethylation of multiple genes in the tumor and bronchoalveolar lavage of patients with lung cancer. Clin Cancer Res. 2004 Apr 1; 10(7):2284-8. ¿ Moon C, Oh Y, Roth JA. Current status of gene therapy for lung cancer and head and neck cancer.Clin Cancer Res. 2003 Nov 1; 9(14):5055-67. Review Dr. Anthony Alberg PhD MPH received his career development award form 2002-2003. He is an epidemiologist in the Bloomberg School of public health with broad interests in cancer research at the community level. On one hand, his research interests include the bridge between epidemiology and the behavioral sciences for cancer prevention and control activities. Previous and current work in this regard includes research concerning tobacco use, skin cancer prevention behaviors, and community cancer control. On the other hand, Dr. Alberg's work has also emphasized the bridge between epidemiology and the laboratory, including etiologic research that incorporates the relationship between biomarkers (e.g., serum micronutrients, hormones, and tumor markers) and genetic polymorphisms in relation to cancer risk. Dr. Alberg wanted to focus his research on tobacco-associated cancers, primarily head/neck and lung cancer. The SPORE support offered him tremendous career development opportunities to engage in multidisciplinary research devoted to better understanding the etiology of head and neck cancer and the development of early detection strategies. He continues to focus on population based studies predominantly in head and neck and lung cancer and remains a strong collaborator with Dr Califano in molecular etiology and detection approaches. He was mentored by Drs. Samet and Califano and is an NCI K07 awardee. ¿ Masayesva BG, Mambo E. Taylor RJ. Goloubeva OG. Zhou S. Cohen Y. Minnas K. Koch W. Sciubba J. Alberq AJ. Sidranskv D. Califano J. Mitochondrial DMAcontent increase in response to cigarette smoking. ¿ Cancer Epidemiol Biomarkers Prev. 2006 Jan; 15(1 ):19-24. Zheng YL, Loffredo CA, Alberg AJ, Yu Z. Jones RT, Perlmutter D. Enewold L. Krasna MJ, Yung R. Shields PG. Harris CC. Less efficient g2-m checkpoint is associated with an increased risk of lung cancer in African Americans. ¿ Cancer Res. 2005 Oct 15; 65(20):9566-73. Trimble CL, Genkinqer JM. Burke AE. Hoffman SC. Helzlsouer KJ. Diener-West M. Comstock GW. Alberq AJ. Active and passive cigarette smoking and the risk of cervical neoplasia. ¿ Obstet Gynecol. 2005 Jan; 105(1): 174-81. Alberq AJ. Park JW. Hager BW. Brock MV. Diener-West M. The use of "overall accuracy" to evaluate the validity of screening or diagnostic tests.J Gen Intern Med. 2004 May; 19(5 Pt 1):460-5. Ralph Tufano M.D. received his career development award from 2003 -2005. He is currently a surgeon and Assistant Professor in the Department of Otolaryngology - Head and Neck Surgery and Oncology at the Johns Hopkins School of Medicine. After discovery of Braf mutations in thyroid cancer as part of this SPORE grant, his work focused on testing for the BRAF mutation in indeterminate thyroid fine needle aspirates as a means for directing extent of surgery. It involved a coordinated effort between radiology and cytopathology and strong collaborations with Drs Xing and Umbricht. A designated study coordinator was responsible for setting up ultrasound guided fine needle aspiration biopsies. A designated research assistant was responsible for collecting specimens to be run for the BRAF assay in the CLIA approved cytopathology lab. The study began accruing patients since the beginning of March of 2004 and all endocrine physicians who treat thyroid disease and see these patients are participating. Five out of eight patients eligible for the study have elected to undergo this research protocol since its inception. It is expected to accrue approximately 50-75 patients this year with a final sample size of at least 125 to provide the power to assess the primary outcome variables. He was mentored by Dr Koch and Dr Forastiere and this study is R21 funded. ¿ Xing M. Tufano RP. Tufaro AP. Basaria S. Ewertz M. Rosenbaum E, Byrne PJ. Wang J, Sidranskv D, Ladenson PW. Detection of BRAF mutation on fine needle aspiration biopsy specimens: a new diagnostic tool for papillary thyroid cancer. J Clin Endocrinol Metab. 2004 Jun;89(6):2867-72. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 375 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Sidransky, David Career Development Xing M, Westra WH, Tufano RP. Cohen Y, Rosenbaum E, Rhoden KJ. Carson KA, Vasko V, Larin A, Tallin! G. Tolanev S, Holt EH, Hui P, Umbricht CB. Basaria S, Ewertz M. Tufaro AP, Califano JA, Ringel MD. Zeiger MA. Sidransky D. Ladenson PW. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab. 2005 Dec; 90(12):6373-9. Hu S. Ewertz M, Tufano RP, Brait M, Carvalho AL, Liu D, Tufaro AP, Basaria S, Cooper PS, Sidransky D. Ladenson PW, Xing M. Detection of serum deoxyribonucleic acid methylation markers: a novel diagnostic tool for thyroid cancer. J Clin Endocrinol Metab. 2006 Jan; 91(1):98-104. Hu S. Liu D. Tufano RP. Carson KA, Rosenbaum E, Cohen Y. Holt EH, Kiseljak-Vassiliades K. Rhoden KJ. Tolanev S. Condouris S, Tallin) G. Westra WH, Umbricht CB, Zeiger MA, Califano JA. Vasko V, Xing M. Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. Int J Cancer. 2006 Christopher Umbricht, MD, PhD received his career development award from 2003 -2005. Originally from Canada, he is currently a researcher in the department of Surgical Oncology at the Johns Hopkins School of Medicine. His investigation delved into the epigenetic silencing of genes by promoter hypermethylation in thyroid cancer. AS a collaborator with DrXing, he made significant progress in investigating the modulation of gene expression profiles of thyroid cancer cell lines by pharmacological intervention and quantitative analysis of 11 gene methylation profiles in a large cohort of clinical thyroid tumors. After assessing the baseline status of several tumor and differentiation markers by RT-PCR as well as methylation markers, he determined the dose-response characteristics of these cell lines to various combinations of demethylating agents such as 5- Azacytidine, ISA,and EGCG, the active component in green tea extract, with vitamins A, D, and E. He performed studies on clinical tissues using QMSP of RassflA, TSHR, RAR-beta2, DAPK, S100, p16, CDH1, CALCA, TIMP3, TGF-beta, and GSTpi in a cohort of 82 thyroid tumors and 5 thyroid cancer cell lines, Hypermethylation was found in cancers for the following markers: RassflA (15%), TSHR (33%), RAR-beta2 (22%), CDH1 (22%), TIMP3 (22%), and TGF-beta (33%). Hypermethylation was also detected in adenomas for TSHR (30%), DAPK (16%) and TGF-beta (29%). A trend toward multiple hypermethylation was evident in cancer tissues, with hypermethylation of 2 or more markers detectable in 25% of hyperplasias, 38% of adenomas, 48% of thyroid cancers, and 100% of cell lines. A rank correlation analysis of marker hypermethylation suggested that at least in thyroid tissue, a subset of these markers are epigenetically modified in concert, independent of histological tumor type, which may reflect an organ-specific regulation process. He was mentored by Dr Zeiger in Surgical Oncology and now Dr Xing. He is currently funded by a K08. ¿ Hu S, Liu D, Tufano RP. Carson KA. Rosenbaum E. Cohen Y. Holt EH. Kiseliak-Vassiliades K, Rhoden KJ, Tolanev S. Condouris S, Tallini G. Westra WH, Umbricht CB, Zeiger MA. Califano JA. Vasko V. Xing M. Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. Int J Cancer. 2006 Jul 20 ¿ Hoque MO, Rosenbaum E. Westra WH, Xing M, Ladenson P. Zeiqer MA. Sidransky D. Umbricht CB. Quantitative assessment of promoter methylation profiles in thyroid neoplasms. J Clin Endocrinol Metab. 2005 Jul;90(7):4011-8. ¿ Rosen J. He M, Umbricht CB, Alexander HR. Dackiw AP, Zeiger MA, Libutti SK. A six-gene model for differentiating benign from malignant thyroid tumors on the basis of gene expression. Surgery. 2005 Dec; 138(6):1050-6; discussion 1056-7. Mingzhao Xing MD PhD, received a Career Development Grant from 2005-2007. He successfully competed for R01 funding last year based on work generated in this SPORE. Following his Ph.D. training in Physiology & Biophysics at Case Western Reserve University in Cleveland, and a research postdoctoral training at University of California, San Diego, Dr. Xing completed his medical residency/endocrine fellowship training at GBMC/Johns Hopkins University School of Medicine in Baltimore. He was recruited to the Division of Endocrinology & Metabolism at Johns Hopkins University as an Assistant Professor in 2003 and promoted to Associate Professor in 2006. As a clinical endocrinologist and a laboratory researcher, Dr. Xing's major PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 376 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Sidransky, David Career Development research interest is in molecular tumorigenesis and pathogenesis of thyroid cancer and their clinical translation. His laboratory team has recently focused on several genetic and epigenetic alterations, such as gene mutation and methylation in the MAP kinase and the PISK/Akt pathways and their clinical application. He is now Co- Investigator on project 5 which is direct result of his findings under this career development award. His overall research interest is to discover novel molecular mechanisms in tumor genesis and progression and to translate them into clinical use in patients. He is particularly interested in the genetic, molecular, and cellular mechanisms involved in the pathogenesis of thyroid cancer, the most common endocrine malignancy Several projects in his laboratory involve efforts to elucidate the role of major genetic alterations, such as BRAF mutation, Ras mutation and RET/PTC rearrangements, and epigenetic alterations, such as gene methylation and chromatin/histone modifications in thyroid cancer. He remains particularly interested in the role of these genetic and epigenetic alterations in the regulation of various thyroid-specific genes, such as TSH receptor and iodide transporter genes as well as certain tumor suppressor genes in thyroid tumors. Efforts are being made to identify the specific molecular events (potential therapeutic targets) involved in the connection between MAP kinase pathway activation and aberrant gene methylation and silencing, triggered by some of the genetic alterations. One important goal of these studies is to elucidate how these molecular events affect some of the unique functions of thyroid cancer with radioiodine. His mentors were Dr David Sidransky and Dr Paul Ladenson. Dr. Xing is currently supported, as the PI, by a FAMRI grant, an American Cancer Society Research Scholar Award, and a NIH RO-1 grant. ¿ Xing M, Westra WH, Tufano RP, Cohen Y. Rosenbaum E, Rhoden KJ, Carson KA, Vasko V. Larin A. Tallin! G, Tolanev S. Holt EH. Hui P, Umbricht CB. Basaria S, Ewertz M. Tufaro AP, Califano JA, Ringel MD. Zeiger MA. Sidransky D, Ladenson PW. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab. 2005 Dec; 90(12):6373-9. ¿ Hu S. Ewertz M. Tufano RP, Brait M. Carvalho AL. Liu D. Tufaro AP. Basaria S, Cooper PS. Sidranskv D. Ladenson PW. Xing M. Detection of serum deoxyribonucleic acid methylation markers: a novel diagnostic tool for thyroid cancer. J Clin Endocrinol Metab. 2006 Jan; 91(1):98-104. ¿ Hu S, Liu D, Tufano RP, Carson KA, Rosenbaum E. Cohen Y. Holt EH. Kiseljak-Vassiliades K, Rhoden KJ, Tolanev S. Condouris S, Tallini G. Westra WH, Umbricht CB, Zeiger MA. Califano JA. Vasko V. Xing M. Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. Int J Cancer. 2006 Jul 20 ¿ Liu D, Hu S, Hou P, Condouris S, and Xing M (2006). Suppression of BRAF/MEK/MAP Kinase pathway restores expression of thyroid-specific genes in thyroid cell lines expressing the V600E mutant BRAF. Clin Cancer Res (in revision). ¿ Liu D, Condouris S, and Xing M (2006). BRAF V600E Mutant Is Required to Maintain the Survival of BRAF Mutation-harboring Papillary Thyroid Cancer Cells. J Clin Endocrinol Metab (in revision) PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 377 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Sidfansky, David Career Development DO NOT SUBMIT UNLESS REQUESTED Competing Continuation Applications