Applicant: Dr. Hoang, the candidate, is currently a tenure-track Assistant Professor at the University of California, Irvine. As evident from his biography, the candidate has demonstrated a steadfast commitment to a career in academic medicine. To this end, he would like to continue his research training in a mentored environment with the goal of becoming an independent investigator in musculoskeletal oncology. Environment: The candidate is jointly mentored by several nationally and internationally recognized experts in Wnt signaling in human cancer and the genetics of osteosarcoma. The University of California, Irvine is a collegial environment with a tradition of nurturing career development of young clinician scientists. Research: Osteosarcoma (OS) remains a pediatric bone cancer with substantial mortality due to a high metastatic rate. Although Wnt signaling is activated in several human malignancies, its role in the pathobiology of OS progression is largely unknown. Our preliminary work suggested that secreted Wnt inhibitors modulate the following pro-invasive pathways in OS: (1) Transcriptional repressors Slug and Twist, (2) MMP-2 and 9, and (3) the hepatocyte growth factor receptor Met. Blocking receptor-mediated Wnt signaling by a dominant negative receptor or by the secreted inhibitor Dkk-3 dramatically decreases the invasive potential and motility of OS cells. These findings lead us to propose the following specific aims: 1) To examine whether secreted Wnt inhibitors can decrease invasive capacity of OS cells by suppressing E-cadherin transcriptional repressors;2) To test the hypothesis that secreted Wnt inhibitors decrease OS invasiveness by suppressing MMP-2 and 9 or by regulating Met-dependent activity;3) To determine whether overexpression of Wnt inhibitors will reduce lung metastasis in vivo in a tail-vein injection nude mouse model. These studies will bridge a gap in our knowledge on the role of secreted Wnt inhibitors in the biology of OS. Lessons learned from this investigation may be applicable to a wider range of human sarcomas and serves as a basis for future studies by the applicant as an independent investigator in musculoskeletal oncology.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA116003-05
Application #
7890494
Study Section
Subcommittee G - Education (NCI)
Program Officer
Myrick, Dorkina C
Project Start
2006-08-01
Project End
2011-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
5
Fiscal Year
2010
Total Cost
$127,170
Indirect Cost
Name
University of California Irvine
Department
Orthopedics
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Lin, Carol H; Guo, Yi; Ghaffar, Samia et al. (2013) Dkk-3, a secreted wnt antagonist, suppresses tumorigenic potential and pulmonary metastasis in osteosarcoma. Sarcoma 2013:147541
Sakai, Toshinori; Eskander, Ramez N; Guo, Yi et al. (2012) Flavokawain B, a kava chalcone, induces apoptosis in synovial sarcoma cell lines. J Orthop Res 30:1045-50
Rubin, Elyssa M; Guo, Yi; Tu, Khoa et al. (2010) Wnt inhibitory factor 1 decreases tumorigenesis and metastasis in osteosarcoma. Mol Cancer Ther 9:731-41
Tang, Yaxiong; Simoneau, Anne R; Liao, Wu-xiang et al. (2009) WIF1, a Wnt pathway inhibitor, regulates SKP2 and c-myc expression leading to G1 arrest and growth inhibition of human invasive urinary bladder cancer cells. Mol Cancer Ther 8:458-68