This proposed five year training program is designed to expand the applicant's knowledge in advanced molecular biology. The primary goals of the training program are to expand the applicant's ability in performing basic research into a hypothesis-driven, mechanistic understanding of tumorigenesis, and to provide her with the skills necessary to develop a productive, independently funded, laboratory. To accomplish these goals, a rigorous training program has been proposed, including didactic instruction in advanced molecular biology, fundamental instruction in the conduct of clinical investigation, and a research experience focusing on advanced laboratory techniques. The training program has been thoughtfully constructed to help the applicant achieve her long term career goal of the investigation of novel treatment strategies for neuroblastoma. The research program incorporates several unique aspects available at the University of Florida, namely the University of Florida Shands Cancer Center with expertise of a number of scientists in the field of cancer research, and the Department of Surgery Cancer Research Laboratory with its pioneering discoveries in the biology of focal adhesion kinase (FAK). The proposed research focuses on the expression and function of FAK in neuroblastoma, a childhood tumor with a dismal prognosis. This proposal builds upon preliminary data demonstrating a correlation between FAK expression and MYCN oncogene amplification, and the effects of attenuation of FAK upon cellular survival. We hypothesize that FAK is overexpressed in neuroblastomas with MYCN amplification and that MYCN is involved in the transcriptional regulation of FAK. We will study FAK expression in human neuroblastoma tissue samples and cell lines, measure the effects of FAK upon cellular attachment, proliferation, motility, and survival, and determine the effects of FAK inhibition upon tumor growth and survival in an in vivo model of neuroblastoma. Better insight into the relationship between FAK and MYCN offers the potential for translating this knowledge into clinically relevant therapies for this devastating childhood tumor.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA118178-06
Application #
8136297
Study Section
Subcommittee G - Education (NCI)
Program Officer
Perkins, Susan N
Project Start
2007-08-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
6
Fiscal Year
2011
Total Cost
$134,533
Indirect Cost
Name
University of Alabama Birmingham
Department
Surgery
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Gillory, Lauren A; Stewart, Jerry E; Megison, Michael L et al. (2015) Focal adhesion kinase and p53 synergistically decrease neuroblastoma cell survival. J Surg Res 196:339-49
Stewart, Jerry E; Ma, Xiaojie; Megison, Michael et al. (2015) Inhibition of FAK and VEGFR-3 binding decreases tumorigenicity in neuroblastoma. Mol Carcinog 54:9-23
Beierle, Elizabeth A; Ma, Xiaojie; Stewart, Jerry E et al. (2014) Inhibition of the focal adhesion kinase and vascular endothelial growth factor receptor-3 interaction leads to decreased survival in human neuroblastoma cell lines. Mol Carcinog 53:230-42
Waters, Alicia M; Beierle, Elizabeth A (2014) The interaction between FAK, MYCN, p53 and Mdm2 in neuroblastoma. Anticancer Agents Med Chem 14:46-51
Megison, Michael L; Gillory, Lauren A; Stewart, Jerry E et al. (2014) Preclinical evaluation of engineered oncolytic herpes simplex virus for the treatment of pediatric solid tumors. PLoS One 9:e86843
Megison, Michael L; Gillory, Lauren A; Stewart, Jerry E et al. (2014) FAK inhibition abrogates the malignant phenotype in aggressive pediatric renal tumors. Mol Cancer Res 12:514-26
Gillory, Lauren A; Stewart, Jerry E; Megison, Michael L et al. (2013) FAK Inhibition Decreases Hepatoblastoma Survival Both In Vitro and In Vivo. Transl Oncol 6:206-15
Gillory, Lauren A; Megison, Michael L; Stewart, Jerry E et al. (2013) Preclinical evaluation of engineered oncolytic herpes simplex virus for the treatment of neuroblastoma. PLoS One 8:e77753
Megison, Michael L; Gillory, Lauren A; Beierle, Elizabeth A (2013) Cell survival signaling in neuroblastoma. Anticancer Agents Med Chem 13:563-75
Megison, Michael L; Stewart, Jerry E; Nabers, Hugh C et al. (2013) FAK inhibition decreases cell invasion, migration and metastasis in MYCN amplified neuroblastoma. Clin Exp Metastasis 30:555-68

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