For most pediatric sarcoma patients such as osteosarcoma (OS), despite successful management of the primary tumor through multimodality approaches, the development of metastases, commonly to the lungs, is the cause of death. Significant improvements in long-term outcome for these patients have not been achieved in more than 30 years. Furthermore, the long-term outcome for patients who present with metastatic disease is grave. Since its inception in 2004, the Tumor and Metastasis Biology Section, has focused on the problem of metastasis in pediatric sarcoma patients. We believe that opportunities to improve outcomes for patients who present with metastases and those at-risk for metastatic progression require an improved understanding of tumor biology. Our focus on sarcoma metastasis will in many cases be complimentary and informative within the broader metastasis community;however, this focus is necessary specifically to improve outcomes for sarcoma patients. Since the initiation of the Tumor and Metastasis Biology Section we have successfully built a platform for metastasis research in sarcomas, focused but not restricted to ezrin, that includes molecular biology, cellular biology, in vivo biology and translation to the human condition. As suggested above, the foundation of our success has been our development of transplantable murine and xenograft models of sarcoma metastasis. Our murine models have been used widely within virtually all sections of the Pediatric Oncology Branch and in the greater cancer research community. We first identified ezrin in a murine osteosarcoma model and have defined ezrin as causally associated with metastasis in that murine osteosarcoma model, in dogs with naturally occurring osteosarcoma, and, preliminarily, in pediatric osteosarcoma patients. We have assessed ezrin expression in over 5,000 human cancers, identified PKC isoforms as activators of ezrin, and linked ezrin expression with the early metastatic survival of cancer cells using novel imaging of single metastatic cells in the lung. We have used points of convergence between these three projects to prioritize and begin to test novel hypotheses. An exciting and unexpected finding that has come from this convergence has been that ezrin contributes to the efficiency of translation or translation initiation in metastatic cells. The link between ezrin, a protein not directly connected to the translational machinery, and translation initiation is novel and supports a growing hypothesis that suggests the importance of translation in metastasis. In all projects we pursue these hypotheses not only at the biological level but also with an eye toward a therapeutic end. We have now linked our studies of protein translation, and stress with the mTOR pathway. Using established tools in the lab we have developed a growing hypothesis that the classical inhibitors of mTOR (rapalogs) may exert their mechanisms of action through a novel and not previously described pathway, referred to as the unfolded protein response. This understanding is now being used in our lab to predict optimized treatment schedules for rapalogs and for the development of biomarkers that are predictive of therapeutic benefit in in cancer patients. Collaborative Research and Technology Transfer. Essentially all Tumor and Metastasis Biology Section subprojects include collaborations both within and outside the Center for Cancer Research (CCR). In addition, our lab works closely with and provides reagent and approach support to several intramural and extramural investigators, the pharmaceutical industry, and cooperative groups including the Children's Oncology Group and the Sarcoma Alliance for Research Cooperation, of which I serve on leadership committees. Pharmaceutical collaborations are currently defined by MTAs that allow the evaluation of novel agents linked to ezrin biology within our in vivo models. My leadership of the CCR-Comparative Oncology Program (http://ccr.cancer.gov/resources/cop/) and its interactions with the drug development community are outlined in the second Project within this Annual Report, entitled Comparative Oncology Program.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010566-10
Application #
8763138
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2013
Total Cost
$532,781
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Khanna, Chand; Fan, Timothy M; Gorlick, Richard et al. (2014) Toward a drug development path that targets metastatic progression in osteosarcoma. Clin Cancer Res 20:4200-9
Mushinski, J Frederic; Nguyen, Phuongmai; Stevens, Lisa M et al. (2009) Inhibition of tumor cell motility by the interferon-inducible GTPase MxA. J Biol Chem 284:15206-14
Hong, Sung-Hyeok; Briggs, Joseph; Newman, Rachel et al. (2009) Murine osteosarcoma primary tumour growth and metastatic progression is maintained after marked suppression of serum insulin-like growth factor I. Int J Cancer 124:2042-9
Ren, L; Hong, S H; Cassavaugh, J et al. (2009) The actin-cytoskeleton linker protein ezrin is regulated during osteosarcoma metastasis by PKC. Oncogene 28:792-802
Leaner, Virna D; Chick, Jeffrey F; Donninger, Howard et al. (2009) Inhibition of AP-1 transcriptional activity blocks the migration, invasion, and experimental metastasis of murine osteosarcoma. Am J Pathol 174:265-75
Mendoza, Martin; Khanna, Chand (2009) Revisiting the seed and soil in cancer metastasis. Int J Biochem Cell Biol 41:1452-62
Wan, X; Kim, S Y; Guenther, L M et al. (2009) Beta4 integrin promotes osteosarcoma metastasis and interacts with ezrin. Oncogene 28:3401-11
Khanna, Chand (2008) Novel targets with potential therapeutic applications in osteosarcoma. Curr Oncol Rep 10:350-8
Barkan, Dalit; Kleinman, Hynda; Simmons, Justin L et al. (2008) Inhibition of metastatic outgrowth from single dormant tumor cells by targeting the cytoskeleton. Cancer Res 68:6241-50
Lee, Jong Heun; Horak, Christine E; Khanna, Chand et al. (2008) Alterations in Gemin5 expression contribute to alternative mRNA splicing patterns and tumor cell motility. Cancer Res 68:639-44

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