This K08 Career Development Award (CDA) application details the plan for development of an independent clinician-investigator skilled in the application of developmental genetics tools in the area of sarcoma biology. The candidate has recently completed rigorous clinical training in orthopaedic surgery and musculoskeletal oncology, during which aspirations toward science have been on hold. The candidate has nonetheless demonstrated sustained desire for involvement in science beginning during secondary education and culminating in the generation of a unique conditional knock-out mouse in his spare time in the midst of surgical training. Now beginning an academic appointment as a surgeon-scientist in a busy clinical center for pediatric sarcoma treatment and under the research mentorship of a recent Nobel Laureate with extensive experience in the study of pediatric sarcoma mouse models, the candidate is poised to receive intensive preparation for an investigative academic career. After gaining expertise in the reverse translation of hypotheses generated from patient-oriented research to developmental genetic models in mice, it is anticipated that the candidate's career work will not only provide insight into the pathogenesis of pediatric sarcomas-specifically osteosarcoma-and improvements in their treatment, but also expand the currently tiny pool of exemplary models for future would- be orthopaedic surgeon-scientists. Osteosarcoma is a leading cause of cancer death among adolescents and young adults. Further, it has one of the youngest ages of onset among genetically complex non-balanced-translocation-type cancers, making it likely to have patterned pathogenesis and likely to provide a useful window into the understanding of genetically complex cancers in general. A major challenge in the study of the pathogenesis of osteosarcoma is that no benign, low-grade, or even intermediate-grade precursor lesions are recognized. Observations in human tumors and mouse models have elevated p53 and the retinoblastoma susceptibility protein (pRb) as critical gene disruptions for osteosarcomagenesis. Conditional disruption of these genes at varied osteoblast precursor differentiation states and varied mouse host developmental stages will characterize the window of opportunity for osteosarcomagenesis. Transposon-mediated mutagenesis in association with pRb and p53 conditional disruption will identify the cooperative gene disruptions and amplifications needed to complete osteosarcomagenesis and attain the metastatic phenotype.

Public Health Relevance

The development of model orthopaedic surgeon-scientists is crucial to the future attraction of those with scientific aspirations to the field of orthopaedics, which includes care for some of the most frequent, most disabling, and least understood problems in medicine. Improved understanding of osteosarcoma is needed as this remains an unacceptably deadly and disabling cancer in a young population. Further, osteosarcoma is a model for other genetically-complex cancers, many of which are major public health burdens.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA138764-04
Application #
8318781
Study Section
Subcommittee G - Education (NCI)
Program Officer
Jakowlew, Sonia B
Project Start
2009-09-28
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$179,280
Indirect Cost
$13,280
Name
University of Utah
Department
Orthopedics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Horne, Logan; Avilucea, Frank R; Jin, Huifeng et al. (2016) LRP5 Signaling in Osteosarcomagenesis: a Cautionary Tale of Translation from Cell Lines to Tumors. Transl Oncol 9:438-444
Jones, K B; Barrott, J J; Xie, M et al. (2016) The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis. Oncogene 35:5021-32
Calvert, George T; Wright, Jennifer; Agarwal, Jayant et al. (2015) Is claviculo pro humeri of value for limb salvage of pediatric proximal humerus sarcomas? Clin Orthop Relat Res 473:877-82
de Andrea, Carlos E; Zhu, Ju-Fen; Jin, Huifeng et al. (2015) Cell cycle deregulation and mosaic loss of Ext1 drive peripheral chondrosarcomagenesis in the mouse and reveal an intrinsic cilia deficiency. J Pathol 236:210-8
Barrott, Jared J; Illum, Benjamin E; Jin, Huifeng et al. (2015) ?-catenin stabilization enhances SS18-SSX2-driven synovial sarcomagenesis and blocks the mesenchymal to epithelial transition. Oncotarget 6:22758-66
Quist, T; Jin, H; Zhu, J-F et al. (2015) The impact of osteoblastic differentiation on osteosarcomagenesis in the mouse. Oncogene 34:4278-84
Jones, Kevin B (2015) CORR Insights®: what is the use of imaging before referral to an orthopaedic oncologist? A prospective, multicenter investigation. Clin Orthop Relat Res 473:875-6
Monument, Michael J; Bernthal, Nicholas M; Bowles, Austin J et al. (2015) What are the 5-year survivorship outcomes of compressive endoprosthetic osseointegration fixation of the femur? Clin Orthop Relat Res 473:883-90
Bernthal, Nicholas M; Monument, Michael J; Randall, R Lor et al. (2014) Rotationplasty: Beauty is in the Eye of the Beholder. Oper Tech Orthop 24:103-110
Goodwin, Matthew L; Jin, Huifeng; Straessler, Krystal et al. (2014) Modeling alveolar soft part sarcomagenesis in the mouse: a role for lactate in the tumor microenvironment. Cancer Cell 26:851-862

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