Work over the past year has continued to focus on 3 major areas, IGFIR signaling, the role of ezrin in metastatic behavior of pediatric sarcomas, and the identification of oncogene addiction pathways in rhabdomyosarcomas using shRNA screening techniques. We have continued to study IGF signaling in pediatric sarcomas and this is becoming increasingly more clinically relevant as we now have onging clinical studies using IGFIR Ab treatment in the clinic. Since our previous finding correlating IGFIR levels with sensitivity to IGFIR Ab treatment, we now have data to suggest that while low levels of IGFIR will predict lack of response, high IGFIR levels are not sufficient to predict reponse. In collaboration with Dr. Liang Cao we have also found that there may be some RMS tumor cells that use the IGFIR pathway for both proliferation as well as anti-apoptotic signaling, and these tumor are particularly sensitive to IGFIR Ab treatment. We have also continued to analyze the potential interactions between IGFIR blockade and mTOR inhibition. We have shown and published data demonstrating that although IGFIR Ab treatment of RMS xenografts leads to a reduction of tumor growth, invariably tumors begin to re-grow after long-term exposure to Ab. Furthermore, we have shown that this re-growth is associated with a reactivation of Akt signaling in spite of continued suppression of IGFIR levels. Ongoing studies in xenografts are attempting to model optimal timing and combinations of combination therapy of IGFIR Ab and mTOR inhibitors to pick an optimal way to test these combinations in the clinic. We have continued to study the molecular mechanisms of ezrin signaling in pediatric sarcomas. We have now published our studies linking beta-4 integrin to metastatic behavior in osteosarcoma models. Furthermore, we find high beta-4 integrin expression in human osteosarcoma tumor samples. Finally we demonstrated that ezrin interacts with beta-4 integrin and this interaction is required for continued expression of beta-4 integrin in tumors thus linking ezrin, previously shown to be important for metastatic behavior of osteosarcoma, and beta-4 integrin, now shown to be critical for metastatic behavior. We have completed our high throughput shRNA screening to identify critical pathways for survival of human RMS cell lines. Using an inducible shRNA library containing specific barcodes for clone identification in collaboration with Dr. Lou Staudt, we screened an alveolar and an embryonal RMS cell line to identify specific RNAs that when knocked-down with shRNA would lead to growth arrest. We have identified a number of candidate genes that appear to be critical for survival of these tumor cells. The first gene we have just completed our analysis of confirms that CrkL is required for RMS survival and tumor growth both in vitro and in vivo. We have most recently demonstrated that CrkL signaling in RMS is independent of PI3K-Akt signaling but appears to be via Src kinase signaling, thus identifying a new potential critical signaling pathway for RMS. We are currently preparing a manuscript describing this finding. We are also beginning to evaluate additional hits from this shRNA screen. We are also using the same inducible shRNA approach to specifically regulate the expression of the PAX3-FKHR fusion gene in alveolar RMS. We have prepared the construct and plan to use this regulation to identify the critical downstream targets of this fusion transcription factor by expression profiling of alveolar RMS under native conditions and under conditions of PAX3-FKHR supressison via the shRNA.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Cancer Institute Division of Clinical Sciences
Zip Code
Weldon, Christopher B; Madenci, Arin L; Boikos, Sosipatros A et al. (2017) Surgical Management of Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Pediatric and Wildtype GIST Clinic. J Clin Oncol 35:523-528
LeBlanc, Amy K; Breen, Matthew; Choyke, Peter et al. (2016) Perspectives from man's best friend: National Academy of Medicine's Workshop on Comparative Oncology. Sci Transl Med 8:324ps5
Hyun O, Joo; Luber, Brandon S; Leal, Jeffrey P et al. (2016) Response to Early Treatment Evaluated with 18F-FDG PET and PERCIST 1.0 Predicts Survival in Patients with Ewing Sarcoma Family of Tumors Treated with a Monoclonal Antibody to the Insulinlike Growth Factor 1 Receptor. J Nucl Med 57:735-40
Venkatramani, Rajkumar; Murray, Jeffrey; Helman, Lee et al. (2016) Risk-Based Therapy for Localized Osteosarcoma. Pediatr Blood Cancer 63:412-7
Osgood, Christy L; Maloney, Nichole; Kidd, Christopher G et al. (2016) Identification of Mithramycin Analogues with Improved Targeting of the EWS-FLI1 Transcription Factor. Clin Cancer Res 22:4105-18
Pappo, Alberto S; Furman, Wayne L; Schultz, Kris A et al. (2015) Rare Tumors in Children: Progress Through Collaboration. J Clin Oncol 33:3047-54
Boikos, Sosipatros A; Xekouki, Paraskevi; Fumagalli, Elena et al. (2015) Carney triad can be (rarely) associated with germline succinate dehydrogenase defects. Eur J Hum Genet :
Wan, Xiaolin; Yeung, Choh; Heske, Christine et al. (2015) IGF-1R Inhibition Activates a YES/SFK Bypass Resistance Pathway: Rational Basis for Co-Targeting IGF-1R and Yes/SFK Kinase in Rhabdomyosarcoma. Neoplasia 17:358-66
Arnaldez, Fernanda I; Helman, Lee J (2014) New strategies in ewing sarcoma: lost in translation? Clin Cancer Res 20:3050-6
Grohar, Patrick J; Segars, Laure E; Yeung, Choh et al. (2014) Dual targeting of EWS-FLI1 activity and the associated DNA damage response with trabectedin and SN38 synergistically inhibits Ewing sarcoma cell growth. Clin Cancer Res 20:1190-203

Showing the most recent 10 out of 31 publications