Based upon results of both our clinical trial of IGFIR antibody treatment in Ewing's sarcoma and rhabdomyosarcoma patients showing rapid development of acquired resistance among responsive patients with most responding patients developing progressive disease within 5 months of treatment, we have focused on studying mechanisms of resistance in the laboratory. We have already published data showing that rhabdomyosarcoma mouse xenografts develop similar resistance to IGFIR antibody treatment within 60 days. We have now demonstrated that at least 2 mechanisms of resistance are observed. First we found the Src family kinase (SFK) member YES is rapidly activated in rhabdomyosarcoma cell lines and xenografts after exposure to IGFIR antibody. Second we showed that YES is highly expressed in a subset of rhabdomyosarcoma human tumors. Third we showed that simultaneous blockade of SFK with dasatinib or saracatinib leads to enhanced tumor inhibition when combined with IGFIR blockade. This data was recently submitted for publication. We would like to pursue a potential clinical trial testing the combination of SFK and IGFIR inhibition in recurrent rhabdomyosarcoma. We have also established cell lines resistant to IGFIR antibody treatment and used these cell lines to look for phospho-proteomic differences between the resistant and sensitive parental cell lines. We identified PDGFR-beta as being markedly up-regulated in the resistant cell line and are currently exploring whether concomitant inhibition of PDGFR and IGFIR leads to enhanced cell killing. . We have continued to mine our data from an inducible shRNA screen in rhabdomyosarcoma cells in collaboration with Dr. Lou Staudt. We have identified a non-receptor tyrosine kinase, TNK2 as a necessary signaling molecule for rhabdomyosarcoma growth. We have obtained tool compounds that appear to specifically inhibit this kinase to allow us to further study the role of TNK2 in rhabdomyosarcomas and dissect the upstream and downstream partners of this kinase. We have also completed kinome siRNA screen in Ewing's sarcoma cells in collaboration with Natasha Caplen. We have identified 11 candidate kinases that appear to be necessary for Ewing's sarcoma cell growth including Aurora kinase B, Chek1, and Polo-like kinase. Of further interest, the importance of several of these kinases were confirmed in an independent high-throughput compound screen against 63 human sarcoma cell lines including 19 Ewing's sarcoma cell lines, in collaboration with Dr. Bev Teicher's group. This screen independently demonstrated that Ewing's sarcoma cells were particularly sensitive to inhibitors of Aurora kinase, Chek1/2, and Polo-like kinase. We are currently testing these inhibitors in xenograft studies. We have now identified additional mutations in SDH A B C and D in pediatric GIST patients and it appears many if not all of these patients have germline mutaions in these genes with subsequent LOH in the tumor. We further confirmed that these tumors are characterized by global hypermethylation, suggesting that the SDH mutations are correlated with an inability to demethylate DNA. These finding have recently been published in Cancer Discovery.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC006892-25
Application #
8763686
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
25
Fiscal Year
2013
Total Cost
$396,230
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
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

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