Our work in IGF signaling in pediatric sarcomas led to a publication in the last year reporting on results of an international Phase II study evaluating a fully human IGFIR antibody in the treatment of Ewing?s sarcoma. We reported a 15% objective response rate, with several ongoing CRs. However, most responses were short lived, and obviously most patients did not respond. Based on these results, we have been focusing our attention of identifying biomarkers that would allow us to select patients who would likely respond to this treatment, and also to identify mechanisms of acquired resistance to this treatment. In collaboration with Dr. Paul Meltzer group, we have identified an RNA expression profile that correlates with response, and we are working to confirm whether this is true only for Ewing?s sarcoma patients or whether this signature is a general predictor of response to IGFIR disruption regardless of tumor type. Also, in collaboration with Dr. Liang Cao, we have isolated highly resistant rhabdomyosarcoma cell lines to IGFIR antibody treatment, and are beginning to characterize differences between the sensitive parental cell line and the 2 resistant cell lines. We will carry out full phospho-protein analysis of these cells as well as RNA expression analysis. Once we identify potential mechanisms of resistance, we plan to test combination treatment aimed at overcoming this resistance. We have already demonstrated that Akt becomes re-activated with acquired resistance, so we have reason to believe alternative kinase signaling pathways are involved thus giving some re-assurance that combination therapy targeting these alternative kinase signaling pathways may ultimately be beneficial in patient treatment strategies.We have continued to mine our data from an inducible shRNA screen in rhabdomyosarcoma cells in collaboration with Dr. Lou Staudt. Work on our first identified target, CRKL, is now almost ready to submit for publication. We have shown that CRKL signaling is critical for growth of most if not all rhabdomyosarcoma cells, and have also place this signaling within the SRC Family Kinase pathway. We have shown that phospho-CRKL is highly expressed in more than 90% of primary rhabdomyosarcoma patient tumors, and that disruption of downstream YES signaling inhibits growth of these tumors both in vitro and in vivo. These finding may lead to clinical re-evaluation of SRC family kinase inhibitors in the treatment of rhabdomyosarcoma tumors. Using this same screen, we have also identified Bub1b as crucial for rhabdomyosarcoma cell growth. We have also prepared a manuscript describing this finding that demonstrates that Bub1b activity is required for normal spindle assembly checkpoint in rhabdomyosarcoma cells and it appears to be regulated by the transcription factor FoxM1. We have completed a high through-put screen to identify inhibitors of the EWS-FLI-1 onco-protein and identified a lead compound, mithramycin that is a strong inhibitor. We have successfully developed GMP grade drug in collaboration with DTP, DCTD and have just opened a clinical study to treat patients with documented EWS-FLI-1 translocation positive Ewing?s tumors. We have also recently completed a whole genome siRNA screen in Ewing?s sarcoma cell lines, both to identify synergistic pathways interacting with mithramycin, and also to identify novel critical signaling pathways in Ewing?s sarcoma. We are currently analyzing this data and confirming hits identified. We have held 9 pediatric and wild-type GIST clinics and have now clearly identified a distinct subset of pediatric GIST patients whose tumors are characterized by a gastric location and SDH deficiency. We have now identified mutations in SDH A B C and D and it appears many if not all of these patients have germline mutaions in these genes with subsequent LOH in the tumor. We have also found that these tumors are characterized by global hypermethylation, suggesting that the SDH mutations are correlated with an inability to demethylate DNA. These finding have led to a clinical study soon to open utilizing a kinase inhibitor that has shown activity in other SDH mutant tumor types, specifically a type of kidney cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC006892-24
Application #
8554023
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
24
Fiscal Year
2012
Total Cost
$544,955
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Venkatramani, Rajkumar; Murray, Jeffrey; Helman, Lee et al. (2016) Risk-Based Therapy for Localized Osteosarcoma. Pediatr Blood Cancer 63:412-7
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
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
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
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 :
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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
Pappo, Alberto S; Vassal, Gilles; Crowley, John J et al. (2014) A phase 2 trial of R1507, a monoclonal antibody to the insulin-like growth factor-1 receptor (IGF-1R), in patients with recurrent or refractory rhabdomyosarcoma, osteosarcoma, synovial sarcoma, and other soft tissue sarcomas: results of a Sarcoma Alliance Cancer 120:2448-56
Arnaldez, Fernanda I; Helman, Lee J (2014) New strategies in ewing sarcoma: lost in translation? Clin Cancer Res 20:3050-6

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