Signaling Pathways that Determine Ewings Sarcoma Outcome
Principal Investigator: Jeffrey Toretsky
Abstract: DESCRIPTION (provided by applicant): The Ewing's sarcoma family of tumors (ESFTs) contains a characteristic translocation that joins the EWS gene on chromosome 22 to an ets family gene, FLI1, located on chromosome 11, t(11;22). This novel transcript is translated to become the EWS/FLI1 fusion protein, which functions as an oncogenic transcription factor. Another key component of transformation in ESFT is the insulin-like growth factor (IGF) signaling system. The IGF type I receptor (IGF-IR) is required for EWS/FLI1 transformation of fibroblasts. Insulin-Receptor Substrate-1 (IRS-1), the key substrate of IGF-IR is regulated by tyrosine phosphorylation and dephosphorylation. EWS/FLI1 transformation is associated with a basal reduction in tyrosine phosphorylation of IRS-1; until now, the phosphatase responsible for this has eluded discovery. We have identified a protein tyrosine phosphatase (PTP) PTPL1 (aka, PTP-BAS, human PTP1E, PTPN13, and later FAP-1) that we believe could be responsible for the connection between EWS/FLI1 and IGF-IR signaling. We therefore hypothesize that the EWS/FLI1 fusion protein functions as an oncogene by inducing PTPL1 expression. We further hypothesize that PTPL1 tips the balance of signaling in ESFT to favor tumor cell survival and transformation. In addition to IGF-IR, PTPL1 has been reported to modulate other key ESFT signaling pathways including Fas and p75NTR. Our specific aims will (i) identify how PTPL1 contributes to the ESFT malignant phenotype by evaluating growth, survival and tumorigenesis in ESFT clones with reduced PTPL1 levels, (ii) determine relevant PTPL1 clinical pathways and if PTPL1 pathway signatures in ESFT patient tumors affects clinical response to therapy and overall survival (training set, n=100, validation set n>100), and (iii) establish the nature of PTPL1 regulation by EWS/FLI1 in ESFT cell models. We are enthusiastically pursuing how the phosphatase PTPL1 regulates ESFT biology as the logical extension of our current IGF-I studies. One of the more important findings we describe in our Preliminary Data is that reduction of PTPL1 severely reduces ESFT colony formation in soft-agar. PTPL1 is a novel regulator of IGF-IR and Fas pathways. Clearly, if PTPL1 is validated as a supportive oncoprotein and the pathways modulated by PTPL1 are identified, patients with many other tumors that rely on IGF-IR signaling including breast carcinoma could benefit from our findings.
Funding Period: 2001-02-13 - 2010-04-30
more information: NIH RePORT
- Role of neuropeptide Y and dipeptidyl peptidase IV in regulation of Ewing's sarcoma growthJoanna Kitlinska
Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, DC 20057, USA
Adv Exp Med Biol 575:223-9. 2006
- Analysis of serum insulin growth factor-1 concentrations in localized osteosarcoma: a children's oncology group studyScott C Borinstein
Department of Pediatrics, Division of Pediatric Hematology Oncology, Vanderbilt University, Nashville, TN, Tennessee
Pediatr Blood Cancer 61:749-52. 2014..001). These findings show that older patients have higher concentrations of free IGF-1. None of IGF-1, IGFBP-2, nor IGFBP-3 concentrations were associated with event-free nor overall survival...
- Valosin containing protein (VCP/p97) is a novel substrate for the protein tyrosine phosphatase PTPL1Ogan D Abaan
Departments of Oncology and Pediatrics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
Exp Cell Res 319:1-11. 2013..Given our observation that PTPL1 catalytic activity is important for cell transformation, our results may also suggest that VCP regulation by PTPL1 might be important for tumorigenesis...
- Investigation of the insulin-like growth factor-1 signaling pathway in localized Ewing sarcoma: a report from the Children's Oncology GroupScott C Borinstein
Department of Pediatrics, Division of Pediatric Hematology Oncology, Vanderbilt University, Nashville, Tennessee 20057 1469, USA
Cancer 117:4966-76. 2011..Retrospective studies have suggested that levels of IGF-1 and IGF binding protein 3 (IGFBP-3) are correlated with the outcome of patients with ES...
- Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathwayElspeth M Beauchamp
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
J Clin Invest 121:148-60. 2011..These results warrant the clinical investigation of ATO for tumors with activated Hh/GLI signaling, in particular patients who develop resistance to current therapies targeting the Hh pathway upstream of GLI...
- A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcomaHayriye V Erkizan
Georgetown University, Lombardi Comprehensive Cancer Center, Department of Oncology, Washington, DC, USA
Nat Med 15:750-6. 2009....
- GLI1 is a direct transcriptional target of EWS-FLI1 oncoproteinElspeth Beauchamp
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D C 20057, USA
J Biol Chem 284:9074-82. 2009..Our results establish GLI1 as a direct transcriptional target of EWS-FLI1 and suggest a potential role for GLI1 in ESFT tumorigenesis...
- The role of IGF-1R in pediatric malignanciesSu Young Kim
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
Oncologist 14:83-91. 2009..These findings have led to the development of a host of IGF-1R signaling modulators that are currently being tested in clinical trials. This review explores the role of IGF-1R in a range of childhood malignancies...
- Wnt10b induces chemotaxis of osteosarcoma and correlates with reduced survivalKevin Chen
Georgetown University School of Medicine, Washington, District of Columbia, USA
Pediatr Blood Cancer 51:349-55. 2008..Wnt signaling controls normal bone formation during embryogenesis and homeostasis in adult organisms, thus we evaluated Wnt signaling in OS...
- PTPL1: a large phosphatase with a split personalityOgan D Abaan
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
Cancer Metastasis Rev 27:205-14. 2008..Understanding the nature of molecular complexes containing PTPL1, its interaction partners, substrates, regulation and subcellular localization are key to unraveling the complex personality of this protein phosphatase...
- Wnt-3a and Dickkopf-1 stimulate neurite outgrowth in Ewing tumor cells via a Frizzled3- and c-Jun N-terminal kinase-dependent mechanismYoshimi Endo
National Cancer Institute, Bldg 37, Room 2042, 37 Convent Drive, MSC 4256, Bethesda, MD 20892 4256, USA
Mol Cell Biol 28:2368-79. 2008..Our data demonstrate that Fzd3, Dvl, and JNK activity mediate Wnt-dependent neurite outgrowth and that ESFT cell lines will be useful experimental models for the study of Wnt-dependent neurite extension...
- Single-chain antibodies to the EWS NH(2) terminus structurally discriminate between intact and chimeric EWS in Ewing's sarcoma and interfere with the transcriptional activity of EWS in vivoDave N T Aryee
Children s Cancer Research Institute, Vienna, Austria
Cancer Res 66:9862-9. 2006..Thus, we have generated a tool that will prove useful to specifically differentiate between normal and rearranged EWS in functional studies...
- Magnesium, essential for base excision repair enzymes, inhibits substrate binding of N-methylpurine-DNA glycosylaseSanjay Adhikari
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
J Biol Chem 281:29525-32. 2006....
- Oncoprotein EWS-FLI1 activity is enhanced by RNA helicase AJeffrey A Toretsky
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA
Cancer Res 66:5574-81. 2006..These results suggest that RHA interacts with EWS-FLI1 as a transcriptional cofactor to enhance its function...
- Pharmacokinetic modeling optimizes inhibition of the 'undruggable' EWS-FLI1 transcription factor in Ewing SarcomaSung Hyeok Hong
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
Oncotarget 5:338-50. 2014..Thus, (S)-YK-4-279 as a small molecule drug is ready for continued development towards a first-in-human, first-in-class, clinical trial. ..