Skip to main content
Article thumbnail
Location of Repository

MAPK/ERK Signaling in Osteosarcomas, Ewing Sarcomas and Chondrosarcomas: Therapeutic Implications and Future Directions

By Chandhanarat Chandhanayingyong, Yuhree Kim, J. Robert Staples, Cody Hahn and Francis Youngin Lee

Abstract

The introduction of cytotoxic chemotherapeutic drugs in the 1970's improved the survival rate of patients with bone sarcomas and allowed limb salvage surgeries. However, since the turn of the century, survival data has plateaued for a subset of metastatic, nonresponding osteo, and/or Ewing sarcomas. In addition, most high-grade chondrosarcoma does not respond to current chemotherapy. With an increased understanding of molecular pathways governing oncogenesis, modern targeted therapy regimens may enhance the efficacy of current therapeutic modalities. Mitogen-Activated Protein Kinases (MAPK)/Extracellular-Signal-Regulated Kinases (ERK) are key regulators of oncogenic phenotypes such as proliferation, invasion, angiogenesis, and inflammatory responses; which are the hallmarks of cancer. Consequently, MAPK/ERK inhibitors have emerged as promising therapeutic targets for certain types of cancers, but there have been sparse reports in bone sarcomas. Scattered papers suggest that MAPK targeting inhibits proliferation, local invasiveness, metastasis, and drug resistance in bone sarcomas. A recent clinical trial showed some clinical benefits in patients with unresectable or metastatic osteosarcomas following MAPK/ERK targeting therapy. Despite in vitro proof of therapeutic concept, there are no sufficient in vivo or clinical data available for Ewing sarcomas or chondrosarcomas. Further experimental and clinical trials are awaited in order to bring MAPK targeting into a clinical arena

Topics: Review Article
Publisher: Hindawi Publishing Corporation
OAI identifier: oai:pubmedcentral.nih.gov:3345255
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles

    Citations

    1. (2011). A MEK-independent role for CRAF in mitosis and tumor progression,”
    2. (2010). A phase I study of weekly R1507, a human monoclonal antibody insulin-like growth factor-I receptor antagonist, in patients with advanced solid tumors,” Clinical Cancer Research,v o l .1 6 ,n o .8 ,p p .
    3. (2008). A phase II study of imatinib mesylate in children with refractory or relapsed solid tumors: a children’s oncology group study,” Pediatric Blood and Cancer,
    4. (2011). A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study,” Annals of Oncology,
    5. (2011). a u he ta l . ,“ P h a s eI Is t u d yo f themitogen-activatedproteinkinase1/2inhibitorselumetinib in patients with advanced hepatocellular carcinoma,”
    6. (2009). A.Abdeen,A.J.Chou,J.H.Healeyetal.,“Correlationbetween clinical outcome and growth factor pathway expression in osteogenic sarcoma,”
    7. (2011). Actin and ERK1/2-CEBPβ signaling mediates phagocytosis-induced innate immune response of osteoprogenitor cells,”
    8. (2008). Activation of the RAF/mitogen-activated protein/extracellular signal-regulated kinase Kinase/extracellular signal-regulated kinase pathway mediates apoptosis induced by chelerythrine in osteosarcoma,”
    9. (2008). BMP-2 increases migration of human chondrosarcoma cells via PI3K/Akt pathway,”
    10. (2009). C h e n ,Y .Y .W e i ,H .T .C h e ne ta l . ,“ O s t e o p o n t i n increases migration and MMP-9 up-regulation via αvβ3 integrin,FAK,ERK,andNF-κB-dependentpathwayinhuman chondrosarcoma cells,”
    11. (2004). Cerisano et al., “Contribution of MEK/MAPK and PI3-K signaling pathway to the malignant behavior of Ewing’s sarcoma cells: therapeutic prospects,”
    12. (1999). Chondrosarcoma of bone: an assessment of outcome,”
    13. (2005). Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPKSarcoma 7
    14. (2009). Dahlin’s Bone Tumors: General Aspects and
    15. E.AndersKolb,R.Gorlick,P.J.Houghtonetal.,“Initialtesting (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the pediatric preclinical testing program,” PediatricBloodandCancer,vol.50,no.6,pp.1190–1197,2008.
    16. (2009). Efficacy and safety of sorafenib in a subset of patients with advanced soft tissue sarcoma from a Phase II randomized discontinuation trial,”
    17. (1992). Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours,”
    18. (2011). Hallmarks of cancer: the next generation,”
    19. (2009). i r a b e l l o ,R .J .T r o i s i ,a n dS .A .S a v a g e ,“ O s t e o s a r c o m a incidence and survival rates from 1973 to 2004: data from the surveillance, epidemiology, and end results program,”
    20. (2007). Increased β1 integrin is associated with decreased survival in invasive breast cancer,”
    21. increases MMP-2 expression and cell motility in human chondrosarcoma cells,”
    22. (2010). Initial testing (stage 1) of the multi-targeted kinase inhibitor sorafenib by the pediatric preclinical testing program,”
    23. (1994). Insulin-like growth factor I regulation of swarm rat chondrosarcoma chondrocytes in culture,”
    24. (2000). Interference with the constitutive activation of ERK1 and ERK2 impairs EWS/FLI-1-dependent transformation,”
    25. (2009). K i m ,J .A .T o r e t s k y ,D .S c h e r ,a n dL .J .H e l m a n ,“ T h er o l e of IGF-1R in pediatric malignancies,”
    26. (2009). M a k i ,D .R .D ’ A d a m o ,M .L .K e o h a ne ta l . ,“ P h a s eI I study of sorafenib in patients with metastatic or recurrent sarcomas,”
    27. (2004). M a n k i n ,F .J .H o r n i c e k ,A .E .R o s e n b e r g ,D .C .H a r m o n
    28. (2007). MAP kinase signalling pathways in cancer,”
    29. (2007). MAPKs: function, regulation, role in cancer and therapeutic targeting,”
    30. (2007). Molecular diagnosis of Ewing family tumors too many fusions...?”
    31. (2009). Morphoproteomic confirmation of constitutively activated mTOR, ERK, and NF-kappaB pathways in Ewing family of tumors,”
    32. (2009). Patnaik et al., “Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1,”
    33. (2011). Phase I and pharmacokinetic study of sunitinib in pediatric patients with8 Sarcoma refractory solid tumors: a children’s oncology group study,”
    34. (2009). Phase I study of sorafenibinchildrenwithrefractorysolidtumors:aChildren’s Oncology Group Phase I Consortium trial,”
    35. (2007). Preclinical in vivostudyofnewinsulin-likegrowthfactor-Ireceptor-specific inhibitor in Ewing’s sarcoma,”
    36. (2006). Prognostic associations of activated mitogen-activated protein kinase and Akt pathways in glioblastoma,”
    37. (2006). Prognostic factors for osteosarcoma of the extremity trerated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution,”
    38. (2011). Prognostic impact of phosphorylated mitogen-activated protein kinase expression in patients with metastatic gastric cancer,”
    39. (2008). Provero et al., “IGF1 is a common target gene of Ewing’s sarcoma fusion proteins in mesenchymal progenitor cells,”
    40. (2010). R1507, a fully human monoclonal antibody targeting IGF-1R, is effective alone and in combination with rapamycin in inhibiting growth of osteosarcoma xenografts,”
    41. (2010). randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens,”
    42. (2011). Ras/Raf/MEK/ERK pathway is associated with lung metastasis of osteosarcoma in an orthotopic mouse model,”
    43. (2009). Ras/Raf1/MAPK pathway mediates response to tamoxifen but not chemotherapy in breast cancer patients,”
    44. (2005). S e a l e s ,G .A .J u r a d o ,B .A .B r u n s o n ,J .K .W a k e fi e l d
    45. (2010). Safety, pharmacokinetics,andpreliminaryactivityoftheanti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing’s sarcoma: a phase 1 expansion cohort study,” The Lancet Oncology,
    46. (2009). Simultaneous inhibition of mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways augment the sensitivity to actinomycin D in Ewing sarcoma,”
    47. (2005). siRNA mediated inhibition of MMP-1 reduces invasive potential of a human chondrosarcoma cell line,”
    48. Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrinpathways,”MolecularCancer,vol.8,articleno.118,2009.
    49. Sorafenib induces growth inhibition and apoptosis of human chondrosarcoma cells by blocking the RAF/ERK/MEK pathway,” JournalofSurgicalOncology,vol.102,no.7,pp.821–826,2010.
    50. (2007). Specific inhibitor of MEK-mediated cross-talk between ERK and p38 MAPK during differentiation of human osteosarcoma cells,”
    51. (2008). Specific tyrosine kinase inhibitors regulate human osteosarcoma cells
    52. (2009). Stromal cell-derived factor-1 increase αvβ3 integrin expression and invasion in human chondrosarcoma cells,”
    53. (2009). Stromal cell-derived factor-1/CXCR4 enhanced motility of human osteosarcoma cells involves MEK1/2, ERK and NF-κB-dependent pathways,”
    54. (2011). Surmounting chemotherapy and radioresistance in chondrosarcoma: molecular mechanisms and therapeutic targets,”
    55. (1997). T o r e t s k y ,T .K a l e b i c ,V .B l a k e s l e y ,D .L e R o i t h ,a n d
    56. (2011). Targeted morphoproteomic profiling of Ewing’s sarcoma treated with insulin-like growth factor 1 receptor (IGF1R) inhibitors: response/resistance signatures,”
    57. (2011). Targeted therapy of Ewing’s sarcoma,”
    58. (2010). Targeting extracellular signal-regulatedkinase(ERK)signalinghastherapeuticimplications for inflammatory osteolysis,”
    59. (2011). Targeting inflammatory kinase as an adjuvant treatment for osteosarcomas,”
    60. (2009). Targeting the RAF-MEK-ERK pathway in cancer therapy,”
    61. TGF-β1 increases motility and αvβ3 integrin up-regulation via PI3K, Akt and NF-κB-dependent pathway in human chondrosarcoma cells,” BiochemicalPharmacology,vol.75,no.6,pp.1292–1301,2008.
    62. (1986). The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity,”
    63. (2010). The firstin-human study of the hydrogen sulfate (hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer,”
    64. (2000). The hallmarks of cancer,”
    65. (2009). The insulin-like growth factor1 receptor-targeting antibody, CP-751,871, suppresses tumorderived VEGF and synergizes with rapamycin in models of childhood sarcoma,”
    66. (2005). The MAPK-AP-1/-Runx2 signalling axes are implicated in chondrosarcomapathobiologyeitherindependentlyorviaupregulation of
    67. (2011). The role of MAPK pathway in bone and soft tissue tumors,”
    68. (2012). The warburg effect
    69. (2005). uan,C.M.Dutt on,andS.P .Scully ,“RN Aimediat edMMP -1silencinginhibitshumanchondrosarcomainvasion,”Journal of

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.