the ewing sarcoma family of tumors , including ewing sarcoma and the more differentiated counterpart , primitive neuroectodermal tumor , are the second most common primary malignancies of bone in childhood and adolescence   but can also occur in the soft tissues . systemic chemotherapy is aimed at treating known or micrometastatic disease as well as improving local control of the cancer . the intergroup ewing sarcoma study ( int-0091 ) demonstrated that a regimen of alternating cycles of vincristine - doxorubicin - cyclophosphamide and ifosfamide - etoposide was superior to vincristine - doxorubicin - cyclophosphamide alone , leading to a 5-year event - free survival of 69% versus 54% in the standard arm . more recently , a randomized trial evaluated dose intensification by interval compression ( administering cycles every 2 weeks ) and found that approach to be superior , with a 4-year event - free survival of 76% in the dose - dense arm compared with 65% in the standard 3-week chemotherapy arm . this is now considered by pediatric oncologists to be the standard chemotherapy regimen for patients with ewing sarcoma , although it has not been adequately evaluated in patients older than 18 . although there have been improvements in the outcome for patients with localized disease , the outcome for patients with metastatic disease and for those who relapse is poor , with survival rates of 20% for those with metastases   and 10 - 20% following a recurrence . therefore , in addition to standard chemotherapeutics , future clinical trials will need to incorporate novel biologic agents in an effort to achieve further survival improvements . the insulin - like growth factor ( igf ) system has two principal ligands : igf-1 and igf-2 . these ligands mediate their stimulatory effects via the igf-1 receptor ( igf-1r ) , a transmembrane receptor tyrosine kinase . under normal physiologic circumstances , igf-1 and igf-2 are stimulated by growth hormone and function in a negative feedback loop to control growth hormone release . the insulin growth factor - binding proteins ( igfbps ) regulate the available free igf proteins available for igf-1r activation [ 7 - 9 ] . upon ligand binding , autophosphorylation of the igf-1r tyrosine kinase initiates activation of the mitogen - activated protein kinase and phosphoinositide 3-kinase / akt pathways , leading to proliferation , survival [ 10 - 13 ] , and enhanced angiogenesis via downstream induction of vascular endothelial growth factor . the igf-2 receptor is a monomeric transmembrane protein with no kinase activity and has not been shown to play a role in the development of ewing sarcoma . the pathway also has a role in promoting neuronal survival , myelination , and postnatal mammary development and lactation . in addition , metabolic pathways use the igf system to help integrate signals from nutrition and stress in order to shift appropriately between anabolic and catabolic states . high circulating levels of igf-1 have been associated with the risk of developing prostate , breast , or colorectal cancer . in addition , igf-1r expression is known to be necessary for cellular transformation and for signal transduction pathways stimulated by the igf-1r to enhance tumor cell growth and proliferation . furthermore , igf-1r gene expression is regulated by a number of tumor suppressors , including wt1 , brca1 , and p53 . there are also data to suggest that signaling through the igf-1r enhances resistance to cytotoxic chemotherapy . therefore , inhibition of the igf-1r is a potentially important therapeutic target against a variety of tumors . the insulin - like growth factor ( igf ) system has two principal ligands : igf-1 and igf-2 . these ligands mediate their stimulatory effects via the igf-1 receptor ( igf-1r ) , a transmembrane receptor tyrosine kinase . under normal physiologic circumstances , igf-1 and igf-2 are stimulated by growth hormone and function in a negative feedback loop to control growth hormone release . the insulin growth factor - binding proteins ( igfbps ) regulate the available free igf proteins available for igf-1r activation [ 7 - 9 ] . upon ligand binding , autophosphorylation of the igf-1r tyrosine kinase initiates activation of the mitogen - activated protein kinase and phosphoinositide 3-kinase / akt pathways , leading to proliferation , survival [ 10 - 13 ] , and enhanced angiogenesis via downstream induction of vascular endothelial growth factor . the igf-2 receptor is a monomeric transmembrane protein with no kinase activity and has not been shown to play a role in the development of ewing sarcoma . the pathway also has a role in promoting neuronal survival , myelination , and postnatal mammary development and lactation . in addition , metabolic pathways use the igf system to help integrate signals from nutrition and stress in order to shift appropriately between anabolic and catabolic states . high circulating levels of igf-1 have been associated with the risk of developing prostate , breast , or colorectal cancer . in addition , igf-1r expression is known to be necessary for cellular transformation and for signal transduction pathways stimulated by the igf-1r to enhance tumor cell growth and proliferation . furthermore , igf-1r gene expression is regulated by a number of tumor suppressors , including wt1 , brca1 , and p53 . there are also data to suggest that signaling through the igf-1r enhances resistance to cytotoxic chemotherapy . therefore , inhibition of the igf-1r is a potentially important therapeutic target against a variety of tumors . the igf signaling pathway and , in particular , the igf-1r play a major role in the development and proliferation of ewing sarcoma . early studies documented the major autocrine role of the igf-1 and igf-1r pathways in ewing sarcoma , and expression of igf-1r has been shown to be a requirement for ews / fli-1 transformation in fibroblasts . a variety of approaches in vitro and in animal models have been undertaken to disrupt the igf-1r signaling pathway , including the development of small - molecule tyrosine kinase inhibitors ( tkis ) and anti - igf-1r antibodies . in preclinical testing , there was an initial difficulty in obtaining specific small - molecule kinase inhibitors of the igf-1r due to a very - high - sequence homology with kinase and atp - binding domains of the insulin receptor . after initial attempts , the tki nvp - aew541 was shown to have a 27-fold increased selectivity for the igf-1r over the insulin receptor . this small - molecule tki has shown promise in preclinical models , where inhibition of migration , metastasis , and angiogenesis was seen in vitro and a significant reduction in tumor growth was seen in xenograft models . further elucidation of the metabolic alterations related to the use of tkis will be necessary prior to entry into clinical trials . more recently , targeted antibodies have been shown not only to disrupt ligand - receptor binding , but also to decrease surface igf-1r expression by internalization and degradation of the antibody - bound receptor . human monoclonal anti - igf-1r antibodies have been produced by many pharmaceutical companies : imc - a12 ( imclone systems , new york , ny , usa ) , amg 479 ( amgen , thousand oaks , ca , usa ) , r1507 ( roche , basel , switzerland ) , cp-751,871 ( pfizer inc , new york , ny , usa ) , sch717454 ( schering - plough corporation , kenilworth , nj , usa ) , mk-0646 ( merck ) , and ave1642 ( immunogen , inc , waltham , ma , usa / sanofi - aventis , paris , france ) . these antibodies have been tested in preclinical settings and ongoing early - phase adult studies [ 30,32 - 36 ] . the sch717454 igf-1r antibody was tested against a panel of pediatric tumors by the pediatric preclinical testing program , a comprehensive program to systematically evaluate new agents against childhood solid tumor and leukemia models . intermediate or high activity was demonstrated in two of five ewing sarcoma xenografts , including one complete response . in addition , the imc - a12 antibody is currently under investigation in a phase ii children 's oncology group ( cog ) trial , with a stratum available for patients with ewing sarcoma . through the sarcoma alliance for research through collaboration ( sarc ) , the r1507 antibody has been tested in two phase i studies in adults . the first study assessed the administration of the antibody on a 3-week basis and was well tolerated , without any dose - limiting toxicity or serious adverse events ; 11 of 26 patients were found to have stable disease , although none had ewing sarcoma . in the second study , four of eight heavily pretreated patients with ewing sarcoma demonstrated stable disease , with two of eight patients demonstrating durable partial responses . the igf signaling pathway and , in particular , the igf-1r play a major role in the development and proliferation of ewing sarcoma . early studies documented the major autocrine role of the igf-1 and igf-1r pathways in ewing sarcoma , and expression of igf-1r has been shown to be a requirement for ews / fli-1 transformation in fibroblasts . a variety of approaches in vitro and in animal models have been undertaken to disrupt the igf-1r signaling pathway , including the development of small - molecule tyrosine kinase inhibitors ( tkis ) and anti - igf-1r antibodies . in preclinical testing , there was an initial difficulty in obtaining specific small - molecule kinase inhibitors of the igf-1r due to a very - high - sequence homology with kinase and atp - binding domains of the insulin receptor . after initial attempts , the tki nvp - aew541 was shown to have a 27-fold increased selectivity for the igf-1r over the insulin receptor . this small - molecule tki has shown promise in preclinical models , where inhibition of migration , metastasis , and angiogenesis was seen in vitro and a significant reduction in tumor growth was seen in xenograft models . further elucidation of the metabolic alterations related to the use of tkis will be necessary prior to entry into clinical trials . more recently , targeted antibodies have been shown not only to disrupt ligand - receptor binding , but also to decrease surface igf-1r expression by internalization and degradation of the antibody - bound receptor . human monoclonal anti - igf-1r antibodies have been produced by many pharmaceutical companies : imc - a12 ( imclone systems , new york , ny , usa ) , amg 479 ( amgen , thousand oaks , ca , usa ) , r1507 ( roche , basel , switzerland ) , cp-751,871 ( pfizer inc , new york , ny , usa ) , sch717454 ( schering - plough corporation , kenilworth , nj , usa ) , mk-0646 ( merck ) , and ave1642 ( immunogen , inc , waltham , ma , usa / sanofi - aventis , paris , france ) . these antibodies have been tested in preclinical settings and ongoing early - phase adult studies [ 30,32 - 36 ] . the sch717454 igf-1r antibody was tested against a panel of pediatric tumors by the pediatric preclinical testing program , a comprehensive program to systematically evaluate new agents against childhood solid tumor and leukemia models . intermediate or high activity was demonstrated in two of five ewing sarcoma xenografts , including one complete response . in addition , the imc - a12 antibody is currently under investigation in a phase ii children 's oncology group ( cog ) trial , with a stratum available for patients with ewing sarcoma . through the sarcoma alliance for research through collaboration ( sarc ) , the r1507 antibody has been tested in two phase i studies in adults . the first study assessed the administration of the antibody on a 3-week basis and was well tolerated , without any dose - limiting toxicity or serious adverse events ; 11 of 26 patients were found to have stable disease , although none had ewing sarcoma . in the second study , four of eight heavily pretreated patients with ewing sarcoma demonstrated stable disease , with two of eight patients demonstrating durable partial responses . human monoclonal antibody therapy directed against the igf-1r holds great promise for improving the prognosis for children , adolescents , and adults with ewing sarcoma . the recent data demonstrating responses in heavily pretreated patients with refractory ewing sarcoma bring a wave of excitement to move these therapies to the forefront . clinical trials are under way to assess the feasibility and efficacy of combining anti - igf-1r therapy with multiagent chemotherapy . over the next 5 years , feasibility testing will be completed , and if successful , phase iii studies will assess whether the addition of these new agents will result in therapeutic improvements .
the insulin - like growth factor ( igf ) signal transduction pathway appears to play a key role in the development and proliferation of the ewing sarcoma family of tumors . 
 integration of anti - igf-1 receptor therapy into the standard treatment for these patients is a novel approach that will likely be incorporated into future treatment to determine whether such agents will improve the outcome for patients with this malignancy .