Synovial sarcoma is a soft tissue malignancy with a predilection for adolescents and young adults. Despite recent improvements in the understanding of its character and etiology, few therapeutic advances have been made. The mortality rate is high among the young population it affects. The low incidence of most subtypes of sarcoma, such as synovial sarcoma, makes disease-specific trials difficult to organize. The biological differences between sarcoma subtypes make inclusion of multiple types in general trials unsatisfactory as well.
Methods
A review of the literature regarding targetable pathways in synovial sarcoma was undertaken. A strategy has been devised to utilize available technologies in order to prioritize drug trial planning.
Results
Cell culture and xenograft research with synovial sarcoma cell lines have identified some critical pathways that may be targetable. Promising therapeutic strategies include newer cytotoxic chemotherapies, antiangiogenic agents, anti-IGF1R pathway agents, anti-Bcl-2/proapoptotic agents, and histone deacetylase complex inhibitors.
Conclusions
We propose to prioritize potential therapeutic strategies via preclinical testing of agents in a genetic mouse model of synovial sarcoma. Preclinical optimization of treatment regimens can guide the development of more focused patient trials.
References
1.
WeitzJ., AntonescuC.R., BrennanM.F.. Localized extremity soft tissue sarcoma: improved knowledge with unchanged survival over time.J Clin Oncol.2003; 21(14): 2719–2725.
2.
BrennanB., StevensM., KelseyA.. Synovial sarcoma in childhood and adolescence: a retrospective series of 77 patients registered by the Children's Cancer and Leukaemia Group between 1991 and 2006.Pediatr Blood Cancer.2010; 55(1): 85–90.
3.
GuadagnoloB.A., ZagarsG.K., BalloM.T.. Long-term outcomes for synovial sarcoma treated with conservation surgery and radiotherapy.Int J Radiat Oncol Biol Phys.2007; 69(4): 1173–1180.
4.
Turc-CarelC., Dal CinP., LimonJ.. Involvement of chromosome X in primary cytogenetic change in human neoplasia: nonrandom translocation in synovial sarcoma.Proc Natl Acad Sci U S A.1987; 84(7): 1981–1985.
5.
ClarkJ., RocquesP.J., CrewA.J.. Identification of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma.Nat Genet.1994; 7(4): 502–508.
6.
FligmanI., LonardoF., JhanwarS.C.. Molecular diagnosis of synovial sarcoma and characterization of a variant SYT-SSX2 fusion transcript.Am J Pathol.1995; 147(6): 1592–1599.
7.
CoindreJ.M., PelmusM., HosteinI.. Should molecular testing be required for diagnosing synovial sarcoma? A prospective study of 204 cases.Cancer.2003; 98(12): 2700–2707.
8.
Pérez-LosadaJ., PintadoB., Gutiérrez-Adá. The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice.Oncogene.2000; 19(20): 2413–2422.
9.
KellerC., ArenkielB.R., CoffinC.M.. Alveolar rhabdomyosarcomas in conditional Pax3: Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function.Genes Dev.2004; 18(21): 2614–2626.
10.
HaldarM., HancockJ.D., CoffinC.M.. A conditional mouse model of synovial sarcoma: insights into a myogenic origin.Cancer Cell.2007; 11(4): 375–388.
11.
VerweijJ., BakerL.H.. Future treatment of soft tissue sarcomas will be driven by histological subtype and molecular aberrations.Eur J Cancer.2010; 46(5): 863–868.
12.
Cancer Facts and Figures 2009.American Cancer Society: Atlanta, GA; 2009.
13.
SingerS., CorsonJ.M., GoninR.. Prognostic factors predictive of survival and local recurrence for extremity soft tissue sarcoma.Ann Surg.1994; 219(2): 165–173.
EilberF.C., BrennanM.F., EilberF.R.. Validation of the postoperative nomogram for 12-year sarcoma-specific mortality.Cancer.2004; 101(10): 2270–2275.
16.
MeyersP.A., SchwartzC.L., KrailoM.D.. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival. A report from the Children's Oncology Group.J Clin Oncol.2008; 26(4): 633–638.
17.
GrierH.E., KrailoM.D., TarbellN.J.. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone.N Engl J Med.2003; 348(8): 694–701.
18.
SleijferS., OualiM., van GlabbekeM.. Prognostic and predictive factors for outcome to first-line ifosfamide-containing chemotherapy for adult patients with advanced soft tissue sarcomas: an exploratory, retrospective analysis on large series from the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STB-SG).Eur J Cancer.2010; 46(1): 72–83.
19.
MinchomA., JonesR.L., FisherC.. Clinical benefit of secondline palliative chemotherapy in advanced soft-tissue sarcoma.Sarcoma.2010; 2010: 264360.
20.
CanterR.J., QinL.X., MakiR.G.. A synovial sarcoma-specific preoperative nomogram supports a survival benefit to ifosfamide-based chemotherapy and improves risk stratification for patients.Clin Cancer Res.2008; 14(24): 8191–8197.
21.
KaravasilisV., SeddonB.M., AshleyS.. Significant clinical benefit of first-line palliative chemotherapy in advanced soft-tissue sarcoma: retrospective analysis and identification of prognostic factors in 488 patients.Cancer.2008; 112(7): 1585–1591.
22.
EilberF.C., BrennanM.F., EilberF.R.. Chemotherapy is associated with improved survival in adult patients with primary extremity synovial sarcoma.Ann Surg.2007; 246(1): 105–113.
23.
PappoA.S., DevidasM., JenkinsJ.. Phase II trial of neoadjuvant vincristine, ifosfamide, and doxorubicin with granulocyte colony-stimulating factor support in children and adolescents with advanced-stage nonrhabdomyosarcomatous soft tissue sarcomas: a Pediatric Oncology Group Study.J Clin Oncol.2005; 23(18): 4031–4038.
24.
SpurrellE.L., FisherC., ThomasJ.M.. Prognostic factors in advanced synovial sarcoma: an analysis of 104 patients treated at the Royal Marsden Hospital.Ann Oncol.2005; 16(3): 437–444.
25.
FerrariA., GronchiA., CasanovaM.. Synovial sarcoma: a retrospective analysis of 271 patients of all ages treated at a single institution.Cancer.2004; 101(3): 627–634.
26.
NielsenO.S., JudsonI., van HoeselQ.. Effect of high-dose ifosfamide in advanced soft tissue sarcomas: a multicentre phase II study of the EORTC Soft Tissue and Bone Sarcoma Group.Eur J Cancer.2000; 36(1): 61–67.
27.
Van GlabbekeM., van OosteromA.T., OosterhuisJ.W.. Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated with anthracycline-containing first-line regimens. A European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study.J Clin Oncol.1999; 17(1): 150–157.
28.
WilsonR.E., WoodW.C., LernerH.L.. Doxorubicin chemotherapy in the treatment of soft-tissue sarcoma. Combined results of two randomized trials.Arch Surg.1986; 121(11): 1354–1359.
29.
PalmeriniE., StaalsE.L., AlberghiniM.. Synovial sarcoma: retrospective analysis of 250 patients treated at a single institution.Cancer.2009; 115(13): 2988–2998.
30.
ItalianoA., PenelN., RobinY.M.. Neo/adjuvant chemotherapy does not improve outcome in resected primary synovial sarcoma: a study of the French Sarcoma Group.Ann Oncol.2009; 20(3): 425–430.
31.
OkcuM.F., DespaS., ChoroszyM.. Synovial sarcoma in children and adolescents: thirty three years of experience with multimodal therapy.Med Pediatr Oncol.2001; 37(2): 90–96.
32.
KeizerH.J., CrowtherD., NielsenO.S.. EORTC Group Phase II Study of Oral Etoposide for Pretreated Soft Tissue Sarcoma.Sarcoma.1997; 1(2): 99–101.
33.
RosenG., ForscherC., LowenbraunS.. Synovial sarcoma. Uniform response of metastases to high dose ifosfamide.Cancer.1994; 73(10): 2506–2511.
34.
KampeC.E., RosenG., EilberF.. Synovial sarcoma. A study of intensive chemotherapy in 14 patients with localized disease.Cancer.1993; 72(7): 2161–2169.
35.
SchöffskiP., DumezH., WolterP.. Clinical impact of trabectedin (ecteinascidin-743) in advanced/metastatic soft tissue sarcoma.Expert Opin Pharmacother.2008; 9(9): 1609–1618.
36.
GargV., ZhangW., GidwaniP.. Preclinical analysis of tasidotin HCl in Ewing's sarcoma, rhabdomyosarcoma, synovial sarcoma, and osteosarcoma.Clin Cancer Res.2007; 13(18 pt 1): 5446–5454.
37.
FayetteJ., CoquardI.R., AlbertiL.. ET-743: a novel agent with activity in soft-tissue sarcomas.Curr Opin Oncol.2006; 18(4): 347–353.
38.
SleijferS., Ray-CoquardI., PapaiZ.. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043).J Clin Oncol.2009; 27(19): 3126–3132.
39.
BeneschM., WindelbergM., SausengW.. Compassionate use of bevacizumab (Avastin) in children and young adults with refractory or recurrent solid tumors.Ann Oncol.2008; 19(4): 807–813.
40.
BhargavaP., MarshallJ.L., DahutW.. A phase I and pharmacokinetic study of squalamine, a novel antiangiogenic agent, in patients with advanced cancers.Clin Cancer Res.2001; 7(12): 3912–3919.
41.
ZitoR.A.. Synovial sarcoma: an Australian series of 48 cases.Pathology.1984; 16(1): 45–52.
42.
FriedrichsN., KüchlerJ., EndlE.. Insulin-like growth factor-1 receptor acts as a growth regulator in synovial sarcoma.J Pathol.2008; 216(4): 428–439.
43.
DobashiY., SuzukiS., SatoE.. EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors.Mod Pathol.2009; 22(10): 1328–1340.
44.
Ray-CoquardI., Le CesneA., WhelanJ.S.. A phase II study of gefitinib for patients with advanced HER-1 expressing synovial sarcoma refractory to doxorubicin-containing regimens.Oncologist.2008; 13(4): 467–473.
45.
OlsenR.J., LydiattW.M., KoepsellS.A.. C-erb-B2 (HER2/ neu) expression in synovial sarcoma of the head and neck.Head Neck.2005; 27(10): 883–892.
46.
OlmosD., Postel-VinayS., MolifeL.R.. Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study.Lancet Oncol.2010; 11(2): 129–135.
47.
PengC.L., GuoW., JiT.. Sorafenib induces growth inhibition and apoptosis in human synovial sarcoma cells via inhibiting the RAF/MEK/ERK signaling pathway.Cancer Biol Ther.2009; 8(18): 1729–1736.
48.
BassoU., BrunelloA., BertuzziA.. Sorafenib is active on lung metastases from synovial sarcoma.Ann Oncol.2009; 20(2): 386–387.
49.
AlbrittonK.H., RandallR.L.. Prospects for targeted therapy of synovial sarcoma.J Pediatr Hematol Oncol.2005; 27(4): 219–222.
50.
MancusoT., MezzelaniA., RivaC.. Analysis of SYT-SSX fusion transcripts and bcl-2 expression and phosphorylation status in synovial sarcoma.Lab Invest.2000; 80(6): 805–813.
51.
JoynerD.E., AlbrittonK.H., BastarJ.D.. G3139 antisense oligonucleotide directed against antiapoptotic Bcl-2 enhances doxorubicin cytotoxicity in the FU-SY-1 synovial sarcoma cell line.J Orthop Res.2006; 24(3): 474–480.
52.
TomekS., KoestlerW., HorakP.. Trail-induced apoptosis and interaction with cytotoxic agents in soft tissue sarcoma cell lines.Eur J Cancer.2003; 39(9): 1318–1329.
53.
LubienieckaJ.M., de BruijnD.R., SuL.Histone deacetylase inhibitors reverse SS18-SSX-mediated polycomb silencing of the tumor suppressor early growth response 1 in synovial sarcoma.Cancer Res.2008; 68(11): 4303–4310.
54.
ItoT., OuchidaM., MorimotoY.. Significant growth suppression of synovial sarcomas by the histone deacetylase inhibitor FK228 in vitro and in vivo.Cancer Lett.2005; 224(2): 311–319.
55.
SuL., ChengH., SampaioA.V.. EGR1 reactivation by histone deacetylase inhibitors promotes synovial sarcoma cell death through the PTEN tumor suppressor.Oncogene.2010; 29(30): 4352–4361.
56.
NguyenA., SuL., CampbellB.. Synergism of heat shock protein 90 and histone deacetylase inhibitors in synovial sarcoma.Sarcoma.2009; 2009: 794901.
HaldarM., HedbergM.L., HockinM.F.. A CreER-based random induction strategy for modeling translocation-associated sarcomas in mice.Cancer Res.2009; 69(8): 3657–3664.
59.
HaldarM., HedbergM., TvrdikP.. Bioluminescence based in vivo monitoring of synovial sarcomas in a genetically engineered mouse model.Proc Am Assoc Cancer Res.2009. Abstract LB-67.
