Antiangiogenic approaches for the treatment of advanced synovial sarcomas

Abstract

Purpose of review

Synovial sarcomas are regarded as chemosensitive tumors compared to other types of soft tissue sarcomas, however, prognosis for advanced refractory disease remains poor. In light of the vascular nature of sarcomas, current molecularly targeted therapies aim at an antiangiogenic approach to management of this disease.

Recent findings

Recent studies with oral vascular endothelial growth factor receptor (VEGFR) inhibitors such as sunitinib, sorafenib and cediranib have shown disease stabilization in patients with advanced synovial sarcoma. Forty-nine percent of patients with synovial sarcoma on the phase II trial of pazopanib had no evidence of disease progression at 12 weeks.

Summary

The overall impact of chemotherapy on survival has been minimal in advanced soft tissue sarcomas. Anti-VEGF therapies have resulted in improved outcomes for patients with various solid tumors, and have shown preliminary evidence of activity in synovial sarcomas. Combinations of anti-VEGF therapies with agents targeting other pathways dysregulated in sarcomas have the potential to improve the outcome of this difficult-to-treat disease.

INTRODUCTION

Synovial sarcomas account for approximately 5–10% of all soft tissue sarcomas. These are high-grade neoplasms with epithelial differentiation and no histologic resemblance to synovial tissue for which they were originally named. Three main histologic subtypes of synovial sarcomas have been described: biphasic, monophasic, and poorly differentiated. The more common biphasic subtype demonstrates both an epithelial as well as spindle cell component whereas monophasic forms are composed entirely of spindle cells. Synovial sarcomas are characterized by a chromosomal translocation t(x;18) (p11.2;q11.2) resulting in a fusion product of the SYT gene on chromosome 18 with SSX1, SSX2, or SSX4 on the X chromosome [1], This translocation is found in over 90% of synovial sarcomas; the biphasic variant typically carries the SYT-SSX1 translocation, whereas the monophasic variant carries either the SYT-SSX1 or SYT-SSX2 translocation.

Synovial sarcomas can develop at any anatomic site, but have a predilection for the extremities, accounting for approximately 60% of all primary tumors. Other common sites of disease include the trunk, retroperitoneum, and head and neck region [2]. Primary treatment for localized disease is surgical resection, followed by radiotherapy if negative margins are unattainable or if the lesion is greater than 5 cm. The three most important prognostic variables for synovial sarcomas are grade, size, and the location of the tumor [3,4]. Tumors arising in the trunk have a worse prognosis compared to tumors arising in the extremity. Despite optimal locoregional control, synovial sarcomas are associated with a high risk of recurrence, estimated to be 12% locally and 39% at distant sites at 5 years [5], with a median survival of 22 months from onset of metastatic disease [6].

Cytotoxic chemotherapy

Synovial sarcomas are among the more chemoresponsive subtypes of soft tissue sarcomas. Anthracycline-based chemotherapies were the first class of chemotherapy agents to demonstrate efficacy in soft tissue sarcomas. A meta-analysis of 14 randomized trials using doxorubicin alone or in combination with other chemotherapeutic agents in 1568 patients with soft tissue sarcomas demonstrated response rates of 10–30%, with disease-free survival of 55 versus 45% at 10 years, for doxorubicin-containing combinations as compared with doxorubicin alone. However, no statistically significant difference in overall survival was observed between the cohorts [7]. A phase III study of patients with advanced soft tissue sarcomas comparing doxorubicin alone versus doxorubicin-ifosfamide versus the combination of mitomycin, doxorubicin, and cisplatin revealed a higher regression rate for the combination of doxorubicin and ifosfamide (34%; total 88 patients) compared with doxorubicin alone (20%; total 90 patients), or the combination of mitomycin, doxorubicin, and cisplatin (32%; total 84 patients). Combination therapy, however, was associated with additional myelosuppresion, and did not produce statistically significant differences in overall survival. Of the 20 patients with synovial sarcoma treated in the study, half demonstrated tumor regression following chemotherapy [8]. A follow-up study demonstrated objective responses in 13 patients with advanced synovial sarcoma treated with high-dose ifosfamide alone, with four patients achieving a complete response [9].

Antiangiogenic therapy

Chemotherapy for metastatic soft tissue sarcomas has for the most part failed to improve overall survival. More recent approaches using targeted therapy have focused on antiangiogenic agents. Angiogenesis is crucial for the growth and dissemination of soft tissue sarcomas, as with some other solid tumors, such as colorectal or lung cancer. Vascular endothelial growth factor (VEGF) is a crucial angiogenic factor that has been implicated in tumor blood vessel formation and disease progression. In mammals, five members of the VEGF family have been identified: VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placenta growth factor. Alternative splicing of these factors give rise to additional isoforms with markedly different biologic activities [10]. Interaction of these factors with their respective receptors results in activation of tyrosine kinase-mediated signaling cascades that promote endothelial cell growth from pre-existing vasculature. Two high-affinity VEGF transmembrane receptors (VEGFRs) with associated tyrosine kinase activity have been identified on human vascular endothelium, VEGFR-1 (also known as feline sarcoma oncogene-like tyrosine kinase 1 or Flt-1) and VEGFR-2 (also known as kinase insert domain-containing receptor, KDR or fetal liver kinase-1) [11]. A third receptor, VEGFR-3 (also known as Flt4) has been implicated in lymphatic-endothelial cell development and function [12]. VEGFR-2 has been shown to be the more potent mediator of postembryonic vascular formation of the three receptors, producing increased microvascular permeability and perpetuation of endothelial cell proliferation, invasion, migration, and survival [13,14^■■]. Yoon et al. [15] demonstrated 10-fold higher levels of VEGF by angiogenic profiling of soft tissue sarcomas compared to normal tissue controls. The authors also found a signature of angiogenesis-related genes unique among each soft tissue sarcoma subtype studied.

Initial clinical trials data from studies of VEGF inhibition in solid tumors showed objective tumor regressions that were most evident in renal cell cancer as well as bladder carcinomas and melanomas [16]. Thalidomide, which inhibits basic fibroblast growth factor in addition to VEGF, was one of the first agents to be tested against soft tissue sarcomas, although no significant clinical activity was found against gynecologic sarcomas [17]. A phase II trial of bevacizumab, a humanized monoclonal antibody directed against VEGF, was conducted in combination with doxorubicin in a cohort of patients with soft tissue sarcomas. Of 17 patients evaluated, 11 had stable disease over four or more cycles, with an overall response rate of 12%, which was not superior to that of single-agent doxorubicin [18] (Table 1).

Table 1.

Clinical trials of antiangiogenic agents in the treatment of synovial sarcomas

Agent	Targets	Study design	Results	Number of synovial sarcoma patients in study	Reference
Bevacizumab	VEGF	Phase II; 17 patients with metastatic STS were treated with doxorubicin 75 mg/m2 IVP+bevacizumab 15 mg/kg q3 weeks	11 patients had SD with 4 or more cycles; 12% response rate was equivalent to single-agent doxorubicin; median time to progression 8 months; median OS 16 months	1	D’Adamo et al. [18]
Sunitinib	VEGFR-1,2,3; PDGFR-α/β; KIT; FLT3; RET; and CSF-1	Phase II; 53 pts with advanced non-GIST STS received sunitinib 37.5 mg daily	11 of 48 evaluable pts had SD at 16 weeks of therapy	4; 1 of 4 synovial sarcoma pts had SD at 16 weeks	George et al. [19]
Sorafenib	Raf-1; PDGFR-β; VEGFR-2,3; FLT3; KIT	Phase II; 144 patients with recurrent or metastatic sarcoma received sorafenib at 400 mg twice daily	122 patients were evaluable for response; 5 of 37 patients with angiosarcoma had a PR; minimal activity was seen in all other sarcoma subtypes	12	Maki et al. [20]
Cediranib	VEGFR-1,2,3; c-KIT	Phase I; 16 patients (8–18 years old) with refractory solid tumors, including STS	Maximum tolerated dose 12 mg/m2 per day	2; one patient had a PR with 67% tumor reduction	Fox et al. [21]
Pazopanib	VEGFR-1, 2, 3; PDGFR-αβ; c-KIT	Phase II; 142 pts with intermediate, high grade advanced STS received pazopanib 800 mg daily; patients were stratified into adipocytic STS, leiomyosarcoma, synovial sarcoma, and all others	18 of 41 (44%) leiomyosarcoma patients, 18 of 37 (49%) synovial sarcoma patients, 16 of 41 (39%) all other STS patients achieved the primary endpoint of progression-free rate at 12 weeks	37; 18 patients showed no evidence of progression at 12 weeks	Sleijfer et al. [22]
Brivanib	VEGFR-1,2,3; FGFR-1,2,3	Phase II; 251 patients with STS received brivanib 800 mg daily for 12 weeks; patients who had SD after 12-week period were randomized to brivanib vs. placebo; stratified for FGF2 expression	Median PFS 2.8 months for brivanib vs. 1.4 months for placebo in FGF2+patients; at week 12 ORR was 2.8% with 7 PR overall	Not defined	Schwartz et al. [23]

FGF, fibroblast growth factor; ORR, overall response rate; OS, overall survival; PFS, progression free survival; PR, partial response; STS, soft-tissue sarcoma; VEGF, vascular endothelial growth factor.

Sunitinib malate was the first oral multitargeted tyrosine kinase inhibitor of VEGFR to be tested in patients with soft tissue sarcomas. In addition to activity against VEGFR-1, 2, 3, it also has activity against PDGFR-α,β, KIT, FLT3, RET, and the CSF-1 receptor tyrosine kinases. In a multicenter phase II trial of sunitinib for the treatment of nongastrointestinal stromal tumors, which included four patients with synovial sarcomas, 11 of 48 patients demonstrated stable disease, including one synovial sarcoma patient who had stable disease following 16 weeks of therapy [19]. A phase II study of sorafenib, an inhibitor of Raf-1 in addition to VEGFR-2,3, PDGFR-β, FLT3, and KIT in patients with metastatic or recurrent sarcomas demonstrated some activity in the group of 12 synovial sarcoma patients evaluated with a Kaplan-Meier estimate for progression-free survival of 42% at 3 months [20]. Further studies evaluating newer agents with selective inhibition of VEGF signaling include cediranib, which is a potent inhibitor of VEGFR-1, 2, 3, and c-KIT. A phase I study of cediranib in children and adolescents with refractory solid tumors found objective responses in the sarcoma group, which included two synovial sarcoma patients. One of the patients with synovial sarcoma in the study had a 67% reduction in tumor measurements [21]. More recent data in a phase II study with pazopanib, a multitargeted tyrosine kinase inhibitor with activity against VEGFR-1, 2, 3, PDGFR-α,β, and c-KIT, in relapsed or refractory soft tissue sarcomas demonstrated that 18 of 37 (49%) patients in the synovial sarcoma cohort reached the primary endpoint with no evidence of disease progression at 12 weeks. Similar results were obtained with 14 of 41 (44%) patients in the cohort of leiomyosarcoma patients, and in the cohort with all other soft tissue sarcomas evaluated wherein 16 of 41 (39%) patients also achieved the primary endpoint [22]. Brivanib, an oral dual inhibitor of VEGFR-1, 2, 3 and fibroblast growth factor receptor-1, 2, 3 was evaluated for the treatment of soft tissue sarcomas in a phase II randomized discontinuation trial. Of the 251 patients enrolled with soft tissue sarcoma, there were seven partial responses with an overall response rate (ORR) of 2.8%, and a disease control rate (ORR+SD) of 30%. Median progression-free survival was 2.8 months from the initial 12-week lead-in period in the subgroup of high expressors of fibroblast growth factor receiving brivanib, compared to 1.4 months for placebo control (P = 0.08) [23].

Future therapies

More recent expression profiling studies in synovial sarcoma have demonstrated c-MET and hepatocyte growth factor (HGF) expression [24]. c-MET is essential for embryonic development and wound healing and has been implicated in cellular processes involved in oncogenic progression in a variety of tumors [25]. HGF is the only known ligand of c-MET and is mainly expressed in cells of mesenchymal origin. HGF has been shown to promote epithelial and endothelial cell motility, proliferation, and tubulogenesis [26]; in-vivo studies have demonstrated that HGF acts synergistically with VEGF to augment endothelial angiogenesis [27]. Expression profiling of human umbilical vein endothelial cells treated with HGF and VEGF revealed activation and upregulation of a synergistic but distinct complement of signal transduction pathways [28]. Coadministration of HGF and VEGF resulted in upregulation of growth factor signal transduction pathways early, followed by genes involved in cell cycle progression at later time points. Coexpression of HGF and its receptor c-MET has been shown to significantly correlate with larger tumor size, higher proliferation index, and poor prognosis in synovial sarcomas [24].

When tumors outgrow their blood supply, compensatory neoangiogenic mechanisms result in the development of tumor vasculature that is disorganized and inefficient at delivering oxygen. Clinical studies evaluating hypoxia within tumors reveal not only amplification of HGF signaling but also activation of transcription of the MET proto-oncogene, and promotion of invasive growth. In addition, inhibition of MET expression by RNA interference results in prevention of hypoxia-mediated branching morphogenesis and hypoxia-induced invasive growth [29].

Combination therapy aimed at blocking both the VEGF and the HGF/c-MET pathways presents a potentially attractive approach for the treatment of advanced synovial sarcoma. Dual pathway inhibitors such as cabozantinib and foretinib that inhibit both c-MET and VEGFR-2, are in clinical development and have shown promising activity in a variety of solid tumors such as glioblastoma, papillary renal carcinoma, medullary thyroid carcinoma, prostate cancer, and ovarian cancer [30-32,33^■■]. A phase I clinical trial is being conducted using combination therapy of pazopanib and tivantinib, an oral c-Met inhibitor, in patients with refractory solid tumors, including patients with refractory synovial sarcomas (ClinicalTrials.gov identifier: NCT01468922).

Genetic profiling of soft tissue sarcomas has shown upregulation of genes involved in the EGF and FGF receptor signaling pathways, developmental pathways involving Wnt and Hedgehog, TGF-β signaling pathways, and genes involved in chromatin remodeling providing an array of potential therapeutic targets for future trials [34]. More recent studies have additionally implicated aberrant phosphoinositide 3-kinase (PI3K) signaling in the proliferation of synovial sarcoma demonstrating strong expression of activated PI3K-downstream targets Akt (also known as protein kinase B), mammalian target of rapamycin (mTOR), and glycogen synthase kinase 3 (GSK-3b) in a subgroup of 36 synovial sarcomas analyzed [35^■■]. In-vitro inhibition of PI3K enzymatic activity resulted in decreases in phosphorylated AKT, mTOR, GSK-3β expression and increased apoptosis and inhibition of cellular proliferation. Clinically targeted combination therapy of the RAF/MEK/ERK pathway with sorafenib and the mTOR/AKT pathway with dual administration of sirolimus and nelfinavir have been documented to stabilize disease at 21 months after initiation of therapy in a patient with metastatic poorly differentiated synovial sarcoma [36].

CONCLUSION

Prognosis of advanced synovial sarcoma remains poor. With the advent of the molecularly targeted therapies, there is interest in identifying novel molecular therapeutic targets in soft tissue sarcomas. Anti-VEGF therapies have resulted in improved outcomes for patients with various solid tumors and have shown preliminary evidence of activity in soft tissue sarcomas in general, and specifically in synovial sarcomas. In light of the vascular nature of sarcomas, further evaluation of anti-VEGF therapies, especially in combination with other inhibitors such as MET or mTOR/AKT inhibitors provides an attractive potential approach for management of advanced synovial sarcomas.

KEY POINTS.

• Angiogenesis is crucial for growth and dissemination of soft tissue sarcomas.

• Early clinical studies of antivascular endothelial growth factor therapies have shown activity in synovial sarcomas.

• Gene profiling studies of soft tissue sarcomas are identifying potential new therapeutic targets such as c-Met/hepatocyte growth factor and PI3K/Akt, forming the basis for combination therapies.