Systematic Therapy for Unresectable or Metastatic Soft-Tissue Sarcomas: Past, Present, and Future

Morgan, Sara; Cranmer, Lee D.

doi:10.1007/s11912-011-0182-z

Cited by 11 publications

(14 citation statements)

References 119 publications

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“…NAB-paclitaxel may act as a “Trojan horse,” with the albumin encapsulation serving to direct the paclitaxel chemotherapeutic agent to tumor cells via binding to SPARC. While taxane monotherapy has been shown to be active primarily in angiosarcoma [25,26], several reports have demonstrated that taxane combination therapy is active in STS (reviewed in [7]). Notably, the combination of docetaxel and gemcitabine has demonstrated superiority over gemcitabine monotherapy in a randomized phase 2 trial in STS [27].…”

Section: Discussionmentioning

confidence: 99%

“…Further, only a minority of doxorubicin-treated patients (estimated at 26% in a meta-analysis) demonstrates objective responses to treatment [6]. Other cytotoxics frequently employed in sarcoma therapy include ifosfamide, dacarbazine, gemcitabine, and taxanes [7]. With the exception of gastrointestinal stromal tumors (GIST), targeted therapies have played a minor role in the management of STS so far (reviewed in [7]).…”

Section: Introductionmentioning

confidence: 99%

“…Other cytotoxics frequently employed in sarcoma therapy include ifosfamide, dacarbazine, gemcitabine, and taxanes [7]. With the exception of gastrointestinal stromal tumors (GIST), targeted therapies have played a minor role in the management of STS so far (reviewed in [7]). Treatments available for STS, particularly when disease is unresectable or metastatic, are inadequate and rarely yield durable responses.…”

Section: Introductionmentioning

confidence: 99%

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Serum protein acidic and rich in cysteine (SPARC) as a prognostic marker in soft tissue sarcomas

2014

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BackgroundSerum protein acidic and rich in cysteine (SPARC) is a matricellular secreted glycoprotein that performs several cellular functions and has been implicated in tumorigenesis in a variety of tumor types. The chemotherapeutic agent nanoparticle albumin-encapsulated (NAB)-paclitaxel has been postulated to exploit SPARC expression to target neoplastic cells. SPARC’s role, and potentially the role of NAB-paclitaxel, in the highly heterogeneous class of soft-tissue sarcomas (STS) has not been investigated. Our objective was to explore the pattern of SPARC expression and its prognostic significance in STS.Methods27 tissue specimens representing various STS histologies were stained for SPARC expression by immunohistochemistry (IHC). Staining intensity was scored blindly. Survival was determined from patients’ medical records and analyzed using Kaplan-Meier and log-rank with respect to SPARC expression level.ResultsElevated SPARC expression was observed in 15/27 (56%) specimens. Overall patient survival segregated strongly based on levels of SPARC expression. Patients who expressed low-to-moderate levels of SPARC exhibited median survival of 22.1 months, while the median survival of patients with moderate-to-high expression levels was 4.4 months (log rank; p = 0.0016).ConclusionsSPARC expression is elevated in a significant proportion of STS specimens analyzed in this study, but it does not appear to correlate with specific STS histologies. Given our limited sample size, we cannot draw definitive conclusions regarding association of SPARC with STS subtype. Overall survival segregates strongly by degree of SPARC expression, with elevated expression being adverse. If validated in a larger study, our results suggest that trials in STS with agents potentially targeting SPARC, such as NAB-paclitaxel, should be stratified by SPARC expression level.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Serum protein acidic and rich in cysteine (SPARC) as a prognostic marker in soft tissue sarcomas

2014

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“…Although there are no randomized phase III studies to define the most effective modality, patients with unresectable sarcomas are usually treated with systemic chemotherapy and/ or EBRT [14,15]. Because an adequate response to EBRT and chemotherapy may convert an initially unresectable tumor to one that can be resected and potentially cured, the choice of particular type of chemotherapy regimen or of radiotherapy is usually guided by the sarcoma histologic subtype, given the recognized wide variability of response of different STS subtypes to chemotherapy regimens and radiotherapy.…”

Section: Discussionmentioning

confidence: 99%

Synovial sarcoma presenting with huge mediastinal mass: a case report and review of literature

et al. 2013

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BackgroundSynovial sarcoma presenting in the mediastinum is exceedingly rare. Furthermore, data addressing optimal therapy is limited. Herein we present a case where an attempt to downsize the tumor to a resectable state with chemotherapy was employed.Case presentationA 32 year female presented with massive pericardial effusion and unresectable huge mediastinal mass. Computed axial tomography scan - guided biopsy with adjunctive immunostains and molecular studies confirmed a diagnosis of synovial sarcoma. Following three cycles of combination Ifosfamide and doxorubicin chemotherapy, no response was demonstrated. The patient refused further therapy and had progression of her disease 4 months following the last cycle.ConclusionSynovial sarcoma presenting with unresectable mediastinal mass carry a poor prognosis. Up to the best of our knowledge there are only four previous reports where primary chemotherapy was employed, unfortunately; none of these cases had subsequent complete surgical resection. Identification of the best treatment strategy for patients with unresectable disease is warranted. Our case can be of benefit to medical oncologists and thoracic surgeons who might be faced with this unique and exceedingly rare clinical scenario.

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“…Treatment of unresectable or metastatic SS relies on a limited number of cytotoxic agents [ 21 ]. Responses are not typically durable and most patients will require salvage therapy.…”

Section: Introductionmentioning

confidence: 99%

Vorinostat synergizes with ridaforolimus and abrogates the ridaforolimus-induced activation of AKT in synovial sarcoma cells

Morgan

Cranmer

2014

BMC Research Notes

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BackgroundCurative treatments for patients with metastatic synovial sarcoma (SS) do not exist, and such patients have a poor prognosis. We explored combinations of molecularly-targeted and cytotoxic agents to identify synergistic treatment combinations in SS cells.MethodsTwo SS cell lines (HS-SY-II and SYO-I) were treated with single agents or combinations of molecularly targeted therapies (HDAC inhibitor, vorinostat; mTOR inhibitor, ridaforolimus) and cytotoxic agents. After 72 hours, cell viability was measured using the MTS cell proliferation assay. Combination Indices (CI) were calculated to determine whether each combination was synergistic, additive, or antagonistic. Western Blot analysis assessed alterations in total and phospho-AKT protein levels in response to drug treatment.ResultsWe determined the single-agent IC50 for ridaforolimus, vorinostat, doxorubicin, and melphalan in HS-SY-II and SYO-I. Synergism was apparent in cells co-treated with ridaforolimus and vorinostat: CI was 0.28 and 0.63 in HS-SY-II and SYO-I, respectively. Ridaforolimus/doxorubicin and ridaforolimus/melphalan exhibited synergism in both cell lines. An additive effect was observed with combination of vorinostat/doxorubicin in both cell lines. Vorinostat/melphalan was synergistic in HS-SY-II and additive in SYO-I. Western blot analysis demonstrated that ridaforolimus increased pAKT-ser473 levels; this effect was abrogated by vorinostat co-treatment.ConclusionsThe combination of ridaforolimus and vorinostat demonstrates in vitro synergism in SS. Addition of vorinostat abrogated ridaforolimus-induced AKT activation. Since AKT activation is a possible mechanism of resistance to mTOR inhibitors, adding vorinostat (or another HDAC inhibitor) may be a route to circumvent AKT-mediated resistance to mTOR inhibitors.

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Systematic Therapy for Unresectable or Metastatic Soft-Tissue Sarcomas: Past, Present, and Future

Cited by 11 publications

References 119 publications

Serum protein acidic and rich in cysteine (SPARC) as a prognostic marker in soft tissue sarcomas

Serum protein acidic and rich in cysteine (SPARC) as a prognostic marker in soft tissue sarcomas

Synovial sarcoma presenting with huge mediastinal mass: a case report and review of literature

Vorinostat synergizes with ridaforolimus and abrogates the ridaforolimus-induced activation of AKT in synovial sarcoma cells

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