pazopanib and Sarcoma--Synovial

New molecular insights are being achieved in synovial sarcoma (SS) that can provide new potential diagnostic and prognostic markers as well as therapeutic targets. In particular, the advancement of research on epigenomics and gene regulation is promising. The concrete hypothesis that the pathogenesis of SS might mainly depend on the disruption of the balance of the complex interaction between epigenomic regulatory complexes and the consequences on gene expression opens interesting new perspectives. The standard of care for primary SS is wide surgical resection combined with radiation in selected cases. The role of chemotherapy is still under refinement and can be considered in patients at high risk of metastasis or in those with advanced disease. Cytotoxic chemotherapy (anthracyclines, ifosfamide, trabectedin, and pazopanib) is the treatment of choice, despite several possible side effects. Many possible drug-able targets have been identified. However, the impact of these strategies in improving SS outcome is still limited, thus making current and future research strongly needed to improve the survival of patients with SS.

Topics: Anthracyclines; Antineoplastic Agents; Chemotherapy, Adjuvant; Epigenomics; Gene Expression Regulation, Neoplastic; Genomics; Humans; Ifosfamide; Indazoles; Molecular Targeted Therapy; Pyrimidines; Radiotherapy, Adjuvant; Sarcoma, Synovial; Soft Tissue Neoplasms; Sulfonamides; Surgical Procedures, Operative; Trabectedin

Synovial sarcoma (SS) is a rare, yet highly malignant, type of soft tissue sarcoma (STS), for which survival has not improved significantly during the past years. In this review, we focus on systemic treatment in adults. Compared to other STS, SS are relatively chemosensitive. Ifosfamide and ifosfamide combinations are active in different lines of treatment. In high-risk extremity and chest wall STS, neoadjuvant doxorubicin and ifosfamide has shown as much activity as high-dose ifosfamide. There are indications that combination chemotherapy with doxorubicin and ifosfamide in this setting improves outcome. In the first-line metastatic setting, combination treatment with doxorubicin and ifosfamide is a preferred option in fit patients, while in other patients, sequential doxorubicin and ifosfamide can be considered. In second and later lines, pazopanib and trabectedin have shown activity. Many new approaches to treat metastatic SS are currently under investigation, both preclinical as well as clinical, including other receptor tyrosine kinase inhibitors, epigenetic modulators, compounds interfering with DNA damage response (DDR), and immunotherapy.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Humans; Ifosfamide; Indazoles; Pyrimidines; Sarcoma, Synovial; Sulfonamides; Trabectedin

Synovial sarcoma is part of soft tissue sarcomas, an uncommon group of malignant tumors of mesenchymal origin. Unfortunately, a very limited number of useful drugs are active for most advanced synovial sarcoma. These tumors showed VEGF expression, and elevated serum VEGF levels correlate with higher histologic tumor grade. Inhibition of VEGFR was associated with tumor activity in preclinical models of synovial sarcoma and drugs such as sorafenib, pazopanib and bevacizumab have been employed in synovial sarcoma in monotherapy and in combination with chemotherapy. Other targets such as EGFR, HER2, IGFR-1R and mTOR have been exploited, but their inhibition by drugs such as gefitinib, trastuzumab, figitumumab, and temsirolimus, has not resulted in meaningful activity. Newer approaches include CXCR4 inhibition, immune-based therapies (NY-ESO-1), targeting epigenetic misregulation with HDAC inhibitors and targeting developmental pathways such Notch and Hedgehog. This review will summarize achievements and pitfalls of drugs against emerging therapeutic targets for synovial sarcoma.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Bevacizumab; Everolimus; Humans; Indazoles; Indoles; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sarcoma; Sarcoma, Synovial; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases

Description of patient characteristics, effectiveness and safety in Turkish patients treated with pazopanib for metastatic soft tissue sarcoma (STS).. This multicenter study is based on retrospective review of hospital medical records of patients (≥ 18 years) treated with pazopanib for non-adipocytic metastatic STS at 37 Oncology clinics across Turkey. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were evaluated with further analysis of data on the three most common histological subtypes (leiomyosarcoma [LMS], undifferentiated pleomorphic sarcoma [UPS], synovial sarcoma [SS]) in the cohort.. Data of 552 adults (57.6% women, median age: 52 years) were analyzed. DCR and ORR were 43.1% and 30.8%, respectively. Median PFS was 6.7 months and OS was 13.8 months. For LMS, UPS and SS, median PFSs were 6.1, 5.9 and 7.53 months and median OSs were 15.03, 12.87 and 12.27 months, respectively. ECOG ≥ 2 was associated with poor PFS and OS. Liver metastasis was only a factor for progression. Second-line use of pazopanib (vs. front-line) was associated with better PFS, its use beyond third line predicted worse OS. Adverse events (AE) occurred in 82.7% of patients. Most common AEs were fatigue (58.3%) and anorexia (52.3%) which were graded as ≥ 3 in 8.2% and 7.4% of patients, respectively.. Pazopanib is effective and well-tolerated in treatment of non-adipocytic metastatic STS. Its earlier use (at second-line), good performance status may result in better outcomes. Worldwide scientific collaborations are important to gain knowledge on rarer STS subtypes by conducting studies in larger patient populations.

Topics: Adult; Female; Humans; Indazoles; Leiomyosarcoma; Male; Middle Aged; Neoplasms, Second Primary; Retrospective Studies; Sarcoma; Sarcoma, Synovial; Soft Tissue Neoplasms; Turkey

To determine if a targeted exome panel utilizing matched normal DNA can accurately detect germline and somatic HLA genes in patients with synovial sarcoma (SS) and whether select HLA-A*02 genotypes are prognostic or predictive of outcome in metastatic SS.. Patients with metastatic SS consented to HLA typing by a Clinical Laboratory Improvement Amendments (CLIA)-certified test to determine eligibility for a clinical trial of NY-ESO-1-specific engineered T cells restricted to carriers of HLA-A*02:01, -A*02:05, or -A*02:06 (HLA-A*02 eligible). HLA genotype was determined from Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets (MSK-IMPACT), where feasible, and somatic loss of heterozygosity (LOH) in HLA alleles was identified. Overall survival (OS) was estimated and stratified by HLA-A*02 eligibility.. A total of 23 patients had HLA genotyping by a CLIA-certified lab and MSK-IMPACT. Ninety percent (108/110) of the sequenced alleles were concordant between IMPACT and the outside lab. LOH of HLA genes was detected in three tumors, one had loss of HLA-A*02:01. In total, 66 patients were screened for T-cell therapy and 20 (30%) were HLA-A*02 eligible on outside testing. Univariate analysis of OS from the time of metastasis found HLA-A*02 eligibility was marginally associated with shorter OS [HR = 1.95; 95% confidence interval (CI), 0.995-3.813;. Targeted gene panels like MSK-IMPACT may accurately report HLA type and identify loss of somatic HLA alleles. In a multivariable model, HLA-A*02 eligibility was not significantly associated with OS in patients with metastatic SS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antigens, Neoplasm; Child; Disease-Free Survival; Female; Genotype; HLA-A Antigens; Humans; Indazoles; Loss of Heterozygosity; Male; Membrane Proteins; Middle Aged; Neoplasm Metastasis; Prognosis; Pyrimidines; Sarcoma, Synovial; Sulfonamides; T-Lymphocytes; Treatment Outcome; Young Adult

Synovial sarcoma (SS) is an aggressive subgroup of soft tissue sarcoma (STS) with high grade and high risk of metastasis. However, there are no systemic therapies available that target SS. Therefore, transformative therapy is needed for SS. To establish a patient-derived orthotopic xenograft (PDOX) model, a patient tumor with high grade SS from a lower extremity was grown orthotopically in the right biceps femoris muscle of mice. To test the efficacy of drugs, the PDOX models were randomized into five groups: Group 1 (G1), control-without treatment; Group 2 (G2), doxorubicin (DOX); Group 3 (G3), temozolomide (TEM); Group 4 (G4), gemcitabine (GEM) combined with docetaxel (DOC); and Group 5 (G5), pazopanib (PAZ). Tumor size and body weight were measured twice a week for each treatment group. A significant growth inhibition was found on day 14 in each treatment group compared to the untreated control, except for DOX. However, PAZ was significantly more effective than both TEM and GEM + DOC. In addition, PAZ significantly regressed the tumor volume on day 14 compared to day 0. No change was found in body weight on day 14 compared to day 0 in any treatment group. The present study demonstrated the precision of the SS PDOX models for individualizing SS therapy.

Topics: Animals; Doxorubicin; Drug Resistance, Neoplasm; Humans; Indazoles; Male; Mice; Mice, Nude; Middle Aged; Pyrimidines; Sarcoma, Synovial; Sulfonamides; Xenograft Model Antitumor Assays

The development of drug resistance in tumor cells leads to relapse and distant metastasis. Secreted microRNAs (miRNAs) enclosed in extracellular vesicles (EVs) can act as intercellular messengers. The objective of our study was to elucidate the role of secreted miRNAs to better understand the regulatory network underlying pazopanib-resistance in synovial sarcoma cells. We performed a comprehensive analysis of secreted miRNA abundance in pazopanib treated/untreated synovial sarcoma cells from four different cell lines (SYO-1, HS-SYII, 1273/99, and YaFuSS) using microarray technology, and discovered miR-761 in EVs as a potential biomarker of pazopanib-resistance in synovial sarcoma. Furthermore, we showed that miR-761 putatively targeted three proteins, thyroid hormone receptor interactor 6 (TRIP6), lamin A/C (LMNA), and NAD-dependent protein deacetylase sirtuin-3 (SIRT3). Knockdown of any of these proteins was shown in previous studies to confer increased resistance to chemotherapeutic agents. Our findings provide new insight into the potential role of miR-761, an EV-secreted miRNA from synovial sarcoma cells, making it a potential candidate for use in sarcoma therapy in the future.

Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Drug Resistance, Neoplasm; Extracellular Vesicles; Humans; Indazoles; Lamin Type A; LIM Domain Proteins; MicroRNAs; Pyrimidines; Sarcoma, Synovial; Sirtuin 3; Sulfonamides; Transcription Factors

Secreted proteins enclosed in extracellular vesicles can act as intercellular messengers. The objective of this study was to elucidate the role of proteins secreted from synovial sarcoma cells in the regulatory network underlying pazopanib response. We performed a comprehensive analysis of expression of proteins secreted from four synovial sarcoma cell lines (SYO-1, HS-SYII, 1273/99, and YaFuSS) using mass spectroscopy. Comparison of up-regulated proteins in cells, extracellular vesicles-free conditioned media, and extracellular vesicles revealed significantly up-regulated Wnt in synovial sarcoma vesicles. Furthermore, we compared protein signatures of cells, conditioned media, and extracellular vesicles before and after pazopanib treatment. Interestingly, protein signatures of extracellular vesicles showed robust changes in Wnt signaling pathways in response to pazopanib. Our findings provide insight into the potential role of Wnt, a protein secreted from the extracellular vesicles of synovial sarcoma cells, making it a potential candidate for use in sarcoma diagnosis.

Topics: Cell Line, Tumor; Culture Media, Conditioned; Extracellular Vesicles; Humans; Indazoles; Neoplasm Proteins; Proteomics; Pyrimidines; Sarcoma, Synovial; Signal Transduction; Sulfonamides

Synovial sarcoma (SS) is a rare high-grade malignant mesenchymal tumour with a relatively poor prognosis despite intensive multimodal therapy. Although pazopanib, a multi-kinase inhibitor, is often used for advanced SS, most cases eventually become resistant to pazopanib. In the present study, we investigated the mechanisms of acquired pazopanib resistance in SS. To examine acquired pazopanib resistance, two SS cell lines, SYO-1 and HS-SY-II, were isolated after multiple selection steps with increasing concentrations of pazopanib. SYO-1 was also used in vivo. Then, pazopanib-resistant clones were investigated to assess potential mechanisms of acquired pazopanib resistance. Stable pazopanib-resistant clones were established and exhibited enhanced cell cycle progression, cell growth with increased ERK1/2 phosphorylation, and higher sensitivity than parental cells to a MEK-inhibitor, trametinib, both in vitro and in vivo. Furthermore, addition of low-dose trametinib partially reversed the pazopanib resistance. In the pazopanib-resistant clones, dual specificity phosphatase 6 (DUSP6) was downregulated. Inhibition of DUSP6 expression in parental HS-SY-II cells partially recapitulated acquired pazopanib resistance. Acquired pazopanib resistance in SS was associated with activation of ERK1/2 through downregulation of DUSP6 expression. Simultaneous treatment with pazopanib and a MEK inhibitor could be a promising strategy to overcome pazopanib resistance in SS.

Topics: Animals; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Resistance, Neoplasm; Dual Specificity Phosphatase 6; Female; Humans; Indazoles; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-raf; Pyridones; Pyrimidines; Pyrimidinones; ras Proteins; Sarcoma, Synovial; Sulfonamides

The prognosis of synovial sarcoma (SS), an aggressive soft tissue sarcoma, remains poor. We previously reported that c-MET or platelet-derived growth factor receptor α (PDGFRα) signalling pathway is related to SS progression based upon the findings of phospho-receptor tyrosine kinase (RTK) arrays. TAS-115 is a novel c-MET/ vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitor that has been shown to inhibit multiple RTKs. Here we aimed to investigate the therapeutic potential of TAS-115 against SS.. We first evaluated which signalling pathway was relevant to the viability of three human SS cell lines: Yamato-SS, SYO-1 and HS-SY-II. Next, we assessed the anticancer activity and mechanism of action of TAS-115 in these SS cell lines. Finally, we compared the ability of TAS-115 to inhibit c-MET and PDGFRα phosphorylation with that of pazopanib.. We classified the SS cell lines as c-MET-dependent or PDGFRα-dependent based upon the differences in the signalling pathway relevant for growth and/or survival. We also found that c-MET and PDGFRα were the primary activators of both phosphatidylinositol 3-kinase/AKT and mitogen-activated protein kinase pathways in c-MET-dependent and PDGFRα-dependent SS cells, respectively. TAS-115 treatment blocked the phosphorylation of PDGFRα as well as that of c-MET and their downstream effectors, leading to marked growth inhibition in both types of SS cell lines in in vitro and in vivo studies. Furthermore, PDGFRα phosphorylation, on at least four representative autophosphorylation sites, was impeded by TAS-115 equivalently to pazopanib.. These experimental results have demonstrated the significance of c-MET and PDGFRα signalling for growth and/or survival of SS tumours. TAS-115 monotherapy may benefit SS patients whose tumours are dependent upon either c-MET or PDGFRα signalling by functioning as a multiple tyrosine kinase inhibitor to suppress c-MET as well as PDGFRα pathways.

Topics: Angiogenesis Inhibitors; Animals; Cell Line, Tumor; Humans; Indazoles; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Phosphatidylinositol 3-Kinase; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Pyrimidines; Quinolines; Receptor, Platelet-Derived Growth Factor alpha; Sarcoma, Synovial; Signal Transduction; Sulfonamides; Thiourea; Xenograft Model Antitumor Assays

A named patient program (NPP) was designed to provide patients with advanced soft-tissue sarcoma (aSTS) access to pazopanib, a multitargeted tyrosine kinase inhibitor. The SPIRE study was a retrospective chart review of participating patients.. Eligibility criteria for the NPP and SPIRE mirrored those of the pivotal phase-III study, PALETTE, which compared pazopanib with placebo in patients ≥18 years with aSTS and whose disease had progressed during or following prior chemotherapy or were otherwise unsuitable for chemotherapy. Outcomes of interest included treatment patterns, treatment duration, relative dose intensity, progression-free survival (PFS), overall survival (OS), clinical benefit rate, adverse events (AEs) and reasons for treatment discontinuation.. A total of 211 patients were enrolled (median age 56 years; 60% female). Most patients received pazopanib in second- and third-line therapy (28.0% and 28.4%, respectively), followed by fourth line (19.0%) and ≥ fifth line (18.5%). The median duration of pazopanib treatment was 3.1 months (95% CI: 2.8-3.8), with a mean daily dose of 715 mg equating to 92% of recommended dose. Median OS was 11.1 months and clinical benefit rate was 46%. There was evidence of some clinical benefit across most histological subtypes. At study end, 40% of patients were alive and of these, 18% remained on pazopanib. Thirteen percent (13%) of patients discontinued pazopanib due to AEs.. The SPIRE study demonstrated activity of pazopanib in heavily pretreated aSTS patients in a compassionate use setting. No new safety concerns were noted. Reassuringly, the relative dose intensity of pazopanib was 92%.

Topics: Angiogenesis Inhibitors; Compassionate Use Trials; Disease-Free Survival; Female; Hemangiosarcoma; Humans; Indazoles; Leiomyosarcoma; Lung Neoplasms; Male; Middle Aged; Pyrimidines; Retrospective Studies; Sarcoma; Sarcoma, Synovial; Solitary Fibrous Tumors; Sulfonamides; Survival Rate; Time Factors; Uterine Neoplasms

Pazopanib is an oral multikinase inhibitor that has proved effective in adults treated for relapsing soft tissue sarcoma and synovial sarcoma in particular. Two cases are reported here of pediatric patients with pretreated relapsing synovial sarcoma whose tumors showed a prolonged response to pazopanib given on compassionate grounds. These results suggest that new agents found effective in adult patients might achieve similar results in adolescents with the same disease. Facilitating the availability of new drugs for children and adolescents is a major challenge for pediatric oncologists.

Topics: Adolescent; Angiogenesis Inhibitors; Female; Humans; Indazoles; Male; Pyrimidines; Recurrence; Sarcoma, Synovial; Sulfonamides

Because the efficacy and safety of pazopanib in Japanese patients with soft tissue sarcoma (STS) had not been evaluated previously in a large-scale cohort, the authors investigated the efficacy and safety of pazopanib in 156 Japanese patients with relapsed STS. This was a retrospective study based on the collection of real-life, postmarketing surveillance data.. Patients received pazopanib with the objective of treating local recurrence (n = 20), metastasis (n = 104), and both (n = 32). The patient median age was 53.8 years. The primary objective of this study was to clarify the efficacy of pazopanib for patients with STS.. The median treatment duration was 28.7 weeks, and the average dose intensity of pazopanib was 609 mg. Adverse events occurred in 127 patients (81.4%). In addition to the main common toxicities, such as hypertension and liver disorder, pneumothorax (n = 11) and thrombocytopenia (n = 16) also were observed. The median progression-free survival for all patients was 15.4 weeks. The median progression-free survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 18.6 weeks, 16.4 weeks, 15.3 weeks, and 8 weeks, respectively. The median survival for all patients was 11.2 months. The median survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 20.1 months, 10.6 months, 9.5 months, and 7.3 months, respectively.. There were apparent differences in the efficacy of pazopanib treatment among histologic types of STS. Pazopanib treatment is a new treatment option; however, adverse events like pneumothorax and thrombocytopenia, which did not occur frequently in the PALETTE study (pazopanib for metastatic soft-tissue sarcoma), should be taken into consideration. Cancer 2016;122:1408-16. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Chemical and Drug Induced Liver Injury; Disease-Free Survival; Female; Fibrosarcoma; Humans; Hypertension; Indazoles; Japan; Leiomyosarcoma; Liposarcoma; Male; Middle Aged; Neoplasm Recurrence, Local; Neurilemmoma; Pneumothorax; Product Surveillance, Postmarketing; Pyrimidines; Retrospective Studies; Sarcoma; Sarcoma, Synovial; Sulfonamides; Survival Analysis; Thrombocytopenia

Topics: Angiogenesis Inhibitors; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Indazoles; Male; Middle Aged; Neoplasm Recurrence, Local; Prednisolone; Pyrimidines; Salvage Therapy; Sarcoma, Synovial; Sulfonamides

A 42-year-old woman presented with chest pain and breathlessness with a nodule measuring 2×2 cm in size at the base of the right lung. A bronchoscopic examination did not reveal any malignancy. However, the patient developed difficulty in breathing, enlargement of the nodule, and right pleural effusion 14 days later. A video-assisted thoracic surgical biopsy specimen revealed the presence of pleural synovial sarcoma. The patient was treated with doxorubicin-ifosfamide combination chemotherapy because of metastasis to the pelvis. However, after a transient partial clinical response, there was a relapse of refractory disease. Although treated with pazopanib as second-line chemotherapy, the patient died eight months after the initial presentation.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Chest Pain; Doxorubicin; Dyspnea; Fatal Outcome; Female; Humans; Ifosfamide; Indazoles; Neoplasm Recurrence, Local; Pleural Effusion, Malignant; Pleural Neoplasms; Pyrimidines; Sarcoma, Synovial; Sulfonamides

Tyrosine kinase inhibitors, represented by sunitinib, sorafenib, axitinib and pazopanib, are emerging molecules harbouring antitumoural efficacy in multiple neoplasia. We report the case of a 51-year-old woman with right thoracic sarcoma who developed fatal heart failure on pazopanib. The patient had no cardiovascular risk factor, except previous exposure to anthracycline, and her cardiac function was normally controlled before initiating the pazopanib. Despite a rapid tumour response, fatigue rapidly appeared, requiring treatment interruption 2 weeks after pazopanib introduction. After clinical improvement, the pazopanib was reintroduced at reduced dose; however, a few days later, our patient was admitted for worsening dyspnoea and fatigue. Pulmonary embolism was excluded as was pleuropericardial effusion. Brain natriuretic peptide was the only laboratory abnormality, and echocardiography revealed acute and severe heart failure. The patient died despite pazopanib arrest and inotropic support.

Topics: Antineoplastic Agents; Dyspnea; Fatal Outcome; Fatigue; Female; Heart Failure; Humans; Indazoles; Middle Aged; Pyrimidines; Sarcoma, Synovial; Sulfonamides; Thoracic Neoplasms

Synovial sarcoma is an aggressive soft tissue sarcoma with only a modest response to conventional cytotoxic agents. In the present study, we evaluated the potential antitumor effects of a novel anti-angiogenesis agent, pazopanib, against synovial sarcoma cells. We found that pazopanib directly inhibited the growth of synovial sarcoma cells by inducing G1 arrest. Multiplex analyses revealed that the PI3K-AKT pathway was highly suppressed in pazopanib-sensitive synovial sarcoma cells. Furthermore, administration of pazopanib highly suppressed the tumor growth in a xenograft model. Taken together, these results suggest pazopanib as a possible agent against synovial sarcoma and may warrant further clinical studies.

Topics: Animals; Cell Line, Tumor; G1 Phase; Humans; Indazoles; Mice; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sarcoma, Synovial; Signal Transduction; Sulfonamides; Xenograft Model Antitumor Assays