RESUMO
A clinically relevant subset of patients with soft tissue sarcoma presents with either locally advanced or upfront metastatic disease, or will develop distant metastases over time, despite successful treatment of their primary tumour. The currently available systemic agents to treat such advanced cases only provide modest disease control and are not active in all histological subtypes. Thus, there is an unmet need for novel and more efficacious agents to improve the outcome of this rare disease. In the current preclinical in vivo study, we evaluated plocabulin, a novel tubulin inhibitor, in five distinct histological subtypes of soft tissue sarcoma: dedifferentiated liposarcoma, leiomyosarcoma, undifferentiated sarcoma, intimal sarcoma and CIC-rearranged sarcoma. The efficacy was tested in seven patient-derived xenograft models, which were generated by the engraftment of tumour fragments from patients directly into nude mice. The treatment lasted 22 days, and the efficacy of the drug was assessed and compared to the doxorubicin and vehicle groups by volumetric analysis, histopathology and immunohistochemistry. We observed tumour volume control in all the tested histological subtypes. Additionally, in three sarcoma subtypes, extensive central necrosis, associated with significant tumour regression, was seen. This histological response is explained by the drug's vascular-disruptive properties, reflected by a decreased total vascular area in the xenografts. Our results demonstrate the in vivo efficacy of plocabulin in the preclinical models of soft tissue sarcoma and corroborate the findings of our previous study, which demonstrated similar vascular-disruptive effects in gastrointestinal stromal tumours-another subtype of soft tissue sarcoma. Our data provide a convincing rationale for further clinical exploration of plocabulin in soft tissue sarcomas.
Assuntos
Sarcoma , Neoplasias de Tecidos Moles , Animais , Modelos Animais de Doenças , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Policetídeos , Pironas , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/patologia , Moduladores de Tubulina/uso terapêuticoRESUMO
BACKGROUND: Soft tissue sarcoma (STS) comprises a family of rare, heterogeneous tumors of mesenchymal origin. Single-agent doxorubicin remains the first-line standard-of-care treatment for advanced and inoperable STS, but response rates are only around 15%. In 2016, phase Ib/II clinical trial results reported an overall survival benefit of 11.8 months when combining doxorubicin and the platelet-derived growth factor receptor alpha (PDGFRA)-directed antibody olaratumab compared to doxorubicin alone, without providing a scientific rationale for such unprecedented therapeutic effect. We decided to evaluate the efficacy of olaratumab in a panel of STS patient-derived xenografts (PDX). METHODS: NMRI nu/nu mice were bilaterally transplanted with tumor tissue of patient-derived xenograft models expressing PDGFRA, including models of leiomyosarcoma (UZLX-STS22), malignant peripheral nerve sheath tumor (UZLX-STS39), myxofibrosarcoma (UZLX-STS59) and undifferentiated pleomorphic sarcoma (UZLX-STS84). Mice were randomly divided into four different treatment groups: (1) control, (2) doxorubicin (3 mg/kg once weekly), (3) anti-PDGFRA [olaratumab (60 mg/kg twice weekly) + mouse anti-PDGFRA antibody 1E10 (20 mg/kg twice weekly)] and (4) the combination of doxorubicin and anti-PDGFRA (same dose/schedule as in the single treatment arms). Tumor volume, histopathology and Western blotting were used to assess treatment efficacy. RESULTS: Anti-PDGFRA treatment as a single agent did not reduce tumor growth and did not result in significant anti-proliferative or pro-apoptotic activity. Combining doxorubicin and anti-PDGFRA did not reduce tumor burden, though a mild inhibition of proliferation was observed in UZLX-STS39 and -STS59. A pro-apoptotic effect was observed in all models except UZLX-STS22. Antitumor effects on histology were not significantly different comparing doxorubicin and the combination treatment. Moreover, anti-PDGFRA treatment, both as a single agent as well as combined with doxorubicin, did not result in inhibition of the downstream MAPK and PI3K/AKT signaling pathways. CONCLUSIONS: We were not able to demonstrate significant antitumor effects of anti-PDGFRA treatment in selected STS PDX models, neither alone nor in combination with doxorubicin. This is in line with the very recent results of the phase III clinical trial NCT02451943 ANNOUNCE, which did not confirm the clinical benefit of olaratumab in combination with doxorubicin over single agent doxorubicin.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/imunologia , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Quimioterapia Combinada , Feminino , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Sarcoma/patologia , Sarcoma/cirurgia , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/cirurgia , Resultado do Tratamento , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Liposarcoma (LPS) is a common subtype of soft tissue sarcoma. We describe the clinical outcome of patients with advanced LPS treated in a tertiary referral center and explore potential prognostic factors. PATIENTS AND METHODS: We retrospectively reviewed the records of patients with inoperable or metastatic dedifferentiated liposarcoma (DDLPS), myxoid/round cell liposarcoma (MLPS), and pleomorphic liposarcoma (PLPS) diagnosed and/or treated at the University Hospitals Leuven, Leuven, Belgium, between 2000 and 2014. RESULTS: We identified 100 patients with LPS (67 DDLPS, 25 MLPS, and 8 PLPS). Median overall survival from diagnosis of inoperable or metastatic disease was 13.0 months, without substantial variation between histological subtypes. Sixty-seven patients were treated with systemic chemotherapy. The most common first-line chemotherapeutic agents used were doxorubicin (n = 32), doxorubicin + alkylating agent (n = 16), and trabectedin (n = 5). Best response upon first-line treatment was partial/complete response, stable disease, or progressive disease in 17, 25, and 46% of patients, respectively. On multivariate analysis, metastasectomy and objective response or stable disease achieved with first-line chemotherapy were indicators for better overall survival. CONCLUSION: The LPS subtypes analyzed have a poor prognosis and low response rates to chemotherapy. The prognostic factors identified support the concept of offering systemic chemotherapy to patients with inoperable, advanced disease and of considering metastasectomy in eligible patients.
Assuntos
Antineoplásicos/uso terapêutico , Lipossarcoma/tratamento farmacológico , Adulto , Idoso , Progressão da Doença , Doxorrubicina/uso terapêutico , Feminino , Humanos , Ifosfamida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Análise de Sobrevida , Centros de Atenção Terciária , Trabectedina/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
Soft-tissue sarcomas (STS) represent a heterogeneous group of rare, malignant tumors of mesenchymal origin. Reliable in vivo sarcoma research models are scarce. We aimed to establish and characterize histologically and molecularly stable patient-derived xenograft (PDX) models from a broad variety of STS subtypes. A total of 188 fresh tumor samples from consenting patients with localized or advanced STS were transplanted subcutaneously in NMRI-nu/nu-immunodeficient mice. Once tumor growth was observed, the material was passaged to a next generation of mice. A patient-derived tumor sample was considered "successfully engrafted" whenever the sample was transplanted to passage 1. A PDX model was considered "established" when observing stable morphologic and molecular features for at least two passages. With every passage, histologic and molecular analyses were performed. Specific genomic alterations and copy-number profile were assessed by FISH and low coverage whole-genome sequencing. The tumor engraftment rate was 32% (61/188) and 188 patient samples generated a total of 32 PDX models, including seven models of myxofibrosarcoma, five dedifferentiated liposarcoma, five leiomyosarcoma, three undifferentiated pleomorphic sarcoma, two malignant peripheral nerve sheet tumor models, and single models of synovial sarcoma and some other (ultra)rare subtypes. Seventeen additional models are in early stages of engraftment (passage 1-2). Histopathologic and molecular features were compared with the original donor tumor and were stable throughout passaging. The platform is used for studies on sarcoma biology and suited for in vivo preclinical drug testing as illustrated by a number of completed and ongoing laboratory studies.
Assuntos
Modelos Animais de Doenças , Xenoenxertos/patologia , Sarcoma/patologia , Sarcoma/cirurgia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biópsia , Feminino , Genótipo , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Pacientes , Fenótipo , Sequenciamento Completo do Genoma , Adulto JovemRESUMO
The purpose of the present study was to investigate the in vitro and in vivo activity of PLX9486, a tyrosine kinase inhibitor (TKI) targeting both primary KIT exon 9 and 11 and secondary exon 17 and 18 mutations in gastrointestinal stromal tumors (GISTs). Imatinib, a potent inhibitor of mutated KIT, has revolutionized the clinical management of advanced, metastatic GIST. However, secondary resistance develops mainly through acquired mutations in KIT exons 13/14 or exons 17/18. Second-line sunitinib potently inhibits KIT exon 13/14 mutants but is ineffective against exon 17 mutations. In our study, PLX9486 demonstrated in vitro nanomolar potency in inhibiting the growth and KIT phosphorylation of engineered BaF3 cells transformed with KIT exon 17 mutations (p.D816V) and with the double KIT exon 11/17 mutations (p.V560G/D816V). The in vivo efficacy of PLX9486 was evaluated using two imatinib-resistant GIST patient-derived xenograft (PDX) models. In UZLX-GIST9 (KIT: p.P577del;W557LfsX5;D820G), PLX9486 100 mg/kg/day resulted in significant inhibition of proliferation. Pharmacodynamic analysis showed a pronounced reduction in mitogen-activated protein kinase (MAPK) activation and other downstream effects of the KIT signaling pathway but no significant effect on KIT Y703 and Y719 phosphorylation. Similarly, in MRL-GIST1 (KIT: p.W557_K558del;Y823D) PLX9486 treatment led to significant tumor regression and strong inhibition of MAPK activation. Interestingly, the inhibitory effect on MAPK activation was evident even after a single dose of PLX9486. In conclusion, PLX9486 showed anti-tumor efficacy in patient-derived imatinib-resistant GIST xenograft models, mainly through inhibition of KIT signaling. These preclinical efficacy data encourage further testing of PLX9486 in the clinical setting.
Assuntos
Antineoplásicos/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Proteínas Mutantes/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/genética , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Xenoenxertos , Humanos , Camundongos , Proteínas Mutantes/metabolismo , Transplante de Neoplasias , Proteínas Proto-Oncogênicas c-kit/metabolismo , Resultado do TratamentoRESUMO
PURPOSE: Gastrointestinal stromal tumors (GIST) are commonly treated with tyrosine kinase inhibitors (TKI). The majority of patients with advanced GIST ultimately become resistant to TKI due to acquisition of secondary KIT mutations, whereas primary resistance is mainly caused by PDGFRA p.D842V mutation. We tested the activity of avapritinib, a potent and highly selective inhibitor of mutated KIT and PDGFRA, in three patient-derived xenograft (PDX) GIST models carrying different KIT mutations, with differential sensitivity to standard TKI.Experimental Design: NMRI nu/nu mice (n = 93) were transplanted with human GIST xenografts with KIT exon 11+17 (UZLX-GIST9 KIT 11+17 ), exon 11 (UZLX-GIST3 KIT 11 ), or exon 9 (UZLX-GIST2B KIT9 ) mutations, respectively. We compared avapritinib (10 and 30 mg/kg/once daily) versus vehicle, imatinib (50 mg/kg/bid) or regorafenib (30 mg/kg/once daily; UZLX-GIST9 KIT11+17 ); avapritinib (10, 30, 100 mg/kg/once daily) versus vehicle or imatinib [UZLX-GIST3 KIT11 ]; and avapritinib (10, 30, 60 mg/kg/once daily) versus vehicle, imatinib (50, 100 mg/kg/twice daily), or sunitinib (40 mg/kg/once daily; UZLX-GIST2B KIT9 ). RESULTS: In all models, avapritinib resulted in reduction of tumor volume, significant inhibition of proliferation, and reduced KIT signaling. In two models, avapritinib led to remarkable histologic responses, increase in apoptosis, and inhibition of MAPK-phosphorylation. Avapritinib showed superior (UZLX-GIST9 KIT 11+17 and -GIST2B KIT 9 ) or equal (UZLX-GIST3 KIT 11 ) antitumor activity to the standard dose of imatinib. In UZLX-GIST9 KIT 11+17 , the antitumor effects of avapritinib were significantly better than with imatinib or regorafenib. CONCLUSIONS: Avapritinib has significant antitumor activity in GIST PDX models characterized by different KIT mutations and sensitivity to established TKI. These data provide strong support for the ongoing clinical trials with avapritinib in patients with GIST (NCT02508532, NCT03465722).
Assuntos
Antineoplásicos/farmacologia , Tumores do Estroma Gastrointestinal/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , Alelos , Substituição de Aminoácidos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Humanos , Imuno-Histoquímica , Camundongos , Terapia de Alvo Molecular , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Leiomyosarcoma is a common subtype of soft tissue sarcoma originating from smooth muscle. We evaluated the clinical course and treatment outcome of patients with metastatic leiomyosarcoma. METHODS: We retrospectively reviewed the records of patients at the University Hospitals Leuven. RESULTS: We identified 122 patients with metastatic leiomyosarcoma, 77 female, median age 59.5 years. Most patients developed leiomyosarcoma in the extremities (35%), the uterus (20%) or the abdomen (19%); 69% developed metachronous metastasis, 31% had synchronous metastatic disease. Most patients (74%) received palliative systemic therapy. The most common first-line treatments were doxorubicin (n = 47) and an anthracycline combined with an alkylator (n = 28). The objective response rate to first-line palliative systemic therapy was 20% and the median progression-free survival was 4.9 months (range 0.1-17.1). The median survival from diagnosis of metastasis was 20.5 months (range 0.4-126.9). On multivariate analysis, metachronous disease, no progressive disease as best response to first-line treatment, the possibility of metastasectomy with curative intent and use of palliative radiotherapy were indicators for better survival. CONCLUSION: The prognosis of patients with metastatic leiomyosarcoma is limited and objective responses to first-line systemic therapy are rare. The treatment of metastatic leiomyosarcoma remains an unmet medical need.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leiomiossarcoma/mortalidade , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Cuidados Paliativos/métodos , Centros de Atenção Terciária/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leiomiossarcoma/patologia , Leiomiossarcoma/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Adulto JovemRESUMO
Given the very limited efficacy of doxorubicin (doxo) in soft tissue sarcoma, there is a clear need for more active and less toxic treatments for this family of diseases. However, due to the rarity of these malignancies and lack of reliable preclinical models, development of new therapies has lagged behind. We evaluated the efficacy of PhAc-ALGP-doxorubicin (ALGP-doxo), a prodrug metabolized to doxo by peptidases present in tumor cells and/or tumor microenvironment, in a synovial sarcoma (SynSa) and two dedifferentiated liposarcoma (DDLPS) patient-derived xenograft models. Sixty-eight mice were engrafted bilaterally with human DDLPS or SynSa and randomized to control, doxo, or ALGP-doxo treatment, which were administered using an intraperitoneal minipump. Tumor volume measurement, histopathology, and Western blotting were used to assess treatment efficacy. Tumor regrowth was evaluated in a subset of mice over a period of 2 weeks after treatment cessation. Although tumor volume in the control and doxo groups increased steadily, ALGP-doxo caused tumor volume stabilization in the DDLPS xenografts and significant tumor shrinkage in the SynSa model, continuing after treatment cessation. A significant decrease in proliferation and increase in apoptosis compared with control and doxo was observed during and after treatment with ALGP-doxo in all models. In conclusion, ALGP-doxo shows considerably higher antitumoral efficacy compared with doxo in all patient-derived xenograft models tested. Administration of a 30- to 40-fold higher dose of ALGP-doxo than doxo is tolerated without significant adverse events. These results warrant further testing of this prodrug in anthracycline-sensitive and -resistant models of soft tissue sarcoma. Mol Cancer Ther; 16(8); 1566-75. ©2017 AACR.
Assuntos
Antineoplásicos/uso terapêutico , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapêutico , Pró-Fármacos/uso terapêutico , Sarcoma/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose , Diferenciação Celular , Proliferação de Células , Doxorrubicina/química , Doxorrubicina/farmacologia , Humanos , Lipossarcoma/tratamento farmacológico , Lipossarcoma/patologia , Camundongos , Proteínas de Neoplasias/metabolismo , Pró-Fármacos/química , Sarcoma/patologia , Resultado do Tratamento , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Intimal sarcoma is a rare malignancy that, clinically and radiographically, often mimics pulmonary embolism. The intravascular tumor tends to disseminate rapidly and metastases can be present at first diagnosis. METHODS: We reviewed all cases of intimal sarcoma that were diagnosed, treated and followed at the University Hospitals Leuven between April 2006 and April 2016. RESULTS: We identified 13 patients with a median age of 51 years. In 6 patients initial findings were suggestive of thromboembolic disease. Platelet-derived growth factor receptor α (PDGFRA) amplification was the most prevalent molecular finding, present in 11 patients. The MDM2 gene was amplified in 9 cases, and the EGFR gene in 3 patients. The median overall survival was 13 months. 11 patients underwent surgery. In 5 cases with inoperable and/or metastatic disease chemotherapy was given. Treatment with imatinib was initiated in 4 patients. CONCLUSIONS: Intimal sarcoma is an extremely rare and aggressive malignancy that has a very poor prognosis. Mimicking thromboembolic disease, diagnosis and treatment can be delayed. Surgery is the mainstay of treatment but is seldom curative. The disease is highly resistant to cytotoxic and targeted treatment. Given the fact that intimal sarcoma commonly expresses more than 1 molecular target, combination therapy might be an option, although toxicity may be a limitation.
Assuntos
Biomarcadores Tumorais/metabolismo , Estado Terminal/mortalidade , Sarcoma/metabolismo , Sarcoma/mortalidade , Neoplasias Vasculares/metabolismo , Neoplasias Vasculares/mortalidade , Adolescente , Adulto , Distribuição por Idade , Idoso , Bélgica/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Doenças Raras/metabolismo , Doenças Raras/mortalidade , Doenças Raras/terapia , Fatores de Risco , Sarcoma/terapia , Distribuição por Sexo , Taxa de Sobrevida , Resultado do Tratamento , Túnica Íntima/patologia , Neoplasias Vasculares/terapia , Adulto JovemRESUMO
In the majority of gastrointestinal stromal tumors (GIST), oncogenic signaling is driven by KIT mutations. Advanced GIST is treated with tyrosine kinase inhibitors (TKI) such as imatinib. Acquired resistance to TKI is mainly caused by secondary KIT mutations, but can also be attributed to a switch of KIT dependency to another receptor tyrosine kinase (RTK). We tested the efficacy of cabozantinib, a novel TKI targeting KIT, MET, AXL, and vascular endothelial growth factor receptors (VEGFR), in patient-derived xenograft (PDX) models of GIST, carrying different KIT mutations. NMRI nu/nu mice (n = 52) were bilaterally transplanted with human GIST: UZLX-GIST4 (KIT exon 11 mutation, imatinib sensitive), UZLX-GIST2 (KIT exon 9, imatinib dose-dependent resistance), or UZLX-GIST9 (KIT exon 11 and 17 mutations, imatinib resistant). Mice were grouped as control (untreated), imatinib (50 mg/kg/bid), and cabozantinib (30 mg/kg/qd) and treated orally for 15 days. Cabozantinib resulted in significant tumor regression in UZLX-GIST4 and -GIST2 and delayed tumor growth in -GIST9. In all three models, cabozantinib inhibited the proliferative activity, which was completely absent in UZLX-GIST4 and significantly reduced in -GIST2 and -GIST9. Increased apoptotic activity was observed only in UZLX-GIST4. Cabozantinib inhibited the KIT signaling pathway in UZLX-GIST4 and -GIST2. In addition, compared with both control and imatinib, cabozantinib significantly reduced microvessel density in all models. In conclusion, cabozantinib showed antitumor activity in GIST PDX models through inhibition of tumor growth, proliferation, and angiogenesis, in both imatinib-sensitive and imatinib-resistant models. Mol Cancer Ther; 15(12); 2845-52. ©2016 AACR.
Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Tumores do Estroma Gastrointestinal/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , Piridinas/farmacologia , Anilidas/química , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Biópsia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/farmacologia , Camundongos , Necrose , Gradação de Tumores , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-kit/metabolismo , Piridinas/química , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
INTRODUCTION: Clear cell sarcoma (CCS) is an aggressive tumor, typically developing in tendons or aponeuroses. The outcome of this orphan disease is poor, with 5-year and 10-year survival rates of localized CCS around 60-70% and 40-50%. Once the disease has metastasized, it is usually fatal due to its chemotherapy-resistant nature. Systemic treatment options are poorly standardized and the use of chemotherapy is based on weak scientific evidence. AREAS COVERED: In this review, we systematically discuss the current scientific evidence for the systemic treatment of CCS, including tyrosine kinase inhibitors, immunotherapy and MET inhibitors. Expert commentary: Recent insights in the biology of CCS have identified new potential therapeutic targets, which should be tested in prospective clinical trials. Whenever possible, patients with metastatic CCS should be included in clinical trials with good biological rationale. Innovative trial methodology and new regulatory mechanisms are required to provide patients with uncommon cancers with active drugs.
Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia/métodos , Sarcoma de Células Claras/terapia , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Metástase Neoplásica , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Sarcoma de Células Claras/patologia , Taxa de SobrevidaRESUMO
INTRODUCTION: The rarity of dedifferentiated liposarcoma (DDLPS) and the lack of experimental DDLPS models limit the development of novel therapeutic strategies. Pazopanib (PAZ) is a tyrosine kinase inhibitor that is approved for the treatment of non-adipocytic advanced soft tissue sarcoma. The activity of this agent has not yet been properly explored in preclinical liposarcoma models nor in a randomized phase Ш clinical trial in this entity. The aim of the present study was to investigate whether PAZ had antitumor activity in DDLPS models in vivo. MATERIAL AND METHODS: We established two patient-derived DDLPS xenograft models (UZLX-STS3 and UZLX-STS5) through implantation of tumor material from sarcoma patients in athymic nude NMRI mice. An animal model of the SW872 liposarcoma cell line was also used. To investigate the efficacy of PAZ in vivo, mice bearing tumors were treated for 2 weeks with sterile water, doxorubicin (1.2 mg/kg, intraperitoneally, twice per week), PAZ [40 mg/kg, orally (p.o.), twice per day], or PAZ plus doxorubicin (same schedules as for single treatments). RESULTS: Patient-derived xenografts retained the histologic and molecular features of DDLPS. PAZ significantly delayed tumor growth by decreasing proliferation and inhibited angiogenesis in all models tested. Combining the angiogenesis inhibitor with an anthracycline did not show superior efficacy. CONCLUSION: These results suggest that PAZ has potential antitumor activity in DDLPS primarily through antiangiogenic effects and therefore should be explored in clinical trials.
RESUMO
BACKGROUND: Acquired resistance to tyrosine kinase inhibitors (TKIs) in gastrointestinal stromal tumours (GISTs) is most commonly caused by secondary KIT or PDGFRA mutations. In this study we characterize a newly established GIST xenograft model, UZLX-GIST9, and evaluate the in vivo response of the model to standard TKIs (imatinib, sunitinib, and regorafenib). METHODS: Tumour fragments from a metastatic lesion of a GIST patient clinically progressing after treatment with imatinib, sunitinib and regorafenib were engrafted in a nude, immunodeficient mouse. Upon sequential passaging from mouse to mouse, tumour fragments were collected for histopathological and molecular characterization. The sensitivity of the model to treatment with TKIs was evaluated in 28 mice [passage 2 (n = 8), passage 4 (n = 20), 41 tumours]. Mice were grouped as follows: control (untreated), imatinib (50 mg/kg/BID), imatinib (100 mg/kg/BID), sunitinib (40 mg/kg/QD), and regorafenib (30 mg/kg/QD). After three weeks of oral treatment, tumours were collected for subsequent analysis. The efficacy of treatment was assessed by tumour volume, histopathology and Western immunoblotting. RESULTS: UZLX-GIST9 maintains the same typical morphological features and immunohistochemical characteristics as the original patient biopsy and expresses CD117 and DOG1. The KIT mutational profile (p.P577del + W557LfsX5+ D820G) remains the same as the original tissue sample originating from an intraspinal metastatic site. Three week treatment with different TKIs showed that the model is resistant to imatinib. Sunitinib induces tumour growth delay and regorafenib reduces the tumour burden by 30% as compared to control animals. While none of the TKIs had a significant effect on cell proliferation or cell survival, a remarkable increase of necrosis and significant reduction of microvessel density was observed under sunitinib and regorafenib. Western immunoblotting showed a mild reduction in KIT and AKT activation only in regorafenib treated tumours. CONCLUSIONS: We established a novel human GIST xenograft, UZLX-GIST9, harbouring KIT exon 11 and 17 mutations and maintaining the pheno-and genotype of the original tumour. UZLX-GIST9 shows different levels of response to standard TKIs. This model will help to study TKI resistance and to explore novel treatment approaches for patients with TKI-resistant GIST.
RESUMO
Sarcomas are a group of rare solid tumours arising from mesenchymal or connective tissue. This review focuses on soft tissue sarcoma and covers general topics such as the epidemiology, age distribution, site of disease, histogenesis, histological subtypes, prognosis and outcome of treatment. In more detail, the article reviews current systemic treatment standards and selected adverse events of agents such as doxorubicin, ifosfamide, trabectedin and pazopanib, and briefly highlights some drugs that are used off-label in specific subtypes of sarcoma.
Assuntos
Dioxóis/administração & dosagem , Doxorrubicina/administração & dosagem , Ifosfamida/administração & dosagem , Pirimidinas/administração & dosagem , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Sulfonamidas/administração & dosagem , Tetra-Hidroisoquinolinas/administração & dosagem , Antineoplásicos/administração & dosagem , Medicina Baseada em Evidências , Humanos , Indazóis , Trabectedina , Resultado do TratamentoRESUMO
A 56-year-old woman with rheumatoid factor-positive rheumatoid arthritis underwent FDG-PET/CT because of fatigue, fever, coughing, and weight loss for several months. FDG-PET/CT solely revealed a mildly hypermetabolic hypodense area in the left atrium. Subsequently, transthoracic echocardiography and contrast-enhanced MRI showed a left atrial pedunculated soft tissue mass suggestive for myxoma, with histological confirmation. Myocardial involvement by tumors is rare, and FDG-PET/CT has been very useful for identifying cardiac metastases. However, very few cases have been reported using FDG-PET/CT for detecting primary cardiac tumors, but as shown here, abnormal focal myocardial uptake should trigger further morphological assessment.