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.

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.

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 patientderived xenograft (PDX) GIST models carrying different KIT mutations, with differential sensitivity to standard TKI.Experimental Design: NMRI nu/nu mice (n ¼ 93) were transplanted with human GIST xenografts with KIT exon 11þ17 (UZLX-GIST9 KIT 11þ17 ), exon 11 (UZLX-GIST3 KIT 11 ), or exon 9 (UZLX-GIST2B KIT 9 ) 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 KIT 11þ17 ); 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 11þ17 and -GIST2B KIT 9 ) or equal (UZLX-GIST3 KIT 11 ) antitumor activity to the standard dose of imatinib. In UZLX-GIST9 KIT 11þ17 , 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).

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.

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.

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.

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 ¼ 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. Ó2016 AACR.

BackgroundAcquired 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).MethodsTumour 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.ResultsUZLX-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.ConclusionsWe 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.