Jasmien Cornillie

Soft tissue sarcoma: an update on systemic treatment options for patients with advanced disease.

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.

Pazopanib, a Receptor Tyrosine Kinase Inhibitor, Suppresses Tumor Growth through Angiogenesis in Dedifferentiated Liposarcoma Xenograft Models

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.

Biology and management of clear cell sarcoma: state of the art and future perspectives

ABSTRACT 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.

Cabozantinib is active against human gastrointestinal stromal tumor xenografts carrying different KIT mutations

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.

Abstract 1460: Establishment and characterization of a panel of patient-derived soft tissue sarcoma (STS) xenograft models for in vivo testing of novel therapeutic approaches

Background: STS constitutes a rare and very heterogeneous family of tumors of mesenchymal origin. The limited treatment options available for advanced STS underline the need for reliable preclinical models to test novel therapeutic strategies. Methods: A panel of patient-derived xenografts was established and is currently expanded in nu/nu NMRI mice by subcutaneous implantation of fresh, surgically resected tumor specimens from consenting patients with STS, treated at the University Hospitals Leuven, Belgium. We mainly focused on STS subtypes which harbor specific genetic alterations (e.g. translocations, gene amplifications). Once tumor growth was observed, pieces of tissue were re-transplanted to the next generation of mice. At each passage tumor fragments were collected for histological and molecular characterization. Fluorescence in situ hybridization (FISH) was performed to confirm specific genomic alterations in selected xenografts. A STS xenograft model was considered established after observing maintained histological and molecular features for at least two passages. Results: Until now a total of 78 STS patient samples have been transplanted. Fifteen well-characterized, stable STS models have already been established, maintaining the features of the original tumor: myxofibrosarcoma (4 models), dedifferentiated liposarcoma (2), synovial sarcoma (2), epithelioid haemangioendothelioma (1), malignant peripheral nerve sheath tumor (2), mesenchymal chondrosarcoma (1), leiomyosarcoma (2) and sarcoma not otherwise specified (1). Some of these models have already been successfully used for in vivo testing of novel agents, including tyrosine kinase inhibitors or cytotoxic (pro-)drugs. Twelve other xenografts are still in early stages of engraftment, not yet fulfilling our criteria of “established model”. Conclusion: This newly established, representative panel of STS xenografts is characterized by stable histological and molecular features reflecting the pheno- and genotype of the original patient samples. This panel is thus well suited for in vivo drug testing of innovative agents. The unique availability of models of some ultra-rare entities will also allow us to study the biology of these diseases. The platform is available for collaboration with academic and commercial partners (contact patrick.schoffski@uzleuven.be). Citation Format: Haifu Li, Jasmien Cornillie, Agnieszka Wozniak, Thomas Van Looy, Yemarshet Gebreyohannes, Jasmien Wellens, Ulla Vanleeuw, Daphne Hompes, Marguerite Stas, Friedl Sinnaeve, Maria Debiec-Rychter, Raf Sciot, Patrick Schoffski. Establishment and characterization of a panel of patient-derived soft tissue sarcoma (STS) xenograft models for in vivo testing of novel therapeutic approaches. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1460. doi:10.1158/1538-7445.AM2015-1460

In vivo antitumoral efficacy of PhAc-ALGP-doxorubicin, an enzyme-activated doxorubicin prodrug, in patient-derived soft tissue sarcoma xenograft models

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.

Abstract 775: Anti-tumor effects of dovitinib, a multi-target kinase inhibitor, in patient-derived gastrointestinal stromal tumor (GIST) xenograft models

Background: The majority of GISTs are driven by KIT/PDGFRA gain of function mutations. Advanced GIST is routinely treated with tyrosine kinase inhibitors (TKI; e.g imatinib, sunitinib and regorafenib). However, with time, heterogeneous resistance to these agents occurs, mainly due to acquired mutations in KIT. We tested the efficacy of dovitinib, which acts against VEGFR, FGFR, FLT3, PDGFRB and KIT, using patient-derived GIST xenograft models. Methods: NMRI nu/nu mice (n = 47) were bilaterally transplanted with the human GIST xenografts: a dose-dependent-imatinib-sensitive model UZLX-GIST2 (KIT: p.A502_Y503dup) or a model resistant to both imatinib and sunitinib, UZLX-GIST9 (KIT: p.P577del+p.W557LfsX5+p.D820G). Mice were divided to four treatment groups: control (untreated), imatinib (50 mg/kg/bid p.o.), imatinib (100 mg/kg/bid p.o.) and dovitinib (30 mg/kg/qd p.o.). Efficacy was assessed by tumor volume measurement (3x/week), histopathology [hematoxylin & eosin staining (HE p Conclusion: The multi-kinase inhibitor dovitinib showed anti-tumor efficacy in GIST xenograft models, though the effect was more pronounced in KIT exon 9 mutant (UZLX-GIST2). The decrease in MVD in both models suggested that the anti-tumor effect in these models was at least partially mediated by an anti-angiogenic effect of dovitinib. 1 Antonescu et al. Clin Cancer Res. 2005; 11:4182-90 Citation Format: Yemarshet Kelemework Gebreyohannes, Thomas Van Looy, Agnieszka Wozniak, Jasmien Wellens, Haifu Li, Jasmien Cornillie, Ulla Vanleeuw, Lise Vreys, Matthew Squires, Ana-Maria Rodringuez, Maria Debiec-Rychter, Raf Sciot, Patrick Schoffski. Anti-tumor effects of dovitinib, a multi-target kinase inhibitor, in patient-derived gastrointestinal stromal tumor (GIST) xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 775. doi:10.1158/1538-7445.AM2015-775

Abstract 5353: Efficacy of an innovative, enzyme-activated doxorubicin prodrug in patient-derived dedifferentiated liposarcoma and synovial sarcoma xenograft models

Background and objective: Dedifferentiated liposarcoma (DDLPS) and synovial sarcoma (SynSa) are aggressive malignant tumors of mesenchymal origin. Prognosis of advanced disease is poor with low response rates to first-line single agent doxorubicin (doxo) treatment, which is regarded as standard of care in metastatic disease. We evaluated the efficacy of PhAc-ALGP-doxorubicin (ALGP-doxo), a prodrug which is metabolized to doxo by peptidases present in the tumor microenvironment and/or tumor cells, in one SynSa and two DDLPS patient-derived xenografts. Methods: NMRI mice (n = 24) were transplanted subcutaneously on both flanks with human DDLPS (models UZLX-STS3 and UZLX-STS5) or SynSa (UZLX-STS7). Mice were randomized to three treatment groups: control (vehicle), doxo (0.03 mmol/kg for UZLX-STS3; 0.04 mmol/kg for UZLX-STS5 and UZLX-STS7) or ALGP-doxo (1.2 mmol/kg). Treatments were administered using intraperitoneal osmotic pumps, continuously releasing drugs for 7 days. Afterwards, half of mice from each group were sacrificed and tumors were collected. Remaining mice were monitored for another 14 days and tumors were collected on day 21. Treatment efficacy was assessed by tumor volume, hematoxylin and eosin (HE 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5353. doi:10.1158/1538-7445.AM2015-5353

Retrospective Analysis of Outcome of Patients with Metastatic Leiomyosarcoma in a Tertiary Referral Center

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.

Single-Center Experience with Intimal Sarcoma, an Ultra-Orphan, Commonly Fatal Mesenchymal Malignancy

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.