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Potential Therapeutic Implication for Synovial Sarcoma Parag P Published OnlineFirst August 30, 2018; DOI: 10.1158/1535-7163.MCT-18-0319 Small Molecule Therapeutics Molecular Cancer Therapeutics Preclinical Evaluation of Nintedanib, a Triple Angiokinase Inhibitor, in Soft-tissue Sarcoma: Potential Therapeutic Implication for Synovial Sarcoma Parag P. Patwardhan1, Elgilda Musi1, and Gary K. Schwartz1,2 Abstract Sarcomas are rare cancers that make up about 1% of all preclinical efficacy of nintedanib in soft-tissue sarcoma cell cancers in adults; however, they occur more commonly among lines. Nintedanib treatment resulted in significant antiproli- children and young adolescents. Sarcomas are genetically ferative effect in vitro in cell lines with high expression of RTK complex and are often difficult to treat given the lack of clinical drug targets. Furthermore, treatment with nintedanib showed efficacy of any of the currently available therapies. Receptor significant downregulation of downstream phosphorylated tyrosine kinases (RTK) such as c-Kit, c-Met, PDGFR, IGF-1R, as AKT and ERK1/2. Finally, treatment with nintedanib resulted well as FGFR have all been reported to be involved in driving in significant tumor growth suppression in mouse xenograft tumor development and progression in adult and pediatric model of synovial sarcoma. Notably, both the in vitro and soft-tissue sarcoma. These driver kinases often act as critical in vivo efficacy of nintedanib was superiortothatofimatinib, determinants of tumor cell proliferation and targeting these another multikinase inhibitor, previously tested with min- signal transduction pathways remains an attractive therapeutic imal success in clinical trials in sarcoma. Overall, the data approach. Nintedanib, a potent triple angiokinase inhibitor, from this study provide a strong rationale to warrant further targets PDGFR, VEGFR, and FGFR pathways critical for tumor clinical exploration of this drug in patients with synovial angiogenesis and vasculature. In this study, we evaluated the sarcoma. Mol Cancer Ther; 17(11); 2329–40. Ó2018 AACR. Introduction and migration (5). Role of RTKs such as IGF-1R, PDGFR, c-Met, AXL, and FGFR as well as nonreceptor tyrosine kinases (non- Sarcomas are rare cancers with subtypes that are often genet- RTK) such as FAK and Src acting as tumor drivers has been ically and biologically distinct (1, 2). Sarcomas make up about 1% reported in various sarcoma subtypes over the past few years of all cancers in adults with approximately 14,000 people diag- (6–11). However, the translation of these preclinical studies nosed with sarcoma per year in the United States. However, they into effective molecularly targeted therapies has met with only are relatively more common among children making up to 12% to modest clinical success (12, 13). Gastrointestinal stromal 15% of cancers in children under the age of 20 (3). Some of the tumor (GIST) is one of the few sarcoma subtypes where more common and molecularly heterogeneous sarcoma subtypes oncogenic mutations in PDGFRa and c-Kit (14, 15) have been include liposarcoma, leiomyosarcoma, and synovial sarcoma targeted successfully using tyrosine kinase inhibitors such as among others (4). Localized disease is usually surgically resected imatinib and crenolanib (16, 17).In addition, in patients with followed by radiotherapy with or without adjuvant chemother- well- and dedifferentiated liposarcomas carrying CDK4 ampli- apy. However, lack of clinical efficacy coupled with toxicity often fication have shown promising results including progression- limits the treatment options especially in metastatic cases of the free survival in clinical trials (18, 19). disease. Although targeted RTK therapy presents an attractive approach Receptor tyrosine kinases (RTK) actaskeymediatorsofsignal to treat this disease, lack of clinical success using traditional transduction pathways that regulate cell proliferation, survival, therapies warrants exploration of novel agents that block multiple kinases such as PDGFR, FGFR, and VEGFR known to be critical for driving sarcoma progression (8, 20–23). 1Department of Medicine, Columbia University Medical Center, New York, In this study, we tested the in vitro and in vivo antiproliferative 2 New York. Herbert Irving Comprehensive Cancer Center, Columbia University efficacy of nintedanib (BIBF1120), a potent PDGFR, VEGFR, and College of Medicine, New York, New York. FGFR inhibitor, in sarcoma. Nintedanib was recently approved Note: Supplementary data for this article are available at Molecular Cancer for the treatment of non–small-cell lung cancer in the Europian Therapeutics Online (http://mct.aacrjournals.org/). Union (EU). Efficacy of other multikinase inhibitors in vitro and Corresponding Author: Parag P. Patwardhan, Columbia University Medical in clinical trials in sarcoma has been reported previously by our Center, Herbert Irving Comprehensive Cancer Center, 1130 St. Nicholas Avenue, laboratory (24) as well as others (12). However, not many Room 207, New York, NY 10032. Phone: 212-851-4904; Fax: 212-851-4901; effective molecularly targeted therapies are currently available E-mail: [email protected] for patients with sarcoma including those with synovial sarcoma doi: 10.1158/1535-7163.MCT-18-0319 which has a propensity to metastasize in many cases. This is the Ó2018 American Association for Cancer Research. first report describing efficacy of nintedanib in this disease www.aacrjournals.org 2329 Downloaded from mct.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst August 30, 2018; DOI: 10.1158/1535-7163.MCT-18-0319 Patwardhan et al. setting and our results strongly warrant further clinical explora- and visualized by Enhanced Chemiluminescence Reagent (GE tion of this drug in synovial sarcoma. Healthcare). Materials and Methods Xenograft studies Chemicals and drugs Approximately 8-week-old athymic female mice were injected – Nintedanib (BIBF1120) was kindly provided by Boehringer- with 10 15 million cells in Matrigel of the cell line of interest and 3 Ingelheim Pharmaceuticals. Imatinib was purchased from LC allowed to grow until tumors reached 100 mm in volume prior to Laboratories. Selumetinib (MEKi) and MK-2206 (AKTi) were treatment with vehicle, imatinib (30 mg/kg i.p. once daily), or purchased from Selleck Chemicals. Drugs were dissolved in nintedanib (50 mg/kg orally once daily). Tumors were measured DMSO and aliquots were stored at À20C for long-term use. every 2 to 3 days using calipers and volumes calculated using the formula p/6 x (large diameter) Â (small diameter) where p stands for "pi". Animal weights were measured every 2 to 3 days as a Cell culture and reagents surrogate marker for overall toxicity. Animals were sacrificed 4 Cells were cultured in RPMI or DMEM with 10% FBS, 100 m/mL hours after the final dose of treatment (on day 21 for vehicle penicillin, and 100 mg/mL streptomycin, maintained at 37 Cin control or day 24 for imatinib and nintedanib treatment groups). 5% CO , and passaged for no more than 3 months. Synovial 2 Tumors were extracted from surrounding tissue and either flash- sarcoma cell lines (SYO-1 and HSSY-II) were obtained from Dr. frozen in liquid nitrogen for Western immunoblotting or placed Marc Ladanyi (Memorial Sloan Kettering Cancer Center, New in formalin or paraformaldehyde for IHC studies. Flash-frozen York, NY). Malignant peripheral nerve sheath tumor (MPNST) tissue was ground in RIPA lysis buffer and resin as per the cell line was supplied by Dr. Jonathan Fletcher (Dana Farber manufacturer's instructions using Sample Grinding Kit (GE Cancer Institute, Boston, MA). ST8814 cell line was a generous gift Healthcare) and analyzed via Western immunoblotting as from Dr. Karen Cichowski (BWS Biomedical Research Institute, described above. Formalin-fixed tissues were sectioned and Boston, MA), Ewing sarcoma cell lines (CHP100, A673) were stained with the indicated antibodies following standard proto- obtained from Dr. Melinda S. Merchant (Center for Cancer cols using HistoWiz automated histology services. Research, NCI/NIH, Bethesda, MD). Dedifferentiated liposar- coma (LS141, DDLS) were obtained from Dr. Samuel Singer (Memorial Sloan Kettering Cancer Center, New York, NY). Oste- Statistical analysis in vitro osarcoma cell line (SaOS2) was obtained from ATCC. Cell lines All experiments were carried out at least three times P CHP100 and A673 were authenticated using RT-PCR, and found unless otherwise indicated. values were calculated using Student t to have their expected characteristic chromosomal translocations. test, with values of 0.05 determined to be statistically signif- SYO-1 and HS-SY-II cell lines were authenticated by confirming icant. SE was calculated as the SD divided by the square root of the the expression of the pathognomonic SYT-SSX fusion gene by RT- number of samples tested. PCR. All cell lines were determined to be Mycoplasma free by using biochemical assay MycoAlert. Results Target RTKs for nintedanib are expressed in multiple sarcoma Cell viability assays cell lines Cell viability assays were carried out using the Dojindo Nintedanib is a small-molecule inhibitor that targets multiple Molecular Technologies (CCK-8) Kit as per the manufacturer's RTKs involved in tumor angiogenesis such as VEGFR, PDGFR, and instructions. Briefly, 2,000 cells were plated in 96-well plates FGFR (25, 26). It is an indolinone derivative that has been shown and then treated with the indicated drugs for 6 days unless to block RTKs, such as VEGFR and PDGFR families at low indicated
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