Contents lists available at ScienceDirect Tissue and Cell journal homepage: www.elsevier.com/locate/tice Doxorubicin-resistant pleomorphic liposarcoma with PDGFRA gene amplification is targeted and regressed by pazopanib in a patient-derived orthotopic xenograft mouse model Tasuku Kiyuna a,b,c , Takashi Murakami a,b , Yasunori Tome c , Kentaro Igarashi a,b , Kei Kawaguchi a,b , Kentaro Miyake a,b , Masuyo Miyake a,b , Yunfeng Li d , Scott D. Nelson d , Sarah M. Dry d , Arun S. Singh e , Tara A. Russell f , Shree Ram Singh g, ⁎ , Fuminori Kanaya c , Fritz C. Eilber f, ⁎ , Robert M. Hoffman a,b, ⁎⁎ a AntiCancer Inc., San Diego, CA, USA b Department of Surgery, University of California, San Diego, CA, USA c Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan d Department of Pathology, University of California, Los Angeles, CA, USA e Division of Hematology-Oncology, University of California, Los Angeles, CA, USA f Division of Surgical Oncology, University of California, Los Angeles, CA, USA g Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA ARTICLE INFO Keywords: Pleomorphic liposarcoma PDOX Pazopanib PDGFRA Targeted therapy Temozolomide ABSTRACT Pleomorphic liposarcoma (PLPS) is a heterogeneous resistant group of tumors. Complete surgical resection is the only known way to treat PLPS. PLPS is reristant to both radiation and chemotherapy. Therefore, precise in- dividualized therapy is needed to improve outcome of advanced PLPS patients. In this study, a patient-derived orthotopic xenograft (PDOX) model of a PDGFRA-amplified PLPS was established in the biceps femoris of nude mice by surgical orthotopic implantation (SOI) in order to match the patient. The PLPS PDOX was treated with pazopanib (PAZ) which targets PDGFRA, as well as with temozolomide (TEM) and first-line therapy doxorubicin (DOX). The PLPS PDOX was resistant to DOX and responded very well to PAZ as well as TEM. The tumor volume on treatment day-14 relative to day-1 was as follows: DOX (4.50 ± 2.6, p = 0.8087); PAZ (1.29 ± 0.9, p = 0.0008 compared to the control, p = 0.0167 compared to DOX); TEM (1.07 ± 0.8, p = 0.0079 compared to the control, p = 0.0079 compared to DOX). There was no significant difference in body weight between any treated group or control. The PAZ- and TEM-treated tumors showed extensive necrosis compared to the DOX- treated and untreated PDOX tumors. The present study showed that PDGFRA amplification could be effectively targeted by PAZ. The PLPS PDOX model also identified the efficacy of TEM which does not target PDGFRA, indicating that the PDOX model can identify effective targeted therapy as well as standard therapy and at the same time, identify ineffective drugs, even if they are first-line. 1. Introduction Pleomorphic liposarcoma (PLPS) is a heterogeneous recalcitrant group of tumors in need of precise individualized treatment. PLPS fre- quently recurs locally and at distant sites (Manji and Schwartz, 2016). PLPS accounts for only 5%–15% of all liposarcomas and has high me- tastatic potential in 30%–35% of cases. A fraction of PLPS contains mutations or deletions of genes that regulate the tumor suppressor neurofibromin (NF1) gene as well as TP53 mutations (Barretina et al., 2010; Italiano et al., 2011). PLPS has been reported in several tissues (Agarwal et al., 2017; Tiemeier et al., 2018). Most of the PLPS cases have been reported in middle age and older patients with a few ex- ceptions (Ahmed et al., 2004; Saeed et al., 2010; Rudzinski et al., 2011; Tseng et al., 2013). Because of a lack of effective therapeutic options for PLPS, complete surgical resection is the only known therapy. Both ra- diation and chemotherapy are not very effective for advanced un- resectable PLPS (Gebhard et al., 2002; Hornick et al., 2004; Ghadimi et al., 2011; Guan et al., 2015). Therefore, precise individualized https://doi.org/10.1016/j.tice.2018.05.010 Received 4 May 2018; Received in revised form 7 May 2018; Accepted 21 May 2018 ⁎ Corresponding authors: ⁎⁎ Corresponding author at: AntiCancer Inc., San Diego, CA, USA. E-mail addresses: singhshr@mail.nih.gov (S.R. Singh), fceilber@mednet.ucla.edu (F.C. Eilber), all@anticancer.com (R.M. Hoffman). Tissue and Cell 53 (2018) 30–36 Available online 22 May 2018 0040-8166/ Published by Elsevier Ltd. T