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Hedgehog Pathway Inhibition in Chondrosarcoma Using the Smoothened Inhibitor IPI-926 Directly Inhibits Sarcoma Cell Growth

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Hedgehog Pathway Inhibition in Chondrosarcoma Using the Smoothened Inhibitor IPI-926 Directly Inhibits Sarcoma Cell Growth Published OnlineFirst March 14, 2014; DOI: 10.1158/1535-7163.MCT-13-0731 Molecular Cancer Cancer Biology and Signal Transduction Therapeutics Hedgehog Pathway Inhibition in Chondrosarcoma Using the Smoothened Inhibitor IPI-926 Directly Inhibits Sarcoma Cell Growth Veronica T. Campbell1, Puviindran Nadesan3, S. Amanda Ali3, Chang Ye Yale Wang3, Heather Whetstone3, Raymond Poon3, Qingxia Wei3, John Keilty1, Jennifer Proctor1, Lauren W. Wang2, Suneel S. Apte2, Karen McGovern1, Benjamin A. Alman3,5, and Jay S. Wunder4,5 Abstract Hedgehog (Hh) pathway inhibition in cancer has been evaluated in both the ligand-independent and ligand- dependent settings, where Hh signaling occurs either directly within the cancer cells or within the nonmalignant cells of the tumor microenvironment. Chondrosarcoma is a malignant tumor of cartilage in which there is ligand- dependent activation of Hh signaling. IPI-926 is a potent, orally delivered small molecule that inhibits Hh pathway signaling by binding to Smoothened (SMO). Here, the impact of Hh pathway inhibition on primary chondro- sarcoma xenografts was assessed. Mice bearing primary human chondrosarcoma xenografts were treated with IPI- 926. The expression levels of known Hh pathway genes, in both the tumor and stroma, and endpoint tumor volumes were measured. Gene expression profiling of tumors from IPI-926–treated mice was conducted to identify potential novel Hh target genes. Hh target genes were studied to determine their contribution to the chondro- sarcoma neoplastic phenotype. IPI-926 administration results in downmodulation of the Hh pathway in primary chondrosarcoma xenografts, as demonstrated by evaluation of the Hh target genes GLI1 and PTCH1,aswellas inhibition of tumor growth. Chondrosarcomas exhibited autocrine and paracrine Hh signaling, and both were affected by IPI-926. Decreased tumor growth is accompanied by histopathologic changes, including calcification and loss of tumor cells. Gene profiling studies identified genes differentially expressed in chondrosarcomas following IPI-926 treatment, one of which, ADAMTSL1, regulates chondrosarcoma cell proliferation. These studies provide further insight into the role of the Hh pathway in chondrosarcoma and provide a scientific rationale for targeting the Hh pathway in chondrosarcoma. Mol Cancer Ther; 13(5); 1259–69. Ó2014 AACR. Introduction transmembrane receptor Patched (PTCH) is localized in The Hedgehog (Hh) signal transduction pathway the primary cilia and inhibits the activity of the G-pro- plays a critical role in cell differentiation and patterning tein–coupled receptor-like protein Smoothened (SMO), during development, but is inactive in many adult cells which is sequestered within cytosolic vesicles (2). Inhi- (1). There are three Hh ligands—Sonic Hedgehog (SHH), bition of the key signaling protein SMO ensures that GLI Indian Hedgehog (IHH), and Desert Hedgehog (DHH)— transcription factors are held in an inactive form via a that activate the pathway. In the absence of Hh ligand, the complex that contains Suppressor of Fused (SUFU). When Hh ligands bind PTCH, repression of SMO is relieved, resulting in signaling that activates the GLI Authors' Affiliations: 1Infinity Pharmaceuticals, Inc., Cambridge, Massachu- transcription factors, leading to increased expression of setts; 2Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio; 3Program in Developmental and Stem Cell Biology, Hospital for Sick many genes involved in growth and development. A role Children; 4University Musculoskeletal Oncology Unit and Lunenfeld Research for Hh pathway activation has been demonstrated in a 5 Institute, Mount Sinai Hospital; and Division of Orthopaedic Surgery, Depart- broad range of cancers. Ligand-independent signaling ment of Surgery, University of Toronto, Toronto, Ontario Canada occurs in some tumors due to genetic mutations in key Note: Supplementary data for this article are available at Molecular Cancer pathway members such as PTCH (3–5); however, in Therapeutics Online (http://mct.aacrjournals.org/). many tumors, ligand-dependent Hh signaling occurs Current address for B.A. Alman: Department of Orthopaedic Surgery, Duke either directly within the tumor cells, or involves the University, DUMC 2888, 200 Trent Drive, Orange Zone 5th Floor, Durham, cells within the tumor microenvironment. NC 27710. Emerging evidence points to a critical role for Hh Corresponding Author: Jay S. Wunder, University Musculoskeletal Oncology Unit, Mount Sinai Hospital, 476-600 University Avenue, Toronto, signaling in the pathogenesis of chondrosarcoma, a malig- Ontario M5G 1X5, Canada. Phone: 416-586-5995; Fax: 416-586-8611; nant tumor of cartilaginous origin (6). A potential role for E-mail: [email protected] Hh in chondrosarcoma was first implied by studies that doi: 10.1158/1535-7163.MCT-13-0731 evaluated Hh signaling in the biology of chondrocytes Ó2014 American Association for Cancer Research. within the growth plate. IHH regulates the differentiation www.aacrjournals.org 1259 Downloaded from mct.aacrjournals.org on September 25, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst March 14, 2014; DOI: 10.1158/1535-7163.MCT-13-0731 Campbell et al. of chondrocytes during endochondral bone development. Armand Frappier (IAF) (Laval, Quebec, Canada). The During normal bone development, expression of IHH by study was conducted in accordance with current standard prehypertrophic chondrocytes leads to proliferation of operating procedures. Six-week-old CD-1 mice were ran- growth plate chondrocytes. IHH subsequently upregu- domized to receive IPI-926 by oral gavage at 30 mg/kg for lates PTHrP, which inhibits chondrocyte differentiation 14 consecutive days, and the vehicle control mice were and downregulates IHH, thus completing a tightly con- treated with 0.5% methylcellulose, 5% Tween 80 in SWFI, trolled negative feedback loop. Thus, IHH ligand func- USP. On day 14 of dosing, the mice were sacrificed and tions as a central regulator of endochondral ossification tibiofemoral (knee) joints were collected into 10% forma- and regulates the proliferation and differentiation of lin and prepared for histologic evaluation. chondrocytes via a feedback loop essential for mainte- nance of the growth plate (7–9). The importance of Hh Primary chondrosarcoma xenograft mouse model signaling in developing bone was further substantiated in and drug treatment recent studies where young mice treated with a Smo With institutional review board approval, 6 human inhibitor developed severe bone defects, including pre- chondrosarcoma tumor samples were obtained fresh from mature differentiation of chondrocytes, thinning of cor- the operating room at Mount Sinai Hospital (Toronto, tical bone, and fusion of the growth plate (10). Canada). After surgical removal, tumor samples were In chondrosarcoma, signaling through the IHH/PTHrP divided into explants of 5 Â 5 Â 5 mm each, and implanted axis is dysregulated. The ability of PTHrP to inhibit IHH into the subcutaneous tissues on the back of either non- expression is lost, leading to constitutive Hh signaling obese diabetic/severe combined immunodeficient (NOD/ (11). High expression levels of the Hh-regulated genes SCID) or interleukin-2 receptor gamma chain (gamma)- PTCH1 and GLI1 provide evidence for constitutive Hh null NOD/SCID (NSG) mice. For each condition tested in pathway signaling in chondrosarcoma (12). Chondrosar- vivo, 10 mice with tumor explants from each human coma tumor cell proliferation is increased by Hh ligand chondrosarcoma were utilized. In all chondrosarcoma in and decreased by inhibitors of the Hh pathway in cell vivo studies, IPI-926 was administered orally by gavage at culture. Studies using tumor explants found that exposure 40 mg/kg, five times a week on a Monday–Friday sched- to Hh inhibitors downregulated expression of GLI1 and ule. The vehicle control mice were treated with 5% cyclo- PTCH1, supporting the existence of ligand-dependent dextrin in PBS. Treatment was initiated on the day of tumor autocrine Hh signaling in chondrosarcoma. implant, one month after implantation, or after one pas- There are few therapeutic options for patients with sage through the NOD/SCID mice and transplantation chondrosarcoma. These tumors are largely resistant to into NSG mice. Chemotherapies were injected intrave- chemotherapy and radiotherapy, therefore radical surgery nously. Doxorubicin was administered at 5 mg/kg three constitutes the mainstay of therapy in patients. Although times a week on a Monday, Wednesday, and Friday chemotherapy may be beneficial for patients with the rare schedule. Cisplatin was administered at 8 mg/kg once a tumor variant known as mesenchymal chondrosarcoma, week. After sacrifice and removal of the xenograft, tumor there is little evidence of efficacy against dedifferentiated volume was calculated using three-dimensional measure- chondrosarcoma or the most common subtype of conven- ments as previously described (12). For the MIA PaCa-2 tional chondrosarcoma (13–15). In patients with unresect- pancreatic carcinoma cell line in vivo study, tumor cells able disease, there is no treatment option, and the outcome were obtained from American Type Culture Collection is ultimately fatal. The relatively low incidence of chon- (ATCC) and cultured in RPMI-1640 media supplemented drosarcoma has made the study of new therapeutic agents with 10% FBS and 1% penicillin/streptomycin. Cells were difficult. Given the role of the Hh pathway in the biology of prepared in sterile
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