title: Hedgehog pathway inhibition in chondrosarcoma using the smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth.
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 chondrosarcoma 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 chondrosarcoma 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, as well as 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.
authors.affiliation: Authors' Affiliations: Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts; Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio; Program in Developmental and Stem Cell Biology, Hospital for Sick Children; University Musculoskeletal Oncology Unit and Lunenfeld Research Institute, Mount Sinai Hospital; and Division of Orthopaedic Surgery, Department of Surgery, University of Toronto, Toronto, Ontario Canada.
authors.forename: Veronica T
authors.initials: VT
authors.lastname: Campbell
authors.forename: Puviindran
authors.initials: P
authors.lastname: Nadesan
authors.forename: S Amanda
authors.initials: SA
authors.lastname: Ali
authors.forename: Chang Ye Yale
authors.initials: CY
authors.lastname: Wang
authors.forename: Heather
authors.initials: H
authors.lastname: Whetstone
authors.forename: Raymond
authors.initials: R
authors.lastname: Poon
authors.forename: Qingxia
authors.initials: Q
authors.lastname: Wei
authors.forename: John
authors.initials: J
authors.lastname: Keilty
authors.forename: Jennifer
authors.initials: J
authors.lastname: Proctor
authors.forename: Lauren W
authors.initials: LW
authors.lastname: Wang
authors.forename: Suneel S
authors.initials: SS
authors.lastname: Apte
authors.forename: Karen
authors.initials: K
authors.lastname: McGovern
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Alman
authors.forename: Jay S
authors.initials: JS
authors.lastname: Wunder
mesh_terms: D000071096:ADAMTS Proteins; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D002114:Calcinosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002813:Chondrosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D000072086:Smoothened Receptor; D047368:Tumor Burden / Q000187:drug effects; D014704:Veratrum Alkaloids / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C454120:ADAMTSL1 protein, human; D000970:Antineoplastic Agents; D016326:Extracellular Matrix Proteins; D053823:Hedgehog Proteins; C541444:IPI-926; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids; D000071096:ADAMTS Proteins