Table of Contents Author Guidelines Submit a Manuscript
Sarcoma
Volume 2011 (2011), Article ID 483154, 13 pages
http://dx.doi.org/10.1155/2011/483154
Review Article

Liposarcoma: Molecular Genetics and Therapeutics

Sarcoma Genomics & Genetics, Peter MacCallum Cancer Centre, 12 St Andrews Place, East Melbourne, VIC 3002, Australia

Received 16 September 2010; Accepted 29 October 2010

Academic Editor: Stephen Lessnick

Copyright © 2011 Rachel Conyers et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. N. C. Institute, A Snaphsot of Sarcoma, 2010, http://www.cancer.gov/cancertopics/types/soft-tissue-sarcoma.
  2. T. M. Mack, “Sarcomas and other malignancies of soft tissue, retroperitoneum, peritoneum, pleura, heart, mediastinum, and spleen,” Cancer, vol. 75, no. 1, pp. 211–244, 1995. View at Google Scholar · View at Scopus
  3. A. Jemal, R. Siegel, E. Ward, T. Murray, J. Xu, C. Smigal, and M. J. Thun, “Cancer statistics, 2006,” CA Cancer Journal for Clinicians, vol. 56, no. 2, pp. 106–130, 2006. View at Publisher · View at Google Scholar · View at Scopus
  4. W. H. Henricks, Y. C. Chu, J. R. Goldblum, and S. W. Weiss, “Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation,” American Journal of Surgical Pathology, vol. 21, no. 3, pp. 271–281, 1997. View at Publisher · View at Google Scholar · View at Scopus
  5. D. C. Linehan, J. J. Lewis, D. Leung, and M. F. Brennan, “Influence of biologic factors and anatomic site in completely resected liposarcoma,” Journal of Clinical Oncology, vol. 18, no. 8, pp. 1637–1643, 2000. View at Google Scholar · View at Scopus
  6. J. J. Lewis, D. Leung, J. M. Woodruff, and M. F. Brennan, “Retroperitoneal soft-tissue sarcoma: analysis of 500 patients treated and followed at a single institution,” Annals of Surgery, vol. 228, no. 3, pp. 355–365, 1998. View at Publisher · View at Google Scholar · View at Scopus
  7. D. McCormick, T. Mentzel, A. Beham, and C. D. M. Fletcher, “Dedifferentiated liposarcoma: clinicopathologic analysis of 32 cases suggesting a better prognostic subgroup among pleomorphic sarcomas,” American Journal of Surgical Pathology, vol. 18, no. 12, pp. 1213–1223, 1994. View at Google Scholar · View at Scopus
  8. S. Gebhard, J.-M. Coindre, and J.-M. Coindre, “Pleomorphic liposarcoma: clinicopathologic, immunohistochemical, and follow-up analysis of 63 cases: a study from the French Federation of Cancer Centers Sarcoma Group,” American Journal of Surgical Pathology, vol. 26, no. 5, pp. 601–616, 2002. View at Publisher · View at Google Scholar · View at Scopus
  9. S. Singer, C. R. Antonescu, E. Riedel, M. F. Brennan, and R. E. Pollock, “Histologic subtype and margin of resection predict pattern of recurrence and survival for retroperitoneal liposarcoma,” Annals of Surgery, vol. 238, no. 3, pp. 358–371, 2003. View at Google Scholar · View at Scopus
  10. L.-G. Kindblom, “Lipomatous tumors—how we have reached our present views, what controversies remain and why we still face diagnostic problems: a tribute to Dr Franz Enzinger,” Advances in Anatomic Pathology, vol. 13, no. 6, pp. 279–285, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  11. R. J. Rieker, J. Weitz, and J. Weitz, “Genomic profiling reveals subsets of dedifferentiated liposarcoma to follow separate molecular pathways,” Virchows Archiv, vol. 456, no. 3, pp. 277–285, 2010. View at Publisher · View at Google Scholar · View at PubMed
  12. R. L. Jones, C. Fisher, O. Al-Muderis, and I. R. Judson, “Differential sensitivity of liposarcoma subtypes to chemotherapy,” European Journal of Cancer, vol. 41, no. 18, pp. 2853–2860, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  13. R. S. A. de Vreeze, D. de Jong, R. L. Haas, F. Stewart, and F. van Coevorden, “Effectiveness of radiotherapy in myxoid sarcomas is associated with a dense vascular pattern,” International Journal of Radiation Oncology Biology Physics, vol. 72, no. 5, pp. 1480–1487, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  14. G. Pitson, P. Robinson, and P. Robinson, “Radiation response: an additional unique signature of myxoid liposarcoma,” International Journal of Radiation Oncology Biology Physics, vol. 60, no. 2, pp. 522–526, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  15. R. S. A. de Vreeze, D. de Jong, and D. de Jong, “Added value of molecular biological analysis in diagnosis and clinical management of liposarcoma: a 30-year single-institution experience,” Annals of Surgical Oncology, vol. 14, no. 3, pp. 686–693, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. A. P. Dei Tos, C. Doglioni, and C. Doglioni, “Coordinated expression and amplification of the MDM2, CDK4, and HMGI-C genes in atypical lipomatous tumours,” Journal of Pathology, vol. 190, no. 5, pp. 531–536, 2000. View at Google Scholar · View at Scopus
  17. M. D. Kraus, L. Guillou, and C. D. M. Fletcher, “Well-differentiated inflammatory liposarcoma: an uncommon and easily overlooked variant of a common sarcoma,” American Journal of Surgical Pathology, vol. 21, no. 5, pp. 518–527, 1997. View at Publisher · View at Google Scholar · View at Scopus
  18. P. Argani, F. Facchetti, G. Inghirami, and J. Rosai, “Lymphocyte-rich well-differentiated liposarcoma: report of nine cases,” American Journal of Surgical Pathology, vol. 21, no. 8, pp. 884–895, 1997. View at Publisher · View at Google Scholar · View at Scopus
  19. T. Hasegawa, K. Seki, and K. Seki, “Dedifferentiated liposarcoma of retroperitoneum and mesentery: varied growth patterns and histological grades—a clinicopathologic study of 32 cases,” Human Pathology, vol. 31, no. 6, pp. 717–727, 2000. View at Google Scholar · View at Scopus
  20. P. Tontonoz, S. Singer, and S. Singer, “Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor γ and the retinoid X receptor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 1, pp. 237–241, 1997. View at Publisher · View at Google Scholar · View at Scopus
  21. S. W. Weiss and V. K. Rao, “Well-differentiated liposarcoma (atypical lipoma) of deep soft tissue of the extremities, retroperitoneum, and miscellaneous sites: a follow-up study of 92 cases with analysis of the incidence of “dedifferentiation”,” American Journal of Surgical Pathology, vol. 16, no. 11, pp. 1051–1058, 1992. View at Publisher · View at Google Scholar · View at Scopus
  22. J. Rosai, M. Akerman, P. Dal Cin et al., “Combined morphologic and karyotypic study of 59 atypical lipomatous tumors: evaluation of their relationship and differential diagnosis with other adipose tissue tumors. (A report of the CHAMP Study Group),” American Journal of Surgical Pathology, vol. 20, no. 10, pp. 1182–1189, 1996. View at Publisher · View at Google Scholar
  23. F. Pedeutour, A. Forus, and A. Forus, “Structure of the supernumerary ring and giant rod chromosomes in adipose tissue tumors,” Genes Chromosomes and Cancer, vol. 24, no. 1, pp. 30–41, 1999. View at Publisher · View at Google Scholar · View at Scopus
  24. A. Forus, D. O. Weghuis, D. Smeets, O. Fodstad, O. Myklebost, and A. G. Van Kessel, “Comparative genomic hybridization analysis of human sarcomas: I. Occurrence of genomic imbalances and identification of a novel major amplicon at 1q21-q22 in soft tissue sarcomas,” Genes Chromosomes and Cancer, vol. 14, no. 1, pp. 8–14, 1995. View at Publisher · View at Google Scholar · View at Scopus
  25. J. Szymanska, M. Virolainen, and M. Virolainen, “Overrepresentation of 1q21-23 and 12q13-21 in lipoma-like liposarcomas but not in benign lipomas: a comparative genomic hybridization study,” Cancer Genetics and Cytogenetics, vol. 99, no. 1, pp. 14–18, 1997. View at Publisher · View at Google Scholar · View at Scopus
  26. O. Mariani, C. Brennetot, and C. Brennetot, “JUN oncogene amplification and overexpression block adipocytic differentiation in highly aggressive sarcomas,” Cancer Cell, vol. 11, no. 4, pp. 361–374, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. F. Toledo and G. M. Wahl, “Regulating the p53 pathway: in vitro hypotheses, in vivo veritas,” Nature Reviews Cancer, vol. 6, no. 12, pp. 909–923, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. M. Wade, Y. V. Wang, and G. M. Wahl, “The p53 orchestra: Mdm2 and Mdmx set the tone,” Trends in Cell Biology, vol. 20, no. 5, pp. 299–309, 2010. View at Google Scholar
  29. S. M. Mendrysa, M. K. McElwee, J. Michalowski, K. A. O'Leary, K. M. Young, and M. E. Perry, “mdm2 is critical for inhibition of p53 during lymphopoiesis and the response to ionizing irradiation,” Molecular and Cellular Biology, vol. 23, no. 2, pp. 462–473, 2003. View at Publisher · View at Google Scholar · View at Scopus
  30. M. H. G. Kubbutat, R. L. Ludwig, A. J. Levine, and K. H. Vousden, “Analysis of the degradation function of Mdm2,” Cell Growth and Differentiation, vol. 10, no. 2, pp. 87–92, 1999. View at Google Scholar · View at Scopus
  31. J. Momand, G. P. Zambetti, D. C. Olson, D. George, and A. J. Levine, “The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation,” Cell, vol. 69, no. 7, pp. 1237–1245, 1992. View at Publisher · View at Google Scholar · View at Scopus
  32. J. D. Oliner, J. A. Pietenpol, S. Thiagalingam, J. Gyuris, K. W. Kinzler, and B. Vogelstein, “Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53,” Nature, vol. 362, no. 6423, pp. 857–860, 1993. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  33. C. J. Thut, J. A. Goodrich, and R. Tjian, “Repression of p53-mediated transcription by MDM2: a dual mechanism,” Genes and Development, vol. 11, no. 15, pp. 1974–1986, 1997. View at Google Scholar · View at Scopus
  34. Y. Haupt, R. Maya, A. Kazaz, and M. Oren, “Mdm2 promotes the rapid degradation of p53,” Nature, vol. 387, no. 6630, pp. 296–299, 1997. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  35. M. H. G. Kubbutat, S. N. Jones, and K. H. Vousden, “Regulation of p53 stability by Mdm2,” Nature, vol. 387, no. 6630, pp. 299–303, 1997. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. C.-Q. Hu and Y.-Z. Hu, “Small molecule inhibitors of the p53-MDM2,” Current Medicinal Chemistry, vol. 15, no. 17, pp. 1720–1730, 2008. View at Publisher · View at Google Scholar · View at Scopus
  37. J. M. Stommel and G. M. Wahl, “Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation,” The EMBO Journal, vol. 23, no. 7, pp. 1547–1556, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  38. C. L. Brooks and W. Gu, “p53 ubiquitination: Mdm2 and beyond,” Molecular Cell, vol. 21, no. 3, pp. 307–315, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  39. D. Michael and M. Oren, “The p53-Mdm2 module and the ubiquitin system,” Seminars in Cancer Biology, vol. 13, no. 1, pp. 49–58, 2003. View at Publisher · View at Google Scholar · View at Scopus
  40. C. R. Müller, E. B. Paulsen, P. Noordhuis, F. Pedeutour, G. Sæter, and O. Myklebost, “Potential for treatment of liposarcomas with the MDM2 antagonist Nutlin-3A,” International Journal of Cancer, vol. 121, no. 1, pp. 199–205, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  41. S. Pilotti, G. Della Torre, and G. Della Torre, “Distinct mdm2/p53 expression in patterns in liposarcoma subgroups: implications for different pathogenetic mechanisms,” Journal of Pathology, vol. 181, no. 1, pp. 14–24, 1997. View at Publisher · View at Google Scholar · View at Scopus
  42. R. Schneider-Stock, H. Walter, and H. Walter, “MDM2 amplification and loss of heterozygosity at Rb and p53 genes: no simultaneous alterations in the oncogenesis of liposarcomas,” Journal of Cancer Research and Clinical Oncology, vol. 124, no. 10, pp. 532–540, 1998. View at Publisher · View at Google Scholar · View at Scopus
  43. M. B. N. Binh, X. Sastre-Garau, and X. Sastre-Garau, “MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes: a comparative analysis of 559 soft tissue neoplasms with genetic data,” American Journal of Surgical Pathology, vol. 29, no. 10, pp. 1340–1347, 2005. View at Publisher · View at Google Scholar · View at Scopus
  44. T. Nakayama, J. Toguchida, B.-I. Wadayama, H. Kanoe, Y. Kotoura, and M. S. Sasaki, “MDM2 gene amplification in bone and soft-tissue tumors: association with tumor progression in differentiated adipose-tissue tumors,” International Journal of Cancer, vol. 64, no. 5, pp. 342–346, 1995. View at Publisher · View at Google Scholar · View at Scopus
  45. S. Ortega, M. Malumbres, and M. Barbacid, “Cyclin D-dependent kinases, INK4 inhibitors and cancer,” Biochimica et Biophysica Acta, vol. 1602, no. 1, pp. 73–87, 2002. View at Publisher · View at Google Scholar · View at Scopus
  46. A. Italiano, L. Bianchini, and L. Bianchini, “Clinical and biological significance of CDK4 amplification in well-differentiated and dedifferentiated liposarcomas,” Clinical Cancer Research, vol. 15, no. 18, pp. 5696–5703, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  47. J. W. Harbour, R. X. Luo, A. Dei Santi, A. A. Postigo, and D. C. Dean, “Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1,” Cell, vol. 98, no. 6, pp. 859–869, 1999. View at Publisher · View at Google Scholar · View at Scopus
  48. P. J. Day, A. Cleasby, and A. Cleasby, “Crystal structure of human CDK4 in complex with a D-type cyclin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 11, pp. 4166–4170, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  49. A. P. Dei Tos, C. Doglioni, and C. Doglioni, “Molecular abnormalities of the p53 pathway in dedifferentiated liposarcoma,” Journal of Pathology, vol. 181, no. 1, pp. 8–13, 1997. View at Publisher · View at Google Scholar · View at Scopus
  50. M. Hisaoka, S. Tsuji, Y. Morimitsu, H. Hashimoto, S. Shimajiri, S. Komiya, and M. Ushijima, “Detection of TLS/FUS-CHOP fusion transcripts in myxoid and round cell liposarcomas by nested reverse transcription-polymerase chain reaction using archival paraffin-embedded tissues,” Diagnostic Molecular Pathology, vol. 7, no. 2, pp. 96–101, 1998. View at Publisher · View at Google Scholar · View at Scopus
  51. H. Kanoe, T. Nakayama, and T. Nakayama, “Amplification of the CDK4 gene in sarcomas: tumor specificity and relationship with the RB gene mutation,” Anticancer Research, vol. 18, no. 4 A, pp. 2317–2321, 1998. View at Google Scholar · View at Scopus
  52. A. Italiano, L. Bianchini, and L. Bianchini, “HMGA2 is the partner of MDM2 in well-differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon,” International Journal of Cancer, vol. 122, no. 10, pp. 2233–2241, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  53. N. Sirvent, J.-M. Coindre, and J.-M. Coindre, “Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR,” American Journal of Surgical Pathology, vol. 31, no. 10, pp. 1476–1489, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  54. P. B. Aleixo, A. A. Hartmann, I. C. Menezes, R. T. Meurer, and A. M. Oliveira, “Can MDM2 and CDK4 make the diagnosis of well differentiated/ dedifferentiated liposarcoma? An immunohistochemical study on 129 soft tissue tumours,” Journal of Clinical Pathology, vol. 62, no. 12, pp. 1127–1135, 2009. View at Publisher · View at Google Scholar · View at PubMed
  55. P. Arlotta, A. K.-F. Tai, G. Manfioletti, C. Clifford, G. Jay, and S. J. Ono, “Transgenic mice expressing a truncated form of the high mobility group I-C protein develop adiposity and an abnormally high prevalence of lipomas,” The Journal of Biological Chemistry, vol. 275, no. 19, pp. 14394–14400, 2000. View at Publisher · View at Google Scholar · View at Scopus
  56. M. Bustin and R. Reeves, “High-mobility-group chromosomal proteins: architectural components that facilitate chromatin function,” Progress in Nucleic Acid Research and Molecular Biology, vol. 54, pp. 35–100, 1996. View at Google Scholar · View at Scopus
  57. L. A. Meza-Zepeda, J.-M. Berner, and J.-M. Berner, “Ectopic sequences from truncated HMGIC in liposarcomas are derived from various amplified chromosomal regions,” Genes Chromosomes and Cancer, vol. 31, no. 3, pp. 264–273, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  58. F. Mantovani, S. Covaceuszach, A. Rustighi, R. Sgarra, C. Heath, G. H. Goodwin, and G. Manfioletti, “NF-κB mediated transcriptional activation is enhanced by the architectural factor HMGI-C,” Nucleic Acids Research, vol. 26, no. 6, pp. 1433–1439, 1998. View at Publisher · View at Google Scholar · View at Scopus
  59. R. Schwanbeck, G. Manfioletti, and J. R. Wiśniewski, “Architecture of high mobility group protein I-C·DNA complex and its perturbation upon phosphorylation by Cdc2 kinase,” The Journal of Biological Chemistry, vol. 275, no. 3, pp. 1793–1801, 2000. View at Publisher · View at Google Scholar · View at Scopus
  60. M. Fedele, M. T. Berlingieri, and M. T. Berlingieri, “Truncated and chimeric HMGI-C genes induce neoplastic transformation of NIH3T3 murine fibroblasts,” Oncogene, vol. 17, no. 4, pp. 413–418, 1998. View at Google Scholar · View at Scopus
  61. J.-M. Berner, L. A. Meza-Zepeda, and L. A. Meza-Zepeda, “HMGIC, the gene for an architectural transcription factor, is amplified and rearranged in a subset of human sarcomas,” Oncogene, vol. 14, no. 24, pp. 2935–2941, 1997. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  62. G. Gamberi, P. Ragazzini, and P. Ragazzini, “Analysis of 12q13-15 genes in parosteal osteosarcoma,” Clinical Orthopaedics and Related Research, no. 377, pp. 195–204, 2000. View at Google Scholar · View at Scopus
  63. P. S. Meltzer, S. A. Jankowski, P. Dal Cin, A. A. Sandberg, I. B. Paz, and M. A. Coccia, “Identification and cloning of a novel amplified DNA sequence in human malignant fibrous histiocytoma derived from a region of chromosome 12 frequently rearranged in soft tissue tumors,” Cell Growth, vol. 2, no. 10, pp. 495–501, 1991. View at Google Scholar · View at Scopus
  64. V. A. Florenes, G. M. Moelandsmo, A. Forus, A. Andreassen, O. Myklebost, and O. Fodstad, “MDM2 gene amplification and transcript levels in human sarcomas: relationship to TP53 gene status,” Journal of the National Cancer Institute, vol. 86, no. 17, pp. 1297–1302, 1994. View at Google Scholar · View at Scopus
  65. S. E. Noble-Topham, S. R. Burrow, K. Eppert, R. A. Kandel, P. S. Meltzer, R. S. Bell, and I. L. Andrulis, “SAS is amplified predominantly in surface osteosarcoma,” Journal of Orthopaedic Research, vol. 14, no. 5, pp. 700–705, 1996. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  66. A. Forus, V. A. Florenes, G. M. Maelandsmo, P. S. Meltzer, O. Fodstad, and O. Myklebost, “Mapping of amplification units in the q13-14 region of chromosome-12 in human sarcomas—some amplica do not include MDM2,” Cell Growth and Differentiation, vol. 4, no. 12, pp. 1065–1070, 1993. View at Google Scholar · View at Scopus
  67. L. A. Meza-Zepeda, A. Forus, and A. Forus, “Positional cloning identifies a novel cyclophilin as a candidate amplified oncogene in 1q21,” Oncogene, vol. 21, no. 14, pp. 2261–2269, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  68. M. Nilsson, L. A. Meza-Zepeda, F. Mertens, A. Forus, O. Myklebost, and N. Mandahl, “Amplification of chromosome 1 sequences in lipomatous tumors and other sarcomas,” International Journal of Cancer, vol. 109, no. 3, pp. 363–369, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  69. F. Chibon, O. Mariani, and O. Mariani, “A subgroup of malignant fibrous histiocytomas is associated with genetic changes similar to those of well-differentiated liposarcomas,” Cancer Genetics and Cytogenetics, vol. 139, no. 1, pp. 24–29, 2002. View at Publisher · View at Google Scholar · View at Scopus
  70. D. Vallone, S. Battista, and S. Battista, “Neoplastic transformation of rat thyroid cells requires the junB and fra-1 gene induction which is dependent on the HMGI-C gene product,” The EMBO Journal, vol. 16, no. 17, pp. 5310–5321, 1997. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  71. J.-M. Coindre, F. Pédeutour, and A. Aurias, “Well-differentiated and dedifferentiated liposarcomas,” Virchows Archiv, vol. 456, no. 2, pp. 167–179, 2010. View at Publisher · View at Google Scholar · View at PubMed
  72. F. Chibon, O. Mariani, and O. Mariani, “ASK1 (MAP3K5) as a potential therapeutic target in malignant fibrous histiocytomas with 12q14q-q15 and 6q23 amplifications,” Genes Chromosomes and Cancer, vol. 40, no. 1, pp. 32–37, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  73. C. K. U. Fletcher, K. Krishnan, and F. Mertens, Pathology and Genetics of Tumours of Soft Tissue and Bone, IARC Press, Lyon, France, 2002.
  74. J. H. Schwab, P. Boland, T. Guo, M. F. Brennan, S. Singer, J. H. Healey, and C. R. Antonescu, “Skeletal metastases in myxoid liposarcoma: an unusual pattern of distant spread,” Annals of Surgical Oncology, vol. 14, no. 4, pp. 1507–1514, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  75. K. Sheah, H. A. Ouellette, M. Torriani, G. P. Nielsen, S. Kattapuram, and M. A. Bredella, “Metastatic myxoid liposarcomas: imaging and histopathologic findings,” Skeletal Radiology, vol. 37, no. 3, pp. 251–258, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  76. S. E. ten Heuvel, H. J. Hoekstra, R. J. Van Ginkel, E. Bastiaannet, and A. J. H. Suurmeijer, “Clinicopathologic prognostic factors in myxoid liposarcoma: a retrospective study of 49 patients with long-term follow-up,” Annals of Surgical Oncology, vol. 14, no. 1, pp. 222–229, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  77. R. J. Canter, L.-X. Qin, C. R. Ferrone, R. G. Maki, S. Singer, and M. F. Brennan, “Why do patients with low-grade soft tissue sarcoma die?” Annals of Surgical Oncology, vol. 15, no. 12, pp. 3550–3560, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  78. P. W. M. Chung, B. M. Deheshi, and B. M. Deheshi, “Radiosensitivity translates into excellent local control in extremity myxoid liposarcoma: a comparison with other soft tissue sarcomas,” Cancer, vol. 115, no. 14, pp. 3254–3261, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  79. C. R. Antonescu, S. J. Tschernyavsky, and S. J. Tschernyavsky, “Prognostic impact of P53 status, TLS-CHOP fusion transcript structure, and histological grade in myxoid liposarcoma: a molecular and clinicopathologic study of 82 cases,” Clinical Cancer Research, vol. 7, no. 12, pp. 3977–3987, 2001. View at Google Scholar · View at Scopus
  80. A. Crozat, P. Aman, N. Mandahl, and D. Ron, “Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma,” Nature, vol. 363, no. 6430, pp. 640–644, 1993. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  81. I. Panagopoulos, M. Höglund, F. Mertens, N. Mandahl, F. Mitelman, and P. Åman, “Fusion of the EWS and CHOP genes in myxoid liposarcoma,” Oncogene, vol. 12, no. 3, pp. 489–494, 1996. View at Google Scholar · View at Scopus
  82. P. Dal Cin, R. Sciot, and R. Sciot, “Additional evidence of a variant translocation t(12;22) with EWS/CHOP fusion in myxoid liposarcoma: clinicopathological features,” Journal of Pathology, vol. 182, no. 4, pp. 437–441, 1997. View at Publisher · View at Google Scholar · View at Scopus
  83. C. Sreekantaiah, C. P. Karakousis, S. P. L. Leong, and A. A. Sandberg, “Trisomy 8 as a nonrandom secondary change in myxoid liposarcoma,” Cancer Genetics and Cytogenetics, vol. 51, no. 2, pp. 195–205, 1991. View at Publisher · View at Google Scholar · View at Scopus
  84. S. Thelin-Järnum, C. Lassen, I. Panagopoulos, N. Mandahl, and P. Åman, “Identification of genes differentially expressed in TLS-CHOP carrying myxoid liposarcomas,” International Journal of Cancer, vol. 83, no. 1, pp. 30–33, 1999. View at Publisher · View at Google Scholar · View at Scopus
  85. H. Cheng, J. Dodge, E. Mehl, S. Liu, N. Poulin, M. van de Rijn, and T. O. Nielsen, “Validation of immature adipogenic status and identification of prognostic biomarkers in myxoid liposarcoma using tissue microarrays,” Human Pathology, vol. 40, no. 9, pp. 1244–1251, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  86. Y. Tao, V. Pinzi, J. Bourhis, and E. Deutsch, “Mechanisms of disease: signaling of the insulin-like growth factor 1 receptor pathway—therapeutic perspectives in cancer,” Nature Clinical Practice Oncology, vol. 4, no. 10, pp. 591–602, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  87. B. Bode-Lesniewska, S. Frigerio, U. Exner, M. T. Abdou, H. Moch, and D. R. Zimmermann, “Relevance of translocation type in myxoid liposarcoma and identification of a novel EWSR1-DDIT3 fusion,” Genes Chromosomes and Cancer, vol. 46, no. 11, pp. 961–971, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  88. C. Forni, M. Minuzzo, and M. Minuzzo, “Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors,” Molecular Cancer Therapeutics, vol. 8, no. 2, pp. 449–457, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  89. F. Grosso, R. L. Jones, and R. L. Jones, “Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study,” Lancet Oncology, vol. 8, no. 7, pp. 595–602, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  90. R. Frapolli, E. Tamborini, E. Virdis et al., “Novel models of Myxoid Liposarcoma Xenografts mimicking the biological and pharmacological features of human tumors,” Clinical Cancer Research, vol. 16, no. 20, pp. 4958–4967, 2010. View at Google Scholar
  91. A. Bertolotti, Y. Lutz, D. J. Heard, P. Chambon, and L. Tora, “hTAF(II)68, a novel RNA/ssDNA-binding protein with homology to the pro-oncoproteins TLS/FUS and EWS is associated with both TFIID and RNA polymerase II,” The EMBO Journal, vol. 15, no. 18, pp. 5022–5031, 1996. View at Google Scholar · View at Scopus
  92. D. T. Stolow and S. R. Haynes, “Cabeza, a Drosophila gene encoding a novel RNA binding protein, shares homology with EWS and TLS, two genes involved in human sarcoma formation,” Nucleic Acids Research, vol. 23, no. 5, pp. 835–843, 1995. View at Google Scholar · View at Scopus
  93. F. Morohoshi, K. Arai, E.-I. Takahashi, A. Tanigami, and M. Ohki, “Cloning and mapping of a human RBP56 gene encoding a putative RNA binding protein similar to FUS/TLS and EWS proteins,” Genomics, vol. 38, no. 1, pp. 51–57, 1996. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  94. F. Morohoshi, Y. Ootsuka, K. Arai, H. Ichikawa, S. Mitani, N. Munakata, and M. Ohki, “Genomic structure of the human RBP56/hTAF(II)68 and FUS/TLS genes,” Gene, vol. 221, no. 2, pp. 191–198, 1998. View at Publisher · View at Google Scholar · View at Scopus
  95. M. K. Andersson, A. Ståhlberg, and A. Ståhlberg, “The multifunctional FUS, EWS and TAF15 proto-oncoproteins show cell type-specific expression patterns and involvement in cell spreading and stress response,” BMC Cell Biology, vol. 9, article 37, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  96. H. Zinszner, D. Immanuel, Y. Yin, F.-X. Liang, and D. Ron, “A topogenic role for the oncogenic N-terminus of TLS: nucleolar localization when transcription is inhibited,” Oncogene, vol. 14, no. 4, pp. 451–461, 1997. View at Google Scholar · View at Scopus
  97. H. Zinszner, J. Sok, D. Immanuel, Y. Yin, and D. Ron, “TLS (FUS) binds RNA in vivo and engages in nucleo-cytoplasmic shuttling,” Journal of Cell Science, vol. 110, no. 15, pp. 1741–1750, 1997. View at Google Scholar · View at Scopus
  98. L. L. Belyanskaya, P. M. Gehrig, and H. Gehring, “Exposure on cell surface and extensive arginine methylation of ewing sarcoma (EWS) Protein,” The Journal of Biological Chemistry, vol. 276, no. 22, pp. 18681–18687, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  99. A. Y. Tan and J. L. Manley, “TLS inhibits RNA polymerase III transcription,” Molecular and Cellular Biology, vol. 30, no. 1, pp. 186–196, 2010. View at Publisher · View at Google Scholar · View at PubMed
  100. X. Wang, S. Arai, and S. Arai, “Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription,” Nature, vol. 454, no. 7200, pp. 126–130, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  101. M. Gardiner, R. Toth, F. Vandermoere, N. A. Morrice, and J. Rouse, “Identification and characterization of FUS/TLS as a new target of ATM,” Biochemical Journal, vol. 415, no. 2, pp. 297–307, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  102. X.-Z. Wang, B. Lawson, and B. Lawson, “Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153),” Molecular and Cellular Biology, vol. 16, no. 8, pp. 4273–4280, 1996. View at Google Scholar · View at Scopus
  103. N. Batchvarova, X.-Z. Wang, and D. Ron, “Inhibition of adipogenesis by the stress-induced protein CHOP (Gadd153),” The EMBO Journal, vol. 14, no. 19, pp. 4654–4661, 1995. View at Google Scholar · View at Scopus
  104. Z. Cao, R. M. Umek, and S. L. McKnight, “Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells,” Genes and Development, vol. 5, no. 9, pp. 1538–1552, 1991. View at Google Scholar · View at Scopus
  105. H. Zinszner, R. Albalat, and D. Ron, “A novel effector domain from the RNA-binding protein TLS or EWS is required for oncogenic transformation by CHOP,” Genes and Development, vol. 8, no. 21, pp. 2513–2526, 1994. View at Google Scholar · View at Scopus
  106. M. Kuroda, T. Ishida, M. Takanashi, M. Satoh, R. Machinami, and T. Watanabe, “Oncogenic transformation and inhibition of adipocytic conversion of preadipocytes by TLS/FUS-CHOP type II chimeric protein,” American Journal of Pathology, vol. 151, no. 3, pp. 735–744, 1997. View at Google Scholar · View at Scopus
  107. P. A. Pérez-Mancera, C. Vicente-Dueñas, I. González-Herrero, M. Sánchez-Martín, T. Flores-Corral, and I. Sánchez-García, “Fat-specific FUS-DDIT3-transgenic mice establish PPARγ inactivation is required to liposarcoma development,” Carcinogenesis, vol. 28, no. 10, pp. 2069–2073, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  108. H. Cheng, J. Dodge, E. Mehl, S. Liu, N. Poulin, M. van de Rijn, and T. O. Nielsen, “Validation of immature adipogenic status and identification of prognostic biomarkers in myxoid liposarcoma using tissue microarrays,” Human Pathology, vol. 40, no. 9, pp. 1244–1251, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  109. J. Pérez-Losada, B. Pintado, and B. Pintado, “The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice,” Oncogene, vol. 19, no. 20, pp. 2413–2422, 2000. View at Google Scholar · View at Scopus
  110. T. Negri, E. Virdis, and E. Virdis, “Functional mapping of receptor tyrosine kinases in myxoid liposarcoma,” Clinical Cancer Research, vol. 16, no. 14, pp. 3581–3593, 2010. View at Publisher · View at Google Scholar · View at PubMed
  111. N. Riggi, L. Cironi, and L. Cironi, “Expression of the FUS-CHOP fusion protein in primary mesenchymal progenitor cells gives rise to a model of myxoid liposarcoma,” Cancer Research, vol. 66, no. 14, pp. 7016–7023, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  112. K. Engström, H. Willén, and H. Willén, “The myxoid/round cell liposarcoma fusion oncogene FUS-DDIT3 and the normal DDIT3 induce a liposarcoma phenotype in transfected human fibrosarcoma cells,” American Journal of Pathology, vol. 168, no. 5, pp. 1642–1653, 2006. View at Publisher · View at Google Scholar · View at Scopus
  113. M. K. Andersson, M. Göransson, A. Olofsson, C. Andersson, and P. Åman, “Nuclear expression of FLT1 and its ligand PGF in FUS-DDIT3 carrying myxoid liposarcomas suggests the existence of an intracrine signaling loop,” BMC Cancer, vol. 10, article 249, 2010. View at Publisher · View at Google Scholar · View at PubMed
  114. Y. Samuels, Z. Wang, and Z. Wang, “High frequency of mutations of the PIK3CA gene in human cancers,” Science, vol. 304, no. 5670, article 554, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  115. R. K. Thomas, A. C. Baker, and A. C. Baker, “High-throughput oncogene mutation profiling in human cancer,” Nature Genetics, vol. 39, no. 3, pp. 347–351, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  116. J. Barretina, B. S. Taylor, and B. S. Taylor, “Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy,” Nature Genetics, vol. 42, no. 8, pp. 715–721, 2010. View at Publisher · View at Google Scholar · View at PubMed
  117. L. C. Cantley, “The phosphoinositide 3-kinase pathway,” Science, vol. 296, no. 5573, pp. 1655–1657, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  118. L. Guillou, C. Wadden, J.-M. Coindre, T. Krausz, and C. D. M. Fletcher, “'Proximal-type' epithelioid sarcoma, a distinctive aggressive neoplasm showing rhabdoid features: clinicopathologic, immunohistochemical, and ultrastructural study of a series,” American Journal of Surgical Pathology, vol. 21, no. 2, pp. 130–146, 1997. View at Publisher · View at Google Scholar · View at Scopus
  119. M. Miettinen and F. M. Enzinger, “Epithelioid variant of pleomorphic liposarcoma: a study of 12 cases of a distinctive variant of high-grade liposarcoma,” Modern Pathology, vol. 12, no. 7, pp. 722–728, 1999. View at Google Scholar · View at Scopus
  120. K. A. Downes, J. R. Goldblum, E. A. Montgomery, and C. Fisher, “Pleomorphic liposarcoma: a clinicopathologic analysis of 19 cases,” Modern Pathology, vol. 14, no. 3, pp. 179–184, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  121. M. G. Stewart, M. R. Schwartz, and B. R. Alford, “Atypical and malignant lipomatous lesions of the head and neck,” Archives of Otolaryngology—Head and Neck Surgery, vol. 120, no. 10, pp. 1151–1155, 1994. View at Google Scholar · View at Scopus
  122. P. W. Allen, I. Strungs, and L. B. MacCormac, “Atypical subcutaneous fatty tumors: a review of 37 referred cases,” Pathology, vol. 30, no. 2, pp. 123–135, 1998. View at Publisher · View at Google Scholar · View at Scopus
  123. B. S. Taylor, J. Barretina, and J. Barretina, “Functional copy-number alterations in cancer,” PLoS ONE, vol. 3, no. 9, Article ID e3179, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  124. A. Idbaih, J.-M. Coindre, and J.-M. Coindre, “Myxoid malignant fibrous histiocytoma and pleomorphic liposarcoma share very similar genomic imbalances,” Laboratory Investigation, vol. 85, no. 2, pp. 176–181, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  125. H. Schmidt, F. Bartel, and F. Bartel, “Gains of 13q are correlated with a poor prognosis in liposarcoma,” Modern Pathology, vol. 18, no. 5, pp. 638–644, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  126. S. Singer, N. D. Socci, and N. D. Socci, “Gene expression profiling of liposarcoma identifies distinct biological types/subtypes and potential therapeutic targets in well-differentiated and dedifferentiated liposarcoma,” Cancer Research, vol. 67, no. 14, pp. 6626–6636, 2007. View at Publisher · View at Google Scholar · View at PubMed
  127. F. Dotiwala, J. C. Harrison, S. Jain, N. Sugawara, and J. E. Haber, “Mad2 prolongs DNA damage checkpoint arrest caused by a double-strand break via a centromere-dependent mechanism,” Current Biology, vol. 20, no. 4, pp. 328–332, 2010. View at Publisher · View at Google Scholar · View at PubMed
  128. L. T. Vassilev, B. T. Vu, and B. T. Vu, “In vivo activation of the p53 pathway by small-molecule antagonists of MDM2,” Science, vol. 303, no. 5659, pp. 844–848, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  129. S. Shangary, D. Qin, and D. Qin, “Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 10, pp. 3933–3938, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  130. K. Ding, Y. Lu, and Y. Lu, “Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction,” Journal of Medicinal Chemistry, vol. 49, no. 12, pp. 3432–3435, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  131. S. Shangary and S. Wang, “Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy,” Annual Review of Pharmacology and Toxicology, vol. 49, pp. 223–241, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  132. I. Ringshausen, C. C. O'Shea, A. J. Finch, L. B. Swigart, and G. I. Evan, “Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo,” Cancer Cell, vol. 10, no. 6, pp. 501–514, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  133. C. Tovar, J. Rosinski, and J. Rosinski, “Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 6, pp. 1888–1893, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  134. M. P. Dickens, R. Fitzgerald, and P. M. Fischer, “Small-molecule inhibitors of MDM2 as new anticancer therapeutics,” Seminars in Cancer Biology, vol. 20, no. 1, pp. 10–18, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  135. J. P. M. Arts, A. Valckx, C. Blattner et al., “JNJ-26854165- a novel hdm2 antagonist in clinical development showing broad-spectrum pre-clinical anti-tumour activity against solid malignancies,” Proceedings of the American Association for Cancer Research, vol. 49, 2008, abstract no. 1592. View at Google Scholar
  136. R. P. Pipeline, 2008 (http://www.ascenta.com/).
  137. ClinicalTrials.gov—RO5045337, 2010, http://clinicaltrials.gov/ct2/results?term=RO5045337.
  138. Y.-N. P. Chen, S. K. Sharma, and S. K. Sharma, “Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 8, pp. 4325–4329, 1999. View at Publisher · View at Google Scholar · View at Scopus
  139. G. I. Shapiro, “Cyclin-dependent kinase pathways as targets for cancer treatment,” Journal of Clinical Oncology, vol. 24, no. 11, pp. 1770–1783, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  140. W. F. De Azevedo, S. Leclerc, L. Meijer, L. Havlicek, M. Strnad, and S.-H. Kim, “Inhibition of cyclin-dependent kinases by purine analogues. Crystal structure of human cdk2 complexed with roscovitine,” European Journal of Biochemistry, vol. 243, no. 1-2, pp. 518–526, 1997. View at Google Scholar · View at Scopus
  141. G. I. Shapiro, “Preclinical and clinical development of the cyclin-dependent kinase inhibitor flavopiridol,” Clinical Cancer Research, vol. 10, no. 12, pp. 4270s–4275s, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  142. H. H. Sedlacek, “Mechanisms of action of flavopiridol,” Critical Reviews in Oncology/Hematology, vol. 38, no. 2, pp. 139–170, 2001. View at Publisher · View at Google Scholar · View at Scopus
  143. C. B. Matranga and G. I. Shapiro, “Selective sensitization of transformed cells to flavopiridol-induced apoptosis following recruitment to S-phase,” Cancer Research, vol. 62, no. 6, pp. 1707–1717, 2002. View at Google Scholar · View at Scopus
  144. K. C. Bible and S. H. Kaufmann, “Cytotoxic synergy between flavopiridol (NSC 649890, L86-8275) and various antineoplastic agents: the importance of sequence of administration,” Cancer Research, vol. 57, no. 16, pp. 3375–3380, 1997. View at Google Scholar · View at Scopus
  145. C. P. Jung, M. V. Motwani, and G. K. Schwartz, “Flavopiridol increases sensitization to gemcitabine in human gastrointestinal cancer cell lines and correlates with down-regulation of ribonucleotide reductase M2 subunit,” Clinical Cancer Research, vol. 7, no. 8, pp. 2527–2536, 2001. View at Google Scholar · View at Scopus
  146. S. Lapenna and A. Giordano, “Cell cycle kinases as therapeutic targets for cancer,” Nature Reviews Drug Discovery, vol. 8, no. 7, pp. 547–566, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  147. C. Benson, J. White, and J. White, “A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days,” British Journal of Cancer, vol. 96, no. 1, pp. 29–37, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  148. D. W. Fry, P. J. Harvey, and P. J. Harvey, “Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts,” Molecular Cancer Therapeutics, vol. 3, no. 11, pp. 1427–1437, 2004. View at Google Scholar · View at Scopus
  149. G. D. Demetri, C. D. M. Fletcher, and C. D. M. Fletcher, “Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-γ ligand troglitazone in patients with liposarcoma,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 7, pp. 3951–3956, 1999. View at Google Scholar · View at Scopus
  150. P. Tontonoz, E. Hu, R. A. Graves, A. I. Budavari, and B. M. Spiegelman, “mPPARγ2: tissue-specific regulator of an adipocyte enhancer,” Genes and Development, vol. 8, no. 10, pp. 1224–1234, 1994. View at Google Scholar · View at Scopus
  151. I. B. Sears, M. A. MacGinnitie, L. G. Kovacs, and R. A. Graves, “Differentiation-dependent expression of the brown adipocyte uncoupling protein gene: regulation by peroxisome proliferator-activated receptor γ,” Molecular and Cellular Biology, vol. 16, no. 7, pp. 3410–3419, 1996. View at Google Scholar · View at Scopus
  152. G. Debrock, V. Vanhentenrijk, R. Sciot, M. Debiec-Rychter, R. Oyen, and A. Van Oosterom, “A phase II trial with rosiglitazone in liposarcoma patients,” British Journal of Cancer, vol. 89, no. 8, pp. 1409–1412, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  153. Y. Takebayashi, P. Pourquier, A. Yoshida, G. Kohlhagen, and Y. Pommier, “Poisoning of human DNA topoisomerase I by ecteinascidin 743, an anticancer drug that selectively alkylates DNA in the minor groove,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 13, pp. 7196–7201, 1999. View at Google Scholar · View at Scopus
  154. J. Fayette, H. Boyle, and H. Boyle, “Efficacy of trabectedin for advanced sarcomas in clinical trials versus compassionate use programs: analysis of 92 patients treated in a single institution,” Anti-Cancer Drugs, vol. 21, no. 1, pp. 113–119, 2010. View at Publisher · View at Google Scholar · View at PubMed
  155. K. A. Thornton, “Trabectedin: the evidence for its place in therapy in the treatment of soft tissue sarcoma,” Core Evidence, vol. 4, pp. 191–198, 2010. View at Google Scholar
  156. Y. Pommier, G. Kohlhagen, C. Bailly, M. Waring, A. Mazumder, and K. W. Kohn, “DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the caribbean tunicate Ecteinascidia turbinata,” Biochemistry, vol. 35, no. 41, pp. 13303–13309, 1996. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  157. D. Friedman, Z. Hu, E. A. Kolb, B. Gorfajn, and K. W. Scotto, “Ecteinascidin-743 inhibits activated but not constitutive transcription,” Cancer Research, vol. 62, no. 12, pp. 3377–3381, 2002. View at Google Scholar · View at Scopus
  158. M. Minuzzo, S. Marchini, M. Broggini, G. Faircloth, M. D'Incalci, and R. Mantovani, “Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 12, pp. 6780–6784, 2000. View at Publisher · View at Google Scholar · View at Scopus
  159. Y. Takebayashi, P. Pourquier, and P. Pourquier, “Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair,” Nature Medicine, vol. 7, no. 8, pp. 961–966, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  160. J. Guirouilh-Barbat, C. Redon, and Y. Pommier, “Transcription-coupled DNA double-strand breaks are mediated via the nucleotide excision repair and the Mre11-Rad50-Nbs1 complex,” Molecular Biology of the Cell, vol. 19, no. 9, pp. 3969–3981, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  161. D. G. Soares, A. E. Escargueil, and A. E. Escargueil, “Replication and homologous recombination repair regulate DNA double-strand break formation by the antitumor alkylator ecteinascidin 743,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 32, pp. 13062–13067, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  162. M. Tavecchio, M. Simone, and M. Simone, “Role of homologous recombination in trabectedin-induced DNA damage,” European Journal of Cancer, vol. 44, no. 4, pp. 609–618, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  163. M. Göransson, E. Elias, A. Ståhlberg, A. Olofsson, C. Andersson, and P. Åman, “Myxoid liposarcoma FUS-DDIT3 fusion oncogene induces C/EBP β-mediated interleukin 6 expression,” International Journal of Cancer, vol. 115, no. 4, pp. 556–560, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  164. M. Göransson, M. K. Andersson, and M. K. Andersson, “The myxoid liposarcoma FUS-DDIT3 fusion oncoprotein deregulates NF-κB target genes by interaction with NFKBIZ,” Oncogene, vol. 28, no. 2, pp. 270–278, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  165. G. Germano, R. Frapolli, and R. Frapolli, “Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells,” Cancer Research, vol. 70, no. 6, pp. 2235–2244, 2010. View at Publisher · View at Google Scholar · View at PubMed
  166. P. Workman, P. A. Clarke, F. I. Raynaud, and R. L.M. Van Montfort, “Drugging the PI3 kinome: from chemical tools to drugs in the clinic,” Cancer Research, vol. 70, no. 6, pp. 2146–2157, 2010. View at Publisher · View at Google Scholar · View at PubMed
  167. A. J. Folkes, K. Ahmadi, and K. Ahmadi, “The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer,” Journal of Medicinal Chemistry, vol. 51, no. 18, pp. 5522–5532, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  168. F. I. Raynaud, S. A. Eccles, and S. A. Eccles, “Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941,” Molecular Cancer Therapeutics, vol. 8, no. 7, pp. 1725–1738, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  169. N. T. Ihle, R. Lemos Jr., and R. Lemos, “Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic ras is a dominant predictor for resistance,” Cancer Research, vol. 69, no. 1, pp. 143–150, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  170. C. O'Brien, J. J. Wallin, and J. J. Wallin, “Predictive biomarkers of sensitivity to the phosphatidylinositol 3′ kinase inhibitor GDC-0941 in breast cancer preclinical models,” Clinical Cancer Research, vol. 16, no. 14, pp. 3670–3683, 2010. View at Publisher · View at Google Scholar · View at PubMed
  171. F. Di Nicolantonio, S. Arena, and S. Arena, “Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus,” The Journal of Clinical Investigation, vol. 120, no. 8, pp. 2858–2866, 2010. View at Publisher · View at Google Scholar · View at PubMed
  172. F. Cecchi, D. C. Rabe, and D. P. Bottaro, “Targeting the HGF/Met signalling pathway in cancer,” European Journal of Cancer, vol. 46, no. 7, pp. 1260–1270, 2010. View at Publisher · View at Google Scholar · View at PubMed
  173. J. P. Eder, G. I. Shapiro, and G. I. Shapiro, “A phase I study of foretinib, a multi-targeted inhibitor of c-Met and vascular endothelial growth factor receptor 2,” Clinical Cancer Research, vol. 16, no. 13, pp. 3507–3516, 2010. View at Publisher · View at Google Scholar · View at PubMed
  174. H. Joensuu, C. Fletcher, S. Dimitrijevic, S. Silberman, P. Roberts, and G. Demetri, “Management of malignant gastrointestinal stromal tumours,” Lancet Oncology, vol. 3, no. 11, pp. 655–664, 2002. View at Publisher · View at Google Scholar · View at Scopus