Current Oncology Reports

, Volume 15, Issue 4, pp 378–385

Novel Pathways and Molecular Targets for the Treatment of Sarcoma

  • Ashley E. Frith
  • Angela C. Hirbe
  • Brian A. Van Tine
Sarcomas (SR Patel, Section Editor)

Abstract

Sarcomas collectively represent over 100 different subtypes of bone and soft tissue tumors of mesenchymal origin. The low response rate to cytotoxic chemotherapies has necessitated the need for development of either histologically driven or pathway-specific targeted therapies. As our understanding of the molecular mechanisms driving certain subtypes is rapidly advancing, the number of targeted therapies is also increasing. Recently identified novel druggable targets include the MDM2 amplifications in well-differentiated and dedifferentiated liposarcomas, the new translocation NAB2:STAT6 of solitary fibrous tumors, the angiopoeitin-TIE2 pathway in angiosarcoma, the suppression of Mcl1 in X:18/synovial sarcomas, the mTOR pathway in malignant peripheral nerve sheath tumors, CDK4 in alveolar rhabdomyosarcoma, cMET regulation in alveolar soft parts sarcoma, the metabolic abnormalities in wild-type/SHD GIST, and the lack of argininosuccinate synthetase 1 expression seen in most sarcomas. It is through a fundamental understanding of sarcoma biology that clinical trials based on molecular targets can be developed.

Keywords

Soft tissue sarcoma Bone sarcoma MDM2 NAB2:STAT6 Angiopoeitin TIE2 Mcl1 mTOR CKD4 cMET SDH ASS1 Succinate dehydrogenase Argininosuccinate Synthetase 1 Liposarcoma Solitary fibrous tumors Angiosarcoma X:18 sarcoma Synovial sarcoma Malignant peripheral nerve sheath tumors Wild-type GIST Alveolar rhabdomyosarcoma Sarcoma 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    •• von Mehren M, Benjamin RS, Bui MM, et al. Soft tissue sarcoma, version 2.2012: featured updates to the NCCN guidelines. Journal of the National Comprehensive Cancer Network 2012;10:951-60. The current treatment guidelines for sarcoma are detailed here and actively updated by committee.Google Scholar
  2. 2.
    Jemal A, Siegel R, Xu J, et al. Cancer Statistics, 2010. CA Cancer J Clin. 2010;60:277–300.PubMedCrossRefGoogle Scholar
  3. 3.
    • Rajendra R, Pollack SM, Jones RL. Management of gastrointestinal stromal tumors. Future Oncology 2013;9:193-206. This is a recent review on the management of GIST.Google Scholar
  4. 4.
    Jones B, Komarnitsky P, Miller GT, et al. Anticancer activity of stabilized palifosfamide in vivo: schedule effects, oral bioavailability, and enhanced activity with docetaxel and doxorubicin. Anti-Cancer Drugs. 2012;23:173–84.PubMedCrossRefGoogle Scholar
  5. 5.
    Ganjoo KN, Cranmer LD, Butrynski JE, et al. A phase I study of the safety and pharmacokinetics of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma. Oncology. 2011;80:50–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Kindblom LG. 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. Adv Anat Pathol. 2006;13:279–85.PubMedCrossRefGoogle Scholar
  7. 7.
    Jones RL, Fisher C, Al-Muderis O, et al. Differential sensitivity of liposarcoma subtypes to chemotherapy. Eur J Cancer. 2005;41:2853–60.PubMedCrossRefGoogle Scholar
  8. 8.
    • Conyers R, Young S, Thomas DM. Liposarcoma: molecular genetics and therapeutics. Sarcoma 2011;2011:483154. This is a current in depth review of liposarcoma.Google Scholar
  9. 9.
    Rieker RJ, Weitz J, Lehner B, et al. Genomic profiling reveals subsets of dedifferentiated liposarcoma to follow separate molecular pathways. Virchows Arch. 2010;456:277–85.PubMedCrossRefGoogle Scholar
  10. 10.
    Pedeutour F, Forus A, Coindre JM, et al. Structure of the supernumerary ring and giant rod chromosomes in adipose tissue tumors. Genes Chromosomes Cancer. 1999;24:30–41.PubMedCrossRefGoogle Scholar
  11. 11.
    Dei Tos AP, Doglioni C, Piccinin S, et al. Coordinated expression and amplification of the MDM2, CDK4, and HMGI-C genes in atypical lipomatous tumours. J Pathol. 2000;190:531–6.PubMedCrossRefGoogle Scholar
  12. 12.
    •• Pei D, Zhang Y, Zheng J. Regulation of p53: a collaboration between Mdm2 and Mdmx. Oncotarget 2012;3:228-35. Review of the interactione between MDM2, MDMX and its regulation of p53.Google Scholar
  13. 13.
    Vassilev LT. MDM2 inhibitors for cancer therapy. Trends Mol Med. 2007;13:23–31.PubMedCrossRefGoogle Scholar
  14. 14.
    Ray-Coquard I, Blay JY, Italiano A, et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol. 2012;13:1133–40.PubMedCrossRefGoogle Scholar
  15. 15.
    Shangary S, Qin D, McEachern D, et al. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc Natl Acad Sci U S A. 2008;105:3933–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Patton JT, Mayo LD, Singhi AD, et al. Levels of HdmX expression dictate the sensitivity of normal and transformed cells to Nutlin-3. Cancer Res. 2006;66:3169–76.PubMedCrossRefGoogle Scholar
  17. 17.
    Wade M, Wong ET, Tang M, et al. Hdmx modulates the outcome of p53 activation in human tumor cells. J Biol Chem. 2006;281:33036–44.PubMedCrossRefGoogle Scholar
  18. 18.
    Vassilev LT. p53 Activation by small molecules: application in oncology. J Med Chem. 2005;48:4491–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Xia M, Knezevic D, Tovar C, et al. Elevated MDM2 boosts the apoptotic activity of p53-MDM2 binding inhibitors by facilitating MDMX degradation. Cell Cycle. 2008;7:1604–12.PubMedCrossRefGoogle Scholar
  20. 20.
    Graves B, Thompson T, Xia M, et al. Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proc Natl Acad Sci U S A. 2012;109:11788–93.PubMedCrossRefGoogle Scholar
  21. 21.
    Park MS, Araujo DM. New insights into the hemangiopericytoma/solitary fibrous tumor spectrum of tumors. Curr Opin Oncol. 2009;21:327–31.PubMedCrossRefGoogle Scholar
  22. 22.
    Penel N, Amela EY, Decanter G, et al. Solitary fibrous tumors and so-called hemangiopericytoma. Sarcoma. 2012;2012:690251.PubMedCrossRefGoogle Scholar
  23. 23.
    •• Robinson DR, Wu YM, Kalyana-Sundaram S, et al. Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat Genet. 2013;45:180-5. The discovery of the NAB2:STAT6 translocation in SFT.Google Scholar
  24. 24.
    Bhattacharyya S, Fang F, Tourtellotte W, et al. Egr-1: new conductor for the tissue repair orchestra directs harmony (regeneration) or cacophony (fibrosis). J Pathol. 2013;229:286–97.PubMedCrossRefGoogle Scholar
  25. 25.
    Goenka S, Kaplan MH. Transcriptional regulation by STAT6. Immunol Res. 2011;50:87–96.PubMedCrossRefGoogle Scholar
  26. 26.
    Stacchiotti S, Negri T, Palassini E, et al. Sunitinib malate and figitumumab in solitary fibrous tumor: patterns and molecular bases of tumor response. Mol Cancer Ther. 2010;9:1286–97.PubMedCrossRefGoogle Scholar
  27. 27.
    Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577–80.PubMedCrossRefGoogle Scholar
  28. 28.
    Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22:3813–25.PubMedCrossRefGoogle Scholar
  29. 29.
    Verweij J, van Oosterom A, Blay JY, et al. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer. 2003;39:2006–11.PubMedCrossRefGoogle Scholar
  30. 30.
    Belinsky MG, Skorobogatko YV, Rink L, et al. High density DNA array analysis reveals distinct genomic profiles in a subset of gastrointestinal stromal tumors. Genes Chromosomes Cancer. 2009;48:886–96.PubMedCrossRefGoogle Scholar
  31. 31.
    Carney JA, Stratakis CA. Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet. 2002;108:132–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Stratakis CA, Carney JA. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J Intern Med. 2009;266:43–52.PubMedCrossRefGoogle Scholar
  33. 33.
    •• Janeway KA, Kim SY, Lodish M, et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A 2011;108:314-8. Defines the defects in succinate dehydrogenase in SDH GIST.Google Scholar
  34. 34.
    Miettinen M, Killian JK, Wang ZF, et al. Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. Am J Surg Pathol. 2013;37:234–40.PubMedCrossRefGoogle Scholar
  35. 35.
    Briere JJ, Favier J, Benit P, et al. Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions. Hum Mol Genet. 2005;14:3263–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Pollard PJ, Briere JJ, Alam NA, et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005;14:2231–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Melillo G. Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev. 2007;26:341–52.PubMedCrossRefGoogle Scholar
  38. 38.
    Young RJ, Brown NJ, Reed MW, et al. Angiosarcoma. Lancet Oncol. 2010;11:983–91.PubMedCrossRefGoogle Scholar
  39. 39.
    Rouhani P, Fletcher CD, Devesa SS, et al. Cutaneous soft tissue sarcoma incidence patterns in the U.S.: an analysis of 12,114 cases. Cancer. 2008;113:616–27.PubMedCrossRefGoogle Scholar
  40. 40.
    Abraham JA, Hornicek FJ, Kaufman AM, et al. Treatment and outcome of 82 patients with angiosarcoma. Ann Surg Oncol. 2007;14:1953–67.PubMedCrossRefGoogle Scholar
  41. 41.
    Mark RJ, Poen JC, Tran LM, et al. Angiosarcoma. A report of 67 patients and a review of the literature. Cancer. 1996;77:2400–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Fury MG, Antonescu CR, Van Zee KJ, et al. A 14-year retrospective review of angiosarcoma: clinical characteristics, prognostic factors, and treatment outcomes with surgery and chemotherapy. Cancer J. 2005;11:241–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Nagano T, Yamada Y, Ikeda T, et al. Docetaxel: a therapeutic option in the treatment of cutaneous angiosarcoma: report of 9 patients. Cancer. 2007;110:648–51.PubMedCrossRefGoogle Scholar
  44. 44.
    Penel N, Bui BN, Bay JO, et al. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study. J Clin Oncol. 2008;26:5269–74.PubMedCrossRefGoogle Scholar
  45. 45.
    Rosen A, Thimon S, Ternant D, et al. Partial response to bevacizumab of an extensive cutaneous angiosarcoma of the face. Br J Dermatol. 2010;163:225–7.PubMedGoogle Scholar
  46. 46.
    De Yao JT, Sun D, Powell AT, et al. Scalp angiosarcoma remission with bevacizumab and radiotherapy without surgery: a case report and review of the literature. Sarcoma. 2011;2011:160369.PubMedGoogle Scholar
  47. 47.
    • Agulnik M, Yarber JL, Okuno SH, et al. An open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas. Annals of Oncology: Official Journal of the European Society for Medical Oncology / ESMO 2013;24:257-63. Open label trial demonstrating a low response rate to VEGF targeting in angiosarcoma.Google Scholar
  48. 48.
    • Huang H, Bhat A, Woodnutt G, et al. Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer 2010;10:575-85. Review of the ANGPT-TIE2 pathway.Google Scholar
  49. 49.
    Coxon A, Bready J, Min H, et al. Context-dependent role of angiopoietin-1 inhibition in the suppression of angiogenesis and tumor growth: implications for AMG 386, an angiopoietin-1/2-neutralizing peptibody. Mol Cancer Ther. 2010;9:2641–51.PubMedCrossRefGoogle Scholar
  50. 50.
    Antonescu CR, Yoshida A, Guo T, et al. KDR activating mutations in human angiosarcomas are sensitive to specific kinase inhibitors. Cancer Res. 2009;69:7175–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Brown LF, Dezube BJ, Tognazzi K, et al. Expression of Tie1, Tie2, and angiopoietins 1, 2, and 4 in Kaposi's sarcoma and cutaneous angiosarcoma. Am J Pathol. 2000;156:2179–83.PubMedCrossRefGoogle Scholar
  52. 52.
    Oliner J, Min H, Leal J, et al. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell. 2004;6:507–16.PubMedCrossRefGoogle Scholar
  53. 53.
    Haldar M, Hancock JD, Coffin CM, et al. A conditional mouse model of synovial sarcoma: insights into a myogenic origin. Cancer Cell. 2007;11:375–88.PubMedCrossRefGoogle Scholar
  54. 54.
    Do K, Doroshow JH, Kummar S. Antiangiogenic approaches for the treatment of advanced synovial sarcomas. Curr Opin Oncol. 2012;24:425–30.PubMedCrossRefGoogle Scholar
  55. 55.
    Smith ME, Fisher C, Wilkinson LS, et al. Synovial sarcoma lack synovial differentiation. Histopathology. 1995;26:279–81.PubMedCrossRefGoogle Scholar
  56. 56.
    Fisher C. Synovial sarcoma: ultrastructural and immunohistochemical features of epithelial differentiation in monophasic and biphasic tumors. Hum Pathol. 1986;17:996–1008.PubMedCrossRefGoogle Scholar
  57. 57.
    Su L, Sampaio AV, Jones KB, et al. Deconstruction of the SS18-SSX fusion oncoprotein complex: insights into disease etiology and therapeutics. Cancer Cell. 2012;21:333–47.PubMedCrossRefGoogle Scholar
  58. 58.
    Nagao K, Ito H, Yoshida H. Chromosomal translocation t(X;18) in human synovial sarcomas analyzed by fluorescence in situ hybridization using paraffin-embedded tissue. Am J Pathol. 1996;148:601–9.PubMedGoogle Scholar
  59. 59.
    •• Jones KB, Su L, Jin H, et al. SS18-SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas. Oncogene 2012;1-7. Demonstration of the suppression of Mcl1 by the X:18 fusion protein.Google Scholar
  60. 60.
    de Bruijn DR, Baats E, Zechner U, et al. Isolation and characterization of the mouse homolog of SYT, a gene implicated in the development of human synovial sarcomas. Oncogene. 1996;13:643–8.PubMedGoogle Scholar
  61. 61.
    Thaete C, Brett D, Monaghan P, et al. Functional domains of the SYT and SYT-SSX synovial sarcoma translocation proteins and co-localization with the SNF protein BRM in the nucleus. Hum Mol Genet. 1999;8:585–91.PubMedCrossRefGoogle Scholar
  62. 62.
    Perani M, Ingram CJ, Cooper CS, et al. Conserved SNH domain of the proto-oncoprotein SYT interacts with components of the human chromatin remodelling complexes, while the QPGY repeat domain forms homo-oligomers. Oncogene. 2003;22:8156–67.PubMedCrossRefGoogle Scholar
  63. 63.
    Hirakawa N, Naka T, Yamamoto I, et al. Overexpression of bcl-2 protein in synovial sarcoma: a comparative study of other soft tissue spindle cell sarcomas and an additional analysis by fluorescence in situ hybridization. Hum Pathol. 1996;27:1060–5.PubMedCrossRefGoogle Scholar
  64. 64.
    Yecies D, Carlson NE, Deng J, et al. Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood. 2010;115:3304–13.PubMedCrossRefGoogle Scholar
  65. 65.
    Tahir SK, Wass J, Joseph MK, et al. Identification of expression signatures predictive of sensitivity to the Bcl-2 family member inhibitor ABT-263 in small cell lung carcinoma and leukemia/lymphoma cell lines. Mol Cancer Ther. 2010;9:545–57.PubMedCrossRefGoogle Scholar
  66. 66.
    Yang J, Zhang W. Genomic and molecular characterization of IGF1R as a promising therapeutic target in malignant peripheral nerve sheath tumor. Available at http://sarcomahelp.org/research/mpnst-IGF1R.html. Accessed March 2013.
  67. 67.
    Kolberg M, Holand M, Agesen TH, et al. Survival meta-analyses for >1800 malignant peripheral nerve sheath tumor patients with and without neurofibromatosis type 1. Neuro Oncol. 2013;15:135–47.PubMedCrossRefGoogle Scholar
  68. 68.
    Guha A, Lau N, Huvar I, et al. Ras-GTP levels are elevated in human NF1 peripheral nerve tumors. Oncogene. 1996;12:507–13.PubMedGoogle Scholar
  69. 69.
    Johannessen CM, Reczek EE, James MF, et al. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci U S A. 2005;102:8573–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18:1926–45.PubMedCrossRefGoogle Scholar
  71. 71.
    Raynaud FI, Eccles S, Clarke PA, et al. Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res. 2007;67:5840–50.PubMedCrossRefGoogle Scholar
  72. 72.
    Marshall AD, Grosveld GC. Alveolar rhabdomyosarcoma - The molecular drivers of PAX3/7-FOXO1-induced tumorigenesis. Skelet Muscle. 2012;2:25.PubMedCrossRefGoogle Scholar
  73. 73.
    Dantonello TM, Int-Veen C, Schuck A, et al. Survival following disease recurrence of primary localized alveolar rhabdomyosarcoma. Pediatr Blood Cancer 2013, In press.Google Scholar
  74. 74.
    Sorensen PH, Lynch JC, Qualman SJ, et al. PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol. 2002;20:2672–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Calhabeu F, Hayashi S, Morgan JE, et al. Alveolar rhabdomyosarcoma-associated proteins PAX3/FOXO1A and PAX7/FOXO1A suppress the transcriptional activity of MyoD-target genes in muscle stem cells. Oncogene. 2013;32:651–62.PubMedCrossRefGoogle Scholar
  76. 76.
    Charytonowicz E, Matushansky I, Domenech JD, et al. PAX7-FKHR fusion gene inhibits myogenic differentiation via NF-kappaB upregulation. Clin Transl Oncol. 2012;14:197–206.PubMedCrossRefGoogle Scholar
  77. 77.
    •• Liu L, Wu J, Ong S, Chen T. Cyclin-dependent kinase 4 phosphorylates and positively regulates PAX3-FOX01 in human alveolar rhabdomyosarcoma cells. PLoS One 2013;8:e58193. Demonstrated the regulation of PAX3:FOXO1 by CDK4.Google Scholar
  78. 78.
    Flaherty K, Lorusso P, Demichele A, et al. Phase I, dose escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res. 2012;18:568–76.PubMedCrossRefGoogle Scholar
  79. 79.
    Gelbert L, Cai S, Lin X, et al. Identification and characterization of LY2835219: a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) with broad in vivo antitumor activity [abstract B233]. Molecular Cancer Therapeutics 2011. doi:10.1158/1535-7163.TARG-11-B233.
  80. 80.
    Hirte H, Raghunadharao D, Baetz T, et al. A phase I study of the selective cyclin dependent kinase inhibitor P276-00 in patients with advanced refactory neoplasms [abstract 4368]. AACR Meeting Abstracts April 2007.Google Scholar
  81. 81.
    Stacchiotti S, Tamborini E, Marrari A, et al. Response to sunitinib malate in advanced alveolar soft part sarcoma. Clin Cancer Res. 2009;15:1096–104.PubMedCrossRefGoogle Scholar
  82. 82.
    Ladanyi M, Lui MY, Antonescu CR, et al. The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene. 2001;20:48–57.PubMedCrossRefGoogle Scholar
  83. 83.
    Tsuda M, Davis IJ, Argani P, et al. TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition. Cancer Res. 2007;67:919–29.PubMedCrossRefGoogle Scholar
  84. 84.
    Kobayashi E, Masuda M, Nakayama R, et al. Reduced argininosuccinate synthetase is a predictive biomarker for the development of pulmonary metastasis in patients with osteosarcoma. Mol Cancer Ther. 2010;9:535–44.PubMedCrossRefGoogle Scholar
  85. 85.
    •• Boone P, Weich D, Shunqiang L, et al. Simultaneous autophagy induction and ihibition induces cell death through necroptosis in sarcomas that lack argininosuccinate synthesase 1 expression. [paper #3]. Presented at the 17th Annual Connective Tissue Oncology Society Meeting. Prague, Czech Republic. November 14–17, 2012. Demonstration that ASS1 is not expressed in the majority of sarcomas.Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Ashley E. Frith
    • 1
  • Angela C. Hirbe
    • 1
  • Brian A. Van Tine
    • 1
    • 2
    • 3
  1. 1.Division of Medical Oncology, Department of Internal MedicineWashington University in St. Louis School of MedicineSt. LouisUSA
  2. 2.Siteman Cancer CenterSt. LouisUSA
  3. 3.Division of Medical Oncology, Department of MedicineWashington University in St. Louis School of MedicineSt. LouisUSA

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