Role of New Chemotherapy Agents in Soft Tissue Sarcoma

Author: Margaret von Mehren MD1
View More View Less
  • 1 Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania

Medical management of soft tissue sarcomas (STS) has been restricted by the limited availability of active drugs. A plethora of new oncologic agents are now available, many of which have specific therapeutic targets. Gemcitabine and docetaxel is a combination of drugs that have limited single-agent activity. Yondelis, a novel chemotherapeutic that binds DNA and functions partially by inhibiting transcription, is being tested alone and in combination with doxorubicin. Inhibitors of mTOR, a serine/threonine kinase that regulates cell cycle activation and cell growth, are also being tested. Growth factor receptor inhibitors are being evaluated in a variety of sarcomas that have been found to express the targets. In addition, a variety of agents are being assessed in gastrointestinal stromal tumors (GIST). Single agents and agents combined with imatinib are being tested in imatinib-refractory and in metastatic GIST. The increased use of targeted agents underscores the need for understanding sarcoma biology.

Correspondence: Margaret von Mehren, MD, Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497. E-mail: margaret.vonmehren@fccc.edu
  • 1

    Jemal A, Tiwari R, Murray T et al.. Cancer statistics, 2004. CA Cancer J Clin 2004;54:829.

  • 2

    Elias A, Ryan L, Aisner J et al.. Mesna, doxorubicin, ifosfamide, dacarbazine (MAID) regimen for adults with advanced sarcoma. Semin Oncol 1990;17:4149.

    • Search Google Scholar
    • Export Citation
  • 3

    Svancarova L, Blay J, Judson I et al.. Gemcitabine in advanced adult soft-tissue sarcomas. A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2002;38:556559.

    • Search Google Scholar
    • Export Citation
  • 4

    Patel SR, Gandhi V, Jenkins J et al.. Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol 2001;19:34833489.

    • Search Google Scholar
    • Export Citation
  • 5

    Look K, Sandler A, Blessing J et al.. Phase II trial of gemcitabine as second-line chemotherapy of uterine leiomyosarcoma: a Gynecologic Oncology Group (GOG) study. Gynecol Oncol 2004;92:644647.

    • Search Google Scholar
    • Export Citation
  • 6

    Hensley M, Maki R, Venkatraman E et al.. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol 2002;20:28242831.

    • Search Google Scholar
    • Export Citation
  • 7

    Hensley M, Anderson S, Soslow R et al.. Activity of gemcitabine plus docetaxel in leiomyosarcomas and other histologies: report of an expanded phase II trial. J Clin Oncol 2004;22:Abstract 9010.

    • Search Google Scholar
    • Export Citation
  • 8

    Leu KM, Ostruszka LJ, Shewach D et al.. Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. J Clin Oncol 2004;22:17061712.

    • Search Google Scholar
    • Export Citation
  • 9

    Buesa J, Losa R, Fernandez A et al.. Phase I clinical trial of fixed-dose rate infusional gemcitabine and dacarbazine in the treatment of advanced soft tissue sarcoma, with assessment of gemcitabine triphosphate accumulation. Cancer 2004;101:22612269.

    • Search Google Scholar
    • Export Citation
  • 10

    Lopez Pousa A, Buesa J, Maurel J et al.. Phase I/II trial of doxorubicin (DX) and dose escalation prolonged infusion gemcitabine (GMC) as first line treatment in advanced soft tissue sarcomas (STS). A study of the Spanish Group for Research in Sarcomas (GEIS) (Abstr), Chicago, IL: American Society of Clinical Oncology; 2003:A3317.

    • Search Google Scholar
    • Export Citation
  • 11

    Morgan J, George S, Desai J et al.. Phase II study of gemcitabine/vinorelbine (GV) as first or second line chemotherapy in patients with metastatic soft tissue sarcoma (STS). J Clin Oncol 2004;22:Abstract 9009.

    • Search Google Scholar
    • Export Citation
  • 12

    Pommier Y, Kohlagen G, Bailly C et al.. 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 1996;35:1330313309.

    • Search Google Scholar
    • Export Citation
  • 13

    Garcia-Rocha M, Garcia-Gravalos MD, Avila J. Characterization of antimitotic products from marine organisms that disorganize the microtubule network: ecteinascidin 743, isohomohalichondrin-B and LL-15. Br J Cancer 1996;73:875883.

    • Search Google Scholar
    • Export Citation
  • 14

    Erba E, Bergamaschi D, Bassano L et al.. Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action. Eur J Cancer 2004;37:97105.

    • Search Google Scholar
    • Export Citation
  • 15

    Takebayashi Y, Pourquier P, Yoshida A et al.. Poisoning of human DNA topoisomerase I by ecteinascidin 743, an anticancer drug that selectively alkylates DNA in the minor groove. Proc Natl Acad Sci U S A. 1999;96:71967201.

    • Search Google Scholar
    • Export Citation
  • 16

    Zewail-Foote M, Ven-Shun L, Kohn H et al.. The inefficiency of incisions of ecteinascidin 743-DNA adducts by the UvrABC nuclease and the unique structural feature of the DNA adducts can be used to explain the repair-dependent toxicities of this antitumor agent. Chem Biol 2004;8:10331049.

    • Search Google Scholar
    • Export Citation
  • 17

    Damia G, Silvestri S, Carrassa L et al.. Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways. Int J Cancer 2001;92:583588.

    • Search Google Scholar
    • Export Citation
  • 18

    Bonfanti M, La Valle E, Fernandez Sousa Faro JM et al.. Effect of ecteinascidin-743 on the interaction between DNA binding proteins and DNA. Anticancer Drug Des 1999;14:179186.

    • Search Google Scholar
    • Export Citation
  • 19

    Li W, Takahashi N, Jhanwar S et al.. Sensitivity of soft tissue sarcoma cell lines to chemotherapeutic agents: indentification of ecteinascidin-743 as a potent cytotoxic agent. Clin Cancer Res 2001;7:29082911.

    • Search Google Scholar
    • Export Citation
  • 20

    Takahashi N, Li W, Banerjee D et al.. Sequence-dependent enhancement of cytotoxicity produced by ecteinascidin 743 (ET-743) with doxorubicin or paclitaxel in soft tissue sarcoma cells. Clin Cancer Res 2001;7:32513257.

    • Search Google Scholar
    • Export Citation
  • 21

    Meco D, Colombo T, Ubezio P et al.. Effective combination of Et-743 and doxorubicin in sarcoma: preclinical studies. Cancer Chemother Pharmacol 2003;52:131138.

    • Search Google Scholar
    • Export Citation
  • 22

    Ryan D, Supko J, Eder J et al.. Phase I and Pharmacokinetic study of ecteinascidin 743 administered as a 72-hour continuous infusion in patients with solid malignancies. Clin Cancer Res 2001;7:231242.

    • Search Google Scholar
    • Export Citation
  • 23

    van Kesteren C, Twelves C, Bowman A et al.. Clinical pharmacology of the novel marine-derived anticancer agent Ecteinascidin 743 administered as a 1- and 3-h infusion in a phase I study. Anticancer Drugs. 2002;13:381393.

    • Search Google Scholar
    • Export Citation
  • 24

    Delaloge S, Yovine A, Taamma A et al.. Ectinascidin-743: a marine-derived compound in advanced, pretreated sarcoma patients—preliminary evidence of activity. J Clin Oncol 2001;19:12481255.

    • Search Google Scholar
    • Export Citation
  • 25

    Villalona-Calero M, Eckhardt S, Weiss G et al.. A phase I and pharmacokinetic study of ecteinascidin-743 on a daily × 5 schedule in patients with solid malignancies. Clin Cancer Res 2002;8:7585.

    • Search Google Scholar
    • Export Citation
  • 26

    Gomez J, Lopez Lazaro L, Guzman C et al.. Identification of biochemical parameters that predict the onset of severe toxicities in patients treated with ET-743 (Abstr). New Orleans, LA: American Society of Clinical Oncology; 2000:187a.

    • Search Google Scholar
    • Export Citation
  • 27

    Puchalski T, Ryan D, Garcia-Carbonero R et al.. Pharmacokinetics of ecteinascidin 743 administered as a 24-h continuous infusion to adult patients with soft tissue sarcomas: associations with clinical characteristics, pathophysiological variables and toxicity. Cancer Chemother Pharmacol 2002;50:309309.

    • Search Google Scholar
    • Export Citation
  • 28

    Donald S, Verschoyle R, Greaves P et al.. Complete protection by high dose dexamethasone against the hepatotoxicity of the novel antitumor drug ecteinascidin-743 (ET-743) in the rat. Cancer Res 2003;63:59025908.

    • Search Google Scholar
    • Export Citation
  • 29

    von Mehren M, Schilder R, Cheng J et al.. Trabectedin in combination with pegylated doxorubicin (PLD) is a well tolerated regimen with good dose intensity in patients with advanced malignancies (Abstr). 29th ESMO Congress, Vienna, Austria: Elsevier; 2004:iii103.

    • Search Google Scholar
    • Export Citation
  • 30

    Demetri GD: ET-743: the US experience in sarcomas of the soft tissues. Anti-Cancer Drugs 2002;13(suppl):S7S9.

  • 31

    Garcia-Carbonero R, Supko J, Manola J et al.. Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J Clin Oncol 2004;22:14801490.

    • Search Google Scholar
    • Export Citation
  • 32

    Yovine A, Riofrio M, Blay J et al.. Phase II study of Ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients. J Clin Oncol 2004;22:890900.

    • Search Google Scholar
    • Export Citation
  • 33

    Lopez-Martin JA, Verweij J, Blay J et al.. An exploratory analysis of tumor growth rate (TGR) variations induced by trabectedin (ecteinascidin-743, ET-743) in patients (pts) with pretreated advanced soft tissue sarcoma (PASTS) (Abstr). Chicago, IL: American Society of Clinical Oncology; 2003:A3293.

    • Search Google Scholar
    • Export Citation
  • 34

    Ryan D, Puchalski T, Supko J et al.. A phase II and pharmacokinetic study of ecteinascidin 743 in patients with gastrointestinal stromal tumors. Oncologist 2002;7:531538.

    • Search Google Scholar
    • Export Citation
  • 35

    Samuels B, Rushing D, Chawla S et al.. Randomized phase II study of trabectedin (ET-743) given by two different dosing schedules in patients (pts) with leiomyosarcomas (LMS) or liposarcomas (LPS) refractory to conventional doxorubicin and ifosfamide chemotherapy. J Clin Oncol 2004;22:A9000.

    • Search Google Scholar
    • Export Citation
  • 36

    Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000;103:253262.

  • 37

    Brown EJ, Schreiber SL. A signaling pathway to translational control. Cell 1996;86:517520.

  • 38

    Yu K, Toral-Barza L, Discafani C et al.. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer 2001;8:249258.

    • Search Google Scholar
    • Export Citation
  • 39

    Neshat MS, Mellinghoff IK, Tran C et al.. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 2001;98:1031410319.

    • Search Google Scholar
    • Export Citation
  • 40

    Shi Y, Gera J, Hu L et al.. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 2002;62:50275034.

  • 41

    Huang S, Houghton PJ. Mechanisms of resistance to rapamycins. Drug Resist Updat 2001;4:378391.

  • 42

    Huang S, Houghton PJ. Resistance to rapamycin: a novel anticancer drug. Cancer Metastasis Rev 2001;20:6978.

  • 43

    Dudkin L, Dilling M, Cheshire P et al.. Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 2001;7:17581764.

    • Search Google Scholar
    • Export Citation
  • 44

    Gallicchio M, van Sinderen M, Bach L. Insulin-like growth factor binding protein-6 and CCI-779, an ester analogue of rapamycin, additively inhibit rhabdomyosarcoma growth. Horm Metab Res 2003;35:822827.

    • Search Google Scholar
    • Export Citation
  • 45

    Hidalgo M, Rowinsky E. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 2000;19:66806686.

  • 46

    Nielsen T, Hsu F, O'Connell J et al.. Tissue microarray validation of epidermal growth factor receptor and SALL2 in synovial sarcoma with comparison to tumors of similar histology. Am J Pathol 2003;163:14491456.

    • Search Google Scholar
    • Export Citation
  • 47

    Perry A, Kunz S, Fuller C et al.. Differential NF1, p16, and EGFR patterns by interphase cytogenetics (FISH) in malignant peripheral nerve sheath tumor (MPNST) and morphologically similar spindle cell neoplasms. J Neuropathol Exp Neurol 2002;61:702709.

    • Search Google Scholar
    • Export Citation
  • 48

    Olofsson A, Willen H, Goransson M et al.. Abnormal expression of cell cycle regulators in FUS-CHOP carrying liposarcomas. Int J Oncol 2004;25:13491355.

    • Search Google Scholar
    • Export Citation
  • 49

    Nuciforo P, Pellegrini C, Fasani R et al.. Molecular and immunohistochemical analysis of HER2/neu oncogene in synovial sarcoma. Hum Pathol 2003;34:639645.

    • Search Google Scholar
    • Export Citation
  • 50

    DeClue J, Heffelfinger S, Benvenuto G et al.. Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models. J Clin Invest 2000:105;12331241.

    • Search Google Scholar
    • Export Citation
  • 51

    Li H, Velasco-Miguel S, Vass W et al.. Epidermal growth factor receptor signaling pathways are associated with tumori-genesis in the Nf1:p53 mouse tumor model. Cancer Res 2002;62:45074513.

    • Search Google Scholar
    • Export Citation
  • 52

    Heymach J. Angiogenesis and antiangiogenic approaches to sarcomas. Curr Opin Oncol 2001;13:261269.

  • 53

    Saenz NC, Heslin MJ, Adsay V et al.. Neovascularity and clinical outcome in high-grade extremity soft tissue sarcomas. Ann Surg Oncol 1998;5:4853.

  • 54

    Chao C, Al-Saleem T, Brooks J et al.. Vascular endothelial growth factor and soft tissue sarcomas: tumor expression correlates with grade. Ann Surg Oncol 2001;8:260267.

    • Search Google Scholar
    • Export Citation
  • 55

    Yoon S, Segal N, Olshen A et al.. Circulating angiogenic factor levels correlate with extent of disease and risk of recurrence in patients with soft tissue sarcoma. Ann Oncol 2004;15:12611266.

    • Search Google Scholar
    • Export Citation
  • 56

    Hashimoto M, Ohsawa M, Ohnishi A et al.. Expression of vascular endothelial growth factor and its receptor mRNA in angiosarcoma. Lab Invest 1995;73:859863.

    • Search Google Scholar
    • Export Citation
  • 57

    Amo Y, Masuzawa M, Hamada Y et al.. Expression of vascular endothelial growth factor in a human hemangiosarcoma cell line (ISO-HAS). Arch Dermatol Res 2001;293:296301.

    • Search Google Scholar
    • Export Citation
  • 58

    Hatva E, Bohling T, Jaaskelainen J et al.. Vascular growth factors and receptors in capillary hemangioblastomas and hemangiopericytomas. Am J Pathol 1996;148:763775.

    • Search Google Scholar
    • Export Citation
  • 59

    Verweij J, Von Oosterom A, Blay J et al.. Imatinib Mesylate is an active agent for GIST but does not yield responses in other soft tissue sarcomas that are unselected for a molecular target. Eur J Cancer 2003;39:20062011.

    • Search Google Scholar
    • Export Citation
  • 60

    Chugh R, Thomas D, Wathen K et al.. Imatinib mesylate in soft tissue and bone sarcomas: Interim results of a Sarcoma Alliance for Research thru Collaboration (SARC) phase II trial. J Clin Oncol 2004;22:Abstract 9001.

    • Search Google Scholar
    • Export Citation
  • 61

    Simon M, Navarro M, Roux D et al.. Structural and functional analysis of a chimeric protein COL1A1-PDGFB generated by the translocation t(17;22)(q22;q13.1) in dermatofibrosarcoma protuberans (DP). Oncogene 2001;20:29652975.

    • Search Google Scholar
    • Export Citation
  • 62

    Sjoblom T, Shimizu A, O'Brien K et al.. Growth inhibition of dermatofibrosarcoma protuberans tumors by the platelet-derived growth factor receptor antagonist STI571 through induction of apoptosis. Cancer Res 2001;61:57785783.

    • Search Google Scholar
    • Export Citation
  • 63

    Maki R, Awan R, Dixon R et al.. Differential sensitivity to imatinib of 2 patients with metastatic sarcoma arising from dermatofibrosarcoma protuberans. Int J Cancer 2002;100:623626.

    • Search Google Scholar
    • Export Citation
  • 64

    Rubin BP, Schuetze SM, Eary JF et al.. Molecular targeting of platelet-derived growth factor B by imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J Clin Oncol 2002;20:35863591.

    • Search Google Scholar
    • Export Citation
  • 65

    Weiner TM, Liu ET, Craven RJ et al.. Expression of growth factor receptors, the focal adhesion kinase, and other tyrosine kinases in human soft tissue tumors. Ann Surg Oncol 1994;1:1827.

    • Search Google Scholar
    • Export Citation
  • 66

    Franklin W, Christison W, Colley M et al.. In situ distribution of the beta-subunit of platelet-derived growth factor receptor in nonneoplastic tissue and in soft tissue tumors. Cancer Res 1990;50:63446348.

    • Search Google Scholar
    • Export Citation
  • 67

    Fletcher CD, Berman JJ, Corless C et al.. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol 2002;33:459465.

  • 68

    Demetri G, George S, Heinrich MC et al.. Clinical activity and tolerability of the multi-targeted tyrosine kinase inhibitor SU11248 in patients (pts) with metastatic gastrointestinal stromal tumor (GIST) refractory to imatinib mesylate (Abstr). Chicago, IL: American Society of Clinical Oncology; 2003.

    • Search Google Scholar
    • Export Citation
  • 69

    Demetri GD, Desai J, Fletcher JA et al.. SU11248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib (IM) resistance caused by diverse genomic mechanisms in patients (pts) with metastatic gastrointestinal stromal tumor (GIST) (Abstr). New Orleans, LA: American Society of Clinical Oncology; 2004:A 3001.

    • Search Google Scholar
    • Export Citation
  • 70

    Shah N, Tran C, Lee F et al.. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004;305:399401.

  • 71

    Sawyers C, Shah N, Kantarjian H et al.. Hematologic and cytogenetic responses in imatinib-resistant chronic phase chronic myelogenous leukemia patients treated with the dual SRC/ABL kinase inhibitor BMS-354835: results from a phase I dose escalation study (Abstr). San Diego, CA: American Society of Hematology; 2004:A1.

    • Search Google Scholar
    • Export Citation
  • 72

    Takahashi R, Tanaka S, Kitadai Y et al.. Expression of vascular endothelial growth factor and angiogenesis in gastrointestinal stromal tumor of the stomach. Oncology 2003;64:266274.

    • Search Google Scholar
    • Export Citation
  • 73

    Van Oosterom A, Dumez H, Desai J et al.. Combination signal transduction inhibition: a phase I/II trial of the oral mTOR-inhibitor everolimus (E, RAD001) and imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM (Abstr). In: ASCO Annual Meeting Proceedings. New Orleans, LA: ASCO; 2004:3002.

    • Search Google Scholar
    • Export Citation
  • 74

    Reichardt P, Pink P, Lindner T et al.. A phase I/II trial of the oral PKC inhibitor PKC412 and imatinib mesylate in patients with gastrointestinal stromal tumors (GIST) refractory to imatinib (IM) (Abstr). Vienna, Austria: Eur Soc Med Oncol; 2004.

    • Search Google Scholar
    • Export Citation
  • 75

    Taamma A, Misset J, Riofrio M et al.. Phase I and pharmacokinetic study of Ecteinascidin-743, a new marine compound, administered as a 24-hour continuous infusion in patients with solid tumors. J Clin Oncol 2001;19:12561265.

    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 758 60 15
PDF Downloads 639 23 1
EPUB Downloads 0 0 0