Trabectedin, a drug acting on both cancer cells and the tumour microenvironment

M D'Incalci, N Badri, C M Galmarini, P Allavena, M D'Incalci, N Badri, C M Galmarini, P Allavena

Abstract

Trabectedin is the first marine-derived anti-neoplastic drug approved for the treatment of advanced soft tissue sarcoma and, in combination with pegylated liposomal doxorubicin, for the treatment of patients with relapsed platinum-sensitive ovarian cancer. From the beginning of its development, trabectedin showed some peculiar properties that clearly distinguished it from other anti-cancer drugs. In this mini-review, we will outline the current state of knowledge regarding the mode of action of trabectedin, which appears to represent a new class of anti-neoplastic drugs acting both on cancer cells and on the tumour microenvironment.

Figures

Figure 1
Figure 1
(A) Chemical structure of trabectedin; (B) trabectedin binding to the DNA minor groove. The figure illustrates that a part of the molecule binds to DNA whereas another part protrudes out of DNA.
Figure 2
Figure 2
Schematic summary of the different mechanisms of action and biological effects on cancer cells and tumour microenvironment.

References

    1. Allavena P, Mantovani A. Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin Exp Immunol. 2012;167:195–205.
    1. Allavena P, Signorelli M, Chieppa M, Erba E, Bianchi G, Marchesi F, Olimpio CO, Bonardi C, Garbi A, Lissoni A, de Braud F, Jimeno J, D'Incalci M. Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production. Cancer Res. 2005;65:2964–2971.
    1. Aune GJ, Takagi K, Sordet O, Guirouilh-Barbat J, Antony S, Bohr VA, Pommier Y. Von Hippel-Lindau-coupled and transcription-coupled nucleotide excision repair-dependent degradation of RNA polymerase II in response to trabectedin. Clin Cancer Res. 2008;14:6449–6455.
    1. Bissell MJ, Hines WC. Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med. 2011;17:320–329.
    1. Bueren-Calabuig JA, Giraudon C, Galmarini CM, Egly JM, Gago F. Temperature-induced melting of double-stranded DNA in the absence and presence of covalently bonded antitumour drugs: insight from molecular dynamics simulations. Nucleic Acids Res. 2011;39:8248–8257.
    1. Callata H, Manzano A, Sanchiz B, Alonso T, Gajate P, Sotelo M, Cabezas S, Aguado C, Diaz-Rubio E, Casado A.2013. Treatment with trabectedin enables retreatment with platinum-based chemotherapy in platinum-resistant and refractory (PRR) and partially platinum-sensitive (PPS) recurrent ovarian cancer (ROC) patients. ESGO 18th International Meeting: Liverpool, UK; 144
    1. Cuevas C, Francesch A. Development of Yondelis (trabectedin, ET-743). A semisynthetic process solves the supply problem. Nat Prod Rep. 2009;26:322–337.
    1. Charytonowicz E, Terry M, Coakley K, Telis L, Remotti F, Cordon-Cardo C, Taub RN, Matushansky I. PPARgamma agonists enhance ET-743-induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma. J Clin Invest. 2012;122:886–898.
    1. D'Incalci M, Galmarini CM. A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther. 2010;9:2157–2163.
    1. D'Incalci M, Galmarini CM, de la Riba Alvarez I, Badri N, Schoffski P. Association between body weight and efficacy outcomes during trabectedin therapy for recurrent advanced soft tissue sarcoma (STS) J Clin Oncol. 2012;30 (suppl:abstr 10047.
    1. Damia G, D'Incalci M. Targeting DNA repair as a promising approach in cancer therapy. Eur J Cancer. 2007;43:1791–1801.
    1. Damia G, Silvestri S, Carrassa L, Filiberti L, Faircloth GT, Liberi G, Foiani M, D'Incalci M. Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways. Int J Cancer. 2001;92:583–588.
    1. Del Campo JM, Sessa C, Krasner CN, Vermorken JB, Colombo N, Kaye S, Gore M, Zintl P, Gomez J, Parekh T, Park YC, McMeekin S. Trabectedin as single agent in relapsed advanced ovarian cancer: results from a retrospective pooled analysis of three phase II trials. Med Oncol. 2013;30:435.
    1. Di Giandomenico S, Frapolli R, Bello E, Uboldi S, Licandro SA, Marchini S, Beltrame L, Brich S, Mauro V, Tamborini E, Pilotti S, Casali PG, Grosso F, Sanfilippo R, Gronchi A, Mantovani R, Gatta R, Galmarini CM, Sousa-Faro JM, D'Incalci M.2013Mode of action of trabectedin in myxoid liposarcomas Oncogenee-pub ahead of print 11 November 2013; doi:10.1038/onc.2013.462
    1. Erba E, Bergamaschi D, Bassano L, Damia G, Ronzoni S, Faircloth GT, D'Incalci M. Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action. Eur J Cancer. 2001;37:97–105.
    1. Ferrandina G, Salutari V, Vincenzi B, Marinaccio M, Naglieri E, Loizzi V, Carpano S, Amadio G, Tonini G, Scambia G, Lorusso D. Trabectedin as single agent in the salvage treatment of heavily treated ovarian cancer patients: a retrospective, multicenter study. Gynecol Oncol. 2013;130:505–510.
    1. Feuerhahn S, Giraudon C, Martinez-Diez M, Bueren-Calabuig JA, Galmarini CM, Gago F, Egly JM. XPF-dependent DNA breaks and RNA polymerase II arrest induced by antitumor DNA interstrand crosslinking-mimetic alkaloids. Chem Biol. 2011;18:988–999.
    1. Forni C, Minuzzo M, Virdis E, Tamborini E, Simone M, Tavecchio M, Erba E, Grosso F, Gronchi A, Aman P, Casali P, D'Incalci M, Pilotti S, Mantovani R. Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors. Mol Cancer Ther. 2009;8:449–457.
    1. Friedman D, Hu Z, Kolb EA, Gorfajn B, Scotto KW. Ecteinascidin-743 inhibits activated but not constitutive transcription. Cancer Res. 2002;62:3377–3381.
    1. Gago F, Hurley LH.2002Devising a structural basis for the potent cytotoxic effects of ecteinascidin 743 Small Molecule DNA and RNA Binders: From Synthesis to Nuclear Acid ComplexesDemeunynck M, Bailly C, Wilson WD, (eds) pp643–675.Wiley-VCH: Weinheim, Germany
    1. Galmarini CM, D'Incalci M, Allavena P. Trabectedin and plitidepsin: drugs from the sea that strike the tumor microenvironment. Mar Drugs. 2014;12:719–733.
    1. Germano G, Frapolli R, Belgiovine C, Anselmo A, Pesce S, Liguori M, Erba E, Uboldi S, Zucchetti M, Pasqualini F, Nebuloni M, van Rooijen N, Mortarini R, Beltrame L, Marchini S, Fuso Nerini I, Sanfilippo R, Casali PG, Pilotti S, Galmarini CM, Anichini A, Mantovani A, D'Incalci M, Allavena P. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell. 2013;23:249–262.
    1. Germano G, Frapolli R, Simone M, Tavecchio M, Erba E, Pesce S, Pasqualini F, Grosso F, Sanfilippo R, Casali PG, Gronchi A, Virdis E, Tarantino E, Pilotti S, Greco A, Nebuloni M, Galmarini CM, Tercero JC, Mantovani A, D'Incalci M, Allavena P. Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. Cancer Res. 2010;70:2235–2244.
    1. Grohar PJ, Griffin LB, Yeung C, Chen QR, Pommier Y, Khanna C, Khan J, Helman LJ. Ecteinascidin 743 interferes with the activity of EWS-FLI1 in Ewing sarcoma cells. Neoplasia. 2011;13:145–153.
    1. Grohar PJ, Helman LJ. Prospects and challenges for the development of new therapies for Ewing sarcoma. Pharmacol Ther. 2013;137:216–224.
    1. Grohar PJ, Segars LE, Yeung C, Pommier Y, D'Incalci M, Mendoza A, Helman LJ. Dual targeting of EWS-FLI1 activity and the associated DNA damage response with Trabectedin and SN38 synergistically inhibits Ewing sarcoma cell growth. Clin Cancer Res. 2013;20 (5:1190–1203.
    1. Grosso F, Jones RL, Demetri GD, Judson IR, Blay JY, Le Cesne A, Sanfilippo R, Casieri P, Collini P, Dileo P, Spreafico C, Stacchiotti S, Tamborini E, Tercero JC, Jimeno J, D'Incalci M, Gronchi A, Fletcher JA, Pilotti S, Casali PG. Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. Lancet Oncol. 2007;8:595–602.
    1. Grosso F, Sanfilippo R, Virdis E, Piovesan C, Collini P, Dileo P, Morosi C, Tercero JC, Jimeno J, D'Incalci M, Gronchi A, Pilotti S, Casali PG. Trabectedin in myxoid liposarcomas (MLS): a long-term analysis of a single-institution series. Ann Oncol. 2009;20:1439–1444.
    1. Herrero AB, Martin-Castellanos C, Marco E, Gago F, Moreno S. Cross-talk between nucleotide excision and homologous recombination DNA repair pathways in the mechanism of action of antitumor trabectedin. Cancer Res. 2006;66:8155–8162.
    1. Hollebecque A, Adenis A, Taieb S, Lebedinsky C, Penel N. Inadequacy of size-based response criteria to assess the efficacy of trabectedin among metastatic sarcoma patients. Invest New Drugs. 2010;28:529–530.
    1. Hurley LH, Zewail-Foote M. The antitumor agent ecteinascidin 743: characterization of its covalent DNA adducts and chemical stability. Adv Exp Med Biol. 2001;500:289–299.
    1. Jin S, Gorfajn B, Faircloth G, Scotto KW. Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation. Proc Natl Acad Sci USA. 2000;97:6775–6779.
    1. Le Cesne A. 13 years of trabectedin, 5 years of Yondelis(R): what have we learnt. Expert Rev Anticancer Ther. 2013;13:11–19.
    1. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–555.
    1. Minuzzo M, Marchini S, Broggini M, Faircloth G, D'Incalci M, Mantovani R. Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743. Proc Natl Acad Sci USA. 2000;97:6780–6784.
    1. Monk BJ, Blessing JA, Street DG, Muller CY, Burke JJ, Hensley ML. A phase II evaluation of trabectedin in the treatment of advanced, persistent, or recurrent uterine leiomyosarcoma: a gynecologic oncology group study. Gynecol Oncol. 2012;124:48–52.
    1. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4:71–78.
    1. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51.
    1. Romano M, Frapolli R, Zangarini M, Bello E, Porcu L, Galmarini CM, Garcia-Fernandez LF, Cuevas C, Allavena P, Erba E, D'Incalci M. Comparison of in vitro and in vivo biological effects of trabectedin, lurbinectedin (PM01183) and Zalypsis(R) (PM00104) Int J Cancer. 2013;133:2024–2033.
    1. Sanfilippo R, Casali PG. The intriguing patterns of tumor response to trabectedin. Expert Rev Anticancer Ther. 2013;13:21–24.
    1. Sanfilippo R, Grosso F, Jones RL, Banerjee S, Pilotti S, D'Incalci M, Dei Tos AP, Raspagliesi F, Judson I, Casali PG. Trabectedin in advanced uterine leiomyosarcomas: a retrospective case series analysis from two reference centers. Gynecol Oncol. 2011;123:553–556.
    1. Schoffski P, Taron M, Jimeno J, Grosso F, Sanfilipio R, Casali PG, Cesne AL, Jones RL, Blay JY, Poveda A, Maki RG, Nieto A, Tercero JC, Rosell R. Predictive impact of DNA repair functionality on clinical outcome of advanced sarcoma patients treated with trabectedin: A retrospective multicentric study. Eur J Cancer. 2011;47:1006–1012.
    1. Soares DG, Escargueil AE, Poindessous V, Sarasin A, de Gramont A, Bonatto D, Henriques JA, Larsen AK. Replication and homologous recombination repair regulate DNA double-strand break formation by the antitumor alkylator ecteinascidin 743. Proc Natl Acad Sci USA. 2007;104:13062–13067.
    1. Takebayashi Y, Pourquier P, Zimonjic DB, Nakayama K, Emmert S, Ueda T, Urasaki Y, Kanzaki A, Akiyama SI, Popescu N, Kraemer KH, Pommier Y. Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nat Med. 2001;7:961–966.
    1. Tavecchio M, Simone M, Erba E, Chiolo I, Liberi G, Foiani M, D'Incalci M, Damia G. Role of homologous recombination in trabectedin-induced DNA damage. Eur J Cancer. 2008;44:609–618.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever