*.- Además, inhibe la producción de mediadores proinflamatorios y angiogénicos, lo que induce cambios en el Microambiente Tumoral y contribuye a su actividad Antitumoral.
The Preclinical-Clinical Development of the Marine Antitumor natural product Trabectedin, from the sea-bed to the bed-side .
Il 20/04/2017 ore 14.30 - 15.30
Sala Conferenze, Area della Ricerca Na1, Via P. Castellino, 111 Napoli
Dr Maurizio D'Incalci from the Department of Oncology - Istituto di Ricerche Farmacologiche Mario Negri in Milan will give a seminar on the critical steps of the preclinical and clinical development of the marine natural product trabectedin, emphasizing the obstacles encountered and how preclinical research was essential to overcome them. Importance of the preclinical and translational research to conduct the clinical investigations of new anticancer drugs in the most rational and safe way.
The development of trabectedin can be considered a paradigmatic example.
Trabectedin is a tetrahydroisoquinoline molecule that binds to the N2 of guanine in the minor groove, causing DNA damage and affecting transcription regulation in a promoter- and gene-specific manner. The antitumor activity of trabectedin appears to be not only related to its direct effects on cancer cells, but also on the tumor microenvironment. In cancer cells, the drug induces cell cycle arrest and cell death that is not dependent on p53 status, and it is increased dramatically in cells deficient in homologous recombination (e.g., cells with mutations of BRCA1/2).
Trabectedin also has potent immunomodulatory effects, being selectively cytotoxic against monocytes and tumor-associated macrophages. In addition, it inhibits production of proinflammatory and angiogenic mediators, which induces changes in the tumor microenvironment and contributes to its antitumor activity.
The opportunity to combine direct cytotoxic activity with a capacity to favorably modify the tumor microenvironment, using either single-agent or combination therapy, is an especially appealing therapeutic option for a diverse range of cancers