Lurbinectedina inhibe la transcripción y, por tanto, la producción de citoquinas y factores angiogénicos por parte de estas células. De esta forma, hace inviable el crecimiento del tumor, incluso cuando las propias células tumorales son resistentes al compuesto.
Abstract Number: 1284
Presentation Time: Monday, Apr 18, 2016, 8:00 AM -12:00 PM .
Author Block:
Paola Allavena1, Cristina Belgiovine1, Manuela Liguori1, Ezia Bello2, Roberta Frapolli2, Carlos M. Galmarini3, Maurizio D'Incalci2. 1Istituto Clinico Humanitas IRCCS, Rozzano (Milan), Italy; 2IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy; 3Pharmamar SA, Colmenar Viejo, Spain .
Abstract Body:
Lurbinectedin, currently undergoing clinical evaluation in ovarian, breast and small-cell lung cancer patients, inhibits active transcription. The drug is structurally related to trabectedin containing the same pentacyclic skeleton of the fused tetrahydroisoquinoline rings, but differing by the presence of a tetrahydro-B-carboline replacing the additional tetrahydroisoquinoline of trabectedin.
We investigated whether lurbinectedin has the ability to regulate the inflammatory tumor microenvironment in vitro and in vivo. Human purified monocytes were highly sensitive to lurbinectedin (IC50: 5-10 nM) and, after drug treatment, underwent caspase-8-dependent apoptosis.
Furthermore, in vitro, lurbinectedin significantly inhibited the production of selected inflammatory chemokines (CCL2, CXCL8) and VEGF by stimulated monocytes and liposarcoma cell lines. Administration of lurbinectedin to mice bearing a murine fibrosarcoma -resistant to this compound in vitro- resulted in significant anti-tumor activity (T/C value around 50%).
The analysis of immune cells of blood spleen and tumor tissues during treatment with lurbinectedin revealed a significant and selective decrease in the subset of monocytes and macrophages, including tumor-associated macrophages (TAM). A gene expression analysis of monocytes treated with lurbinectedin indicated a modulation of the transcriptional program in LPS-stimulated human monocytes.
Overall, these results indicate that lurbinectedin affects the inflammatory micro-environment, with a selective apoptotic-inducing effect on mononuclear phagocytes and a specific inhibition of production of inflammatory cytokines.