Este trabajo demuestra que parte de la actividad antitumoral de lurbinectedina es debida a su acción antiproliferativa en monocitos y macrófagos asociados a tumores, células que son esenciales en el microambiente inflamatorio tumoral.
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.
ALBERTO IGLESIAS FRAGA // Madrid /// 18/04/2016 .
Cuando la situación de la ciencia en España era aún más complicada que la actual, en 1984, la compañía norteamericana Lilly decidió instalar en Alcobendas, una localidad a noreste de Madrid, su mayor laboratorio de I+D fuera de las fronteras de Estados Unidos.
¿Por qué en nuestro país? «En España hay mucho talento, un ecosistema de científicos de lo mejor de Europa y un sistema sanitario ejemplar», explica María Teresa Millán, directora de Asuntos Corporativos de Lilly. «Es muy notorio el trabajo en innovación que llevamos aquí, en un país que no tiene ningún Premio Nobel de Ciencias desde Severo Ochoa», añade Jesús Ezquerra, director del Centro de I+D de Lilly.
Desde su creación, este laboratorio ha crecido de forma notable, pasando de una decena de investigadores en los 90 a los más de 120 científicos que trabajan allí actualmente. En 2002, el laboratorio incorporó un centro de investigación en Química Médica y, siete años más tarde, haría su aparición el laboratorio de Bioquímica y Biología Molecular. «Todo lo que aquí hemos llevado a cabo ha permitido generar nuevo conocimiento para la sociedad», afirma Jesús Ezquerra.Y es que, en todos estos años, el centro no ha logrado aún crear una molécula viable al mercado, aunque se han quedado a las puertas en varias ocasiones .
Algo que no es de extrañar si se tiene en cuenta que apenas una nueva entidad química (NCE) de cada 10.000 candidatas llega a las consultas y farmacias de todo el planeta.
1.200 MILLONES DE DÓLARES es lo que puede llegar a costar el desarrollo de un nuevo fármaco.El proceso se suele prolongar entre 10 y 15 años, motivos que justifican la protección legal (y el coste) a la que están sujetos los nuevos tratamientos.
Aún es pronto para saber a ciencia cierta si el Abemaciclib será la primera molécula de síntesis orgánica que se geste en este laboratorio.
Y es que, de superar los distintos ensayos clínicos que le quedan por delante, podría convertirse en un medicamento más que indispensable en nuestra sociedad.AbemaciclibEl Abemaciclib comenzó a estudiarse en 2006, aunque sus orígenes radican en otros compuestos con los que los científicos experimentaron anteriormente. Se trata de un inhibidor del ciclo celular, capaz de bloquear -al menos en teoría- el crecimiento de las células cancerígenas. Dicho de otro modo, esta molécula podría parar el desarrollo de varios tipos de cáncer.
Los más propicios son el cáncer de mama metastásico y con dependencia de estrógenos o el cáncer de pulmón.Aún no hay fecha para su lanzamiento comercial, ya que el proceso de desarrollar un nuevo fármaco suele llevar, de media, unos 10 o 15 años. Pero, cuando lo haga, puede revolucionar la quimioterapia de este nicho de pacientes.
La propia FDA, el regulador norteamericano de medicamentos, ha reconocido esta molécula como un «tratamiento innovador», categoría con la que admite que el Abemaciclib puede aportar una «mejora clínicamente significativa» sobre las terapias disponibles.Investigación clínicaLos laboratorios de Lilly en España no sólo se dedican a la investigación de nuevas moléculas, sino que también prueban fármacos experimentales provenientes del resto de centros de I+D de la empresa en otros lugares.
46,2 MILLONES de euros es la cantidad que invierte Lilly en investigación en España. De toda su plantilla en nuestro país, el 16% están relacionados con la investigación preclínica o clínica.
Tan sólo en 2015, la firma llevó a cabo 78 estudios clínicos en nuestro país, además de contar con 537 equipos de investigación en centros sanitarios y más de 3.400 pacientes.
Abstract Number : 1183
Presentation Time: Monday, Apr 18, 2016, 8:00 AM -12:00 PM
Author Block:
Ezia Bello1, Roberta Frapolli1, Simonetta Andrea Licandro1, Silvia Brich2, Laura Carrassa1, Roberta Sanfilippo2, Alessandro Gronchi2, Paolo Casali2, Silvana Pilotti2, Maurizio D'Incalci1. 1IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy; 2Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy .
Abstract Body:
Trabectedin (ET-743, Yondelis) is a marine alkaloid isolated from the tunicate Ecteinascidia turbinata, approved in Europe and US for the 2nd line therapy of soft tissue sarcomas. It is particularly effective against myxoid liposarcoma, a specific histological subtype within the family of adults soft tissue sarcomas. More than 90% of usual myxoid/round cell liposarcomas (MRCLS) are characterized by the chromosomal translocation t(12;16) (q13; p11), which produces the FUS-CHOP oncogene.
Different chimera subtypes seem to respond differently to trabectedin in clinical setting. Trabectedin was able to remove FUS-CHOP type I, II and III from its own target genes but it causes adipocytic maturation and tumor regression only in type I and II, not in type III MRCLS (Di Giandomenico et al, Oncogene, 2014 Oct 30; 33(44): 5201-10). Pioglitazone is a PPARgamma[[unable to display character: ]]agonist with pro-differentiation effects in different cancer types included liposarcomas (Tontonoz P. et al, Proc Natl Acad Sci U S A. 1997 Jan 7;94(1): 237-41).
The aim of the study is to evaluate the efficacy of the combination of trabectedin with pioglitazone in type III myxoid liposarcoma xenografts.
ML006 and ML004 type III MRCLS xenografts mice were treated with trabectedin 0.15 mg/kg iv every seven days for three times or pioglitazone 150 mg/kg po daily for 28 days or with their combination. For antitumor activity evaluation, tumor growth was measured with a caliper and the tumor weights (1 mm3 = 1 mg) were calculated with the formula: length × (width)2/2. Fifteen days after the last dose of trabectedin and 4 h after the last dose of pioglitazone tumors were collected from a separate group of mice to perform histological and molecular analyses.
Trabectedin and pioglitazone as single agents have a comparable antitumor activity on these models with T/C around 40-50% with no tumor regression observed. In the combination groups an impressive and long lasting tumor regression was observed in ML 006 xenograft, with an observed optimal T/C of 17 %. In ML004 MRCLS model the combination of trabectedin and pioglitazone induced a minimal regression followed by a long lasting tumor stabilization, resulting in a T/C of 23%. The histological analyses showed adipocytic maturation in tumors treated with pioglitazone alone or in combination but not in samples from mice treated with trabectedin alone.
In conclusion, the combination of trabectedin with pioglitazone was able to induce tumor regression and adipocytic maturation in type III myxoid liposarcoma xenografts that were only marginally sensitive to trabectedin alone. Chromatin Immunoprecipitation, gene expression profile and Western Blot analysis are on-going to unravel the molecular mechanism behind the potentiation of the antitumor efficacy observed with this combination.
Abstract Number: LB-177
Presentation Time: Monday, Apr 18, 2016, 1:00 PM - 5:00 PM
Author Block:
Matt Harlow1, Matthew Easton2, Maria Jose Guillén Navarro3, Lisa Turner2, Galen Hostetter2, Carlos Galmarini3, Pablo Aviles3, Patrick Grohar2. 1Vanderbilt University, Nashville, TN; 2Van Andel Research Institute, Grand Rapids, MI; 3Pharmamar S.A., Madrid, Spain .
Abstract Body: BACKGROUND:
Ewing sarcoma is a bone and soft tissue sarcoma characterized by fusion of the wild-type EWSR1 and FLI1 genes, which creates a constitutively activated transcription factor, EWS/FLI1. Ewing sarcoma cells are dependent on the continued activity of EWS/FLI1 to block differentiation and promote proliferation. For these reasons, EWS/FLI1 represents an ideal drug target. With this in mind, we have shown that the small molecule trabectedin inhibits EWS/FLI1 activity and synergizes with irinotecan in vivo. In addition, we showed that the gene expression response of Ewing sarcoma cells to trabectedin treatment is identical to keratinocytes exposed to UV light. Interestingly, wild-type EWSR1 accumulates in the nucleolus in response to UV light damage. Therefore, we hypothesize that the response and sensitivity of Ewing sarcoma cells to trabectedin is due to the re-localization of EWS/FLI1 in the nucleus.
METHODS:
Here, we utilize confocal microscopy and chromatin immunoprecipitation to characterize the localization of EWS/FLI1 and EWS/FLI1 deletion mutants in response to trabectedin. Because trabectedin has a narrow therapeutic index, we characterize the effect of PM01183, a second-generation structural analog with an improved pharmacokinetic profile, on EWS/FLI1 localization. In addition, we use qPCR and western blotting to determine the kinetics of EWS/FLI1 inhibition in response to this class of compounds. We demonstrate the effects of PM01183 treatment on the EWS/FLI1 gene signature genome-wide. Finally, we translate these findings in vivo using two Ewing sarcoma xenograft models.
RESULTS:
Treatment of Ewing sarcoma cells with Trabectedin and PM01183 causes EWS/FLI1 to accumulate in the nucleolus. This effect is accompanied by a loss of binding at target sequences and a reversal in expression of the gene signature of EWS/FLI1. We found the effect on EWS/FLI1 to be sustained, even after removal of the drug from the cell culture medium. We extended these findings in vivo to demonstrate the efficacy of a previously characterized combination therapy. Interestingly, treatment of Ewing sarcoma xenografts with the combination therapy caused the tumor to be replaced by benign adipocytes.
CONCLUSIONS:
We characterize a novel method of targeting an oncogenic fusion protein by leveraging a property of the wild-type protein to inactivate the oncogenic transcription factor. We demonstrate that wild-type EWSR1 protein’s propensity to accumulate in the nucleolus upon UV light damage is maintained within the oncogenic EWS/FLI1 protein with trabectedin or PM01183 treatment. We believe that this accounts for the heightened sensitivity of Ewing sarcoma cells to this class of compounds and has numerous clinical implications.
