PM01183 esta Consiguiendo Importantes Resultados en Varias Lineas Clinicas Oncologicas : Ovario , Pulmón , Mama ... tambien en el Sarcoma de EWING .

P.J. : Donde no llega Yondelis ... llega y convence PM01183 ... y para PharmaMar y sus Accionistas no es lo mismo Yondelis que PM01183 ... ya que de momento PM01183 es 100 % de PharmaMar .


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PM01183 inactivates the Ewing sarcoma oncoprotein EWS-FLI1 by redistributing it within the nucleus.

Copyright 2016, American Association for Cancer Research.

Published OnlineFirst October 3, 2016 

Harlow ML, Maloney N, Roland J, Guillén-Navarro MJ, Easton MK, Kitchen-Goosen SM, Boguslawski EA, Madaj ZB, Johnson BK, Bowman MJ, D'Incalci M, Winn ME, Turner L, Hostetter G, Galmarini CM, Aviles PM, Grohar PJ.

Abstract

There is a great need to develop novel approaches to target oncogenic transcription factors with small molecules. 

Ewing sarcoma is emblematic of this need, as it depends on the continued activity of the EWS-FLI1 transcription factor to maintain the malignant phenotype. 

We have previously shown that the small molecule trabectedin interferes with EWS-FLI1. Here we report important mechanistic advances and a second-generation inhibitor to provide insight into the therapeutic targeting of EWS-FLI1.

 We discovered that trabectedin functionally inactivated EWS-FLI1 by redistributing the protein within the nucleus to the nucleolus. 

This effect was rooted in the wild-type functions of the EWSR1, compromising the N-terminal half of the chimeric oncoprotein, which is known to be similarly redistributed within the nucleus in the presence of UV light damage.

 A second-generation trabectedin analog lurbinectedin (PM01183) caused the same nuclear redistribution of EWS-FLI1, leading to a loss of activity at the promoter, mRNA, and protein levels of expression. 

Tumor xenograft studies confirmed this effect and it was increased in combination with irinotecan, leading to tumor regression and replacement of Ewing sarcoma cells with benign fat cells. 

The net result of combined lurbinectedin and irinotecan treatment was a complete reversal of EWS-FLI1 activity and elimination of established tumors in 30-70% of mice after only 11 days of therapy. 

Our results illustrate the preclinical safety and efficacy of a disease-specific therapy targeting the central oncogenic driver in Ewing sarcoma.

PharmaMar Shows New Clinical Data on Yondelis® and Lurbinectedin at ESMO 2016 .

MADRID, October 5, 2016 .

* During this congress, PharmaMar will inform in an oral session the results of its Phase II clinical trial with lurbinectedin in patients with BRCA 1/2 metastatic breast cancer .

* A prospective randomized phase III comparing trabectedin versus the best supportive care in patients with pretreated advanced soft tissue sarcoma(T-SAR trial) will be presented in an oral session by the French Sarcoma Group .

PharmaMar (MCE:PHM) will present the data obtained from various clinical trials carried out with its antitumoral compounds of marine origin: Yondelis® (trabectedin) and lurbinectedin (PM1183), at the European Society of Medical Oncology (ESMO) congress that will take place in Copenhagen (Denmark), from the 7th to the 11th of October.

During this congress, PharmaMar will participate at different posters sessions and/or oral presentations the latest clinical advances of these molecules. In this edition, PharmaMar will present, among others, the results of a single-agent (lurbinectedin) Phase II trial in patients with BRCA 1/2 -associated metastatic breast cancer. Moreover, the French Sarcoma Group will introduce the data from a Phase III prospective study carried out in France (T-SAR), which compares trabectedin versus the best supportive care in patients with pretreated advanced soft tissue sarcoma (ASTS).

"At this year's edition of ESMO, we will announce the latest breakthroughs obtained with lurbinectedin in different tumor types. Through the various clinical trials that PharmaMar has running, we can observe that PM1883 is effective in combination and also as single-agent. This allows us to think that we have a great molecule for the treatment of different types of solid tumors, such as breast and endometrial cancers, amongst others", as Dr. Arturo Soto, director of Clinical Development at PharmaMar´s Oncology Business Unit, explains.

Yondelis /// Chronic Lymphocytic Leukemia /// Macrofagos asociados a Tumores ( TAM ) . Lenalidomide and Yondelis Prevent TAM Recruitment Mainly Through CCL2 Blockade.

En Relación : Los Macrófagos Asociados al Tumor.- 

Los Macrófagos asociados al tumor TAM, se comportan como reguladores de la tumorogénesis, bien sea como residentes o como derivados de la médula ósea o bazo. 

Los macrófagos son considerados clásicamente como células efectoras durante la defensa inmune, sin embargo numerosos estudios han demostrado su papel en la progresión tumoral . 

Estos macrófagos son una fuente importante de proteasas, como la cisteína y la catepsina, que participan en la progresión tumoral . Los TAM presentan funciones antagónicas entre la homeostasis del tejido normal y la tumorogénesis, razón por la cual los macrófagos son funcionalmente plásticos y pueden alterar su fenotipo para adaptarse a diferentes condiciones fisiológicas .

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Revista Nature , Octubre 2016 .

B Cells and Macrophages pursue a common path toward the Development and Progression of Chronic Lymphocytic Leukemia .

G Galletti , F Caligaris-Cappio and M T S Bertilaccio .

* Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA .

* Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy .

* Vita-Salute San Raffaele University, Milan, Italy .

The development and progression of chronic B-cell tumors depend on a complex microenvironmental network of cells that include monocyte-derived macrophages. In chronic lymphocytic leukemia (CLL) the survival of malignant cells is supported in vitro by nurse-like cells (NLCs) which differentiate from CD14+ monocytes and have been identified as tumor associated macrophages (TAMs).

The role of the monocyte/macrophage lineage in CLL has been extensively studied in vitro but only recently has been investigated in in vivo models. We here discuss how the cellular and molecular interactions that physiologically occur between B cells and macrophages can be subverted in chronic B lymphoid malignancies. Clinical approaches for the therapeutic targeting of TAMs are under evaluation.

Promising strategies, along with a direct impact on the malignant cells, affect crucial pathways involved in the interaction of leukemic cells with TAMs. As an example, ibrutinib reduces CLL cell chemoattraction by inhibiting macrophage secretion of CXCL13.

Lenalidomide and trabectedin prevent TAM recruitment mainly through CCL2 blockade. 

Most advanced strategies aim at depleting macrophages by targeting the CSF1/CSF1R pathway which is fundamental for TAM survival. Of note, CSF1 transcripts are significantly more abundant in progressive CLL patients when compared with stable CLL and the frequency of CSF1R+ TAMs correlates with poor survival in hematological malignancies.

The successful combination of CSF1R inhibition with currently available agents targeting malignant cells might represent the next therapeutic frontier in CLL.

Conceivably these approaches may become applicable to numerous chronic B lymphoid malignancies.