Therapeutic strategies for targeting the ovarian tumor .

TUMOR-ASSOCIATED MACROPHAGES :

Macrophages are normally present in the peritoneal cavity of healthy women and are abundant in ascites of ovarian cancer patients[45]. Tumor-associated macrophages (TAMs) are the major immune component of the tumor stroma[46,47]. Macrophages exhibit polarized phenotypes in response to different microenvironmental cues.

Macrophages that are stimulated with microbial agents and interferon-γ exhibit an immunostimulatory M1 phenotype. In contrast, TAMs exhibit an immunosuppressive M2 macrophage phenotype[46,47]. Polarization of macrophages towards an M2 phenotype is induced by stimulation with various cytokines such as IL-6, IL-10 and leukemia inhibitory factor (LIF) that are present at elevated levels in ascites of ovarian cancer patients[48,49].
Chemokine (C-C motif) ligand 2 (CCL2) and TGF-β2 are also expressed in ovarian cancer cells and in CAFs, and these ligands have been recently shown to induce normal peritoneal macrophages to acquire an M2 phenotype[50]. CCL2 is also a key chemotactic factor that is responsible for macrophage infiltration into tumors[47].

TAMS are strongly associated with poor outcomes in cancer patients[46]. A principal mechanism by which TAMs promote tumor progression is by suppressing adaptive immunity. The M2 macrophage phenotype is characterized by high expression of immunosuppressive cytokines and chemokines such as CCL17, CCL18, CCL22, IL-10 and TGF-β1[47]. IL-10 and TGF-β1 inhibit T cell proliferation and dendritic cell maturation[47]. CCL18 induces naïve T cell anergy and has been identified to be the most abundant chemokine present in ovarian cancer patient ascite [51]. CCL17 and CCL22 promote recruitment of T regulatory cells (Treg) cells[52,53]. Treg cells suppress activity of effector T cells and have been found to promote ovarian tumor growth and to be predictive of poor survival in ovarian cancer patients[52].

In addition to expressing factors that suppress adaptive immunity, TAMs express MMPs, VEGF-A and other growth factors that stimulate metastasis and angiogenesis[ 46,47]. Depletion of peitoneal macrophages has been found to inhibit ascites and peritoneal spread of ovarian
cancer in xenograft models[54].

The recruitment of macrophages and their polarization towards a tumor-promoting M2 phenotype represent two candidate focal points for therapeutic intervention (Figure 1). Several approaches have been identified that “re-educate” TAMs towards a more tumoricidal M1 phenotype. Inhibition of the colony stimulating factor- 1 receptor has been found to inhibit M2 macrophage polarization and to block glioma progression in animal models[55]. Inhibition of nuclear factor kB signaling in TAMs also induced an M2-to-M1 switch, increased tumoricidalactivity of macrophages and led to regression of ovarian tumor xenografts[56].

Activation of CD40, a member of the tumor necrosis factor receptor superfamily, induced tumoricidal activity of macrophages in mouse models of pancreatic adenocarcinoma[57]. The
combination of agonistic CD40 mAb and gemcitabine chemotherapy has been found to be well-tolerated and to have anti-tumor activity in a phase Ⅰ study of patients with advanced pancreatic adenocarcinoma[58]. Zoledronic acid is clinically used to prevent bone fractures and also impairs M2 polarization of macrophages[59]. CCL2 is an attractive target because of its ability to stimulate monocyte chemotaxis as well as M2 polarization. Neutralization of CCL2 induced regression of prostate cancer xenografts[ 60]. A mAb to CCL2 has recently undergone clinical evaluation[61]. Bindarit, an anti-inflammatory compound that inhibits CCL2 synthesis, has been found to inhibit growth of breast and prostate tumor xenografts[62].

Trabectedin is an alkaloid that binds the minor groove of DNA and disrupts the cell cycle[63]. In a phase Ⅲ study of patients with recurrent ovarian cancer, the combination of Trabectedin and pegylated liposomal doxorubicin (PLD) was found to increase PFS by 1.5 mo as compared
to PLD alone[64]. Trabectedin also inhibits production of CCL2 and IL-6 and inhibits the differentiation of monocytes into macrophages[65]. Germano et al[66] recently demonstrated
the selective toxicity of Trabectedin for macrophages in xenograft models of ovarian cancer and several other solid tumors. In another recent study, Cieslewicz et al[67] identified a peptide (M2pep) that selectively binds to M2 macrophages. Administration of a fusion peptide comprising M2pep and a proapoptotic moiety improved survival rates of xenograft-bearing mice[67], raising the possibility that the M2pep peptide could be used as a vehicle for delivering cytotoxic agents to TAMs.

ASEBIO : La biotecnología sanitaria ‘made in Spain’ crece un 26% . Hay en Marcha 449 Proyectos .

Lunes, 16 de junio de 2014 .

La Asociación Española de Bioempresas (Asebio) acaba de publicar su ‘pipeline’ de biotecnología sanitaria en el que se recogen 449 proyectos, una cifra que supone un 26 por ciento más respecto a 2013, según la patronal.

Estos proyectos se dividen en 239 productos con 292 indicaciones de medicamentos investigados en España que aún no están comercializándose pertenecientes tanto a entidades nacionales como a filiales de multinacionales, 107 productos y servicios de diagnóstico y de medicina personalizada, 42 tecnologías cuya aplicación final es el ámbito sanitario y 61 plataformas de investigación.

En total, se han contabilizado 106 productos para 119 indicaciones que están investigando 43 compañías nacionales. 50 de ellos se encuentran en fase preclínica, 28 en fase I, 28 en fase II, 7 en fase III y 6 están a punto de comercializarse.

También se recogen 133 productos para 173 indicaciones del área de medicamentos de diez multinacionales con filial en España, en los que alguna de sus fases clínicas se ha realizado en España. De ellos 15 están en fase I, 62 en fase II, 75 en fase III y 21 están a punto de comercializarse.

Por otro lado, en el caso de los productos y servicios de diagnóstico y de medicina personalizada, 24 están listos para lanzarlos al mercado siete están ya registrados, 37 se encuentran en validación clínica, 18 en validación preliminar y 21 en I+D. Mientras, en cuanto a las tecnologías, dos están listas para lanzarse al mercado, una está en fase de registro, nueve en validación clínica, 16 en preliminar y 14 en I+D.

Oncología, líder

Por áreas terapéuticas, la oncología continúa siendo el ámbito en el que más productos se están desarrollando (el 29 por ciento de los medicamentos en el caso de compañías nacionales y 46 porciento el caso de multinacionales con filial en España). El segmento de neurociencias es la segunda área con mayor número de medicamentos en investigación y desarrollo en territorio nacional .

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...