[Todos] SEMINARIO QB 2014 - LUNES 26 de mayo 13:00 h - Nora Navone

[Claudia Sepúlveda]

Estimados Colegas, tenemos el agrado de invitarlos al ciclo 2014 de
Seminarios del Departamento de Química Biológica.
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Lunes 26 de mayo a las 13:00 hs, Aula Cardini del Departamento de Química
Biológica, 4to piso
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Expositor: Nora M. Navone
Associate Professor, Department of Genitourinary Medical Oncology and the
David H. Koch Center for Applied Research of Genitourinary Cancers, The
University of Texas MD Anderson Cancer Center, Houston, Texas.

Título: Prostate cancer cell–stroma cell cross-talk via FGFR1 mediates
antitumor activity of dovitinib in bone metastases

Resumen:
Bone-forming metastases dominate the clinical picture of men with advanced
prostate cancer (PCa). Castration-resistant progression inbone is
frequently the first manifestation of resistance to PCa therapy and is an
indication of a lethal phenotype. The fibroblast growth factor (FGF)/FGF
receptor (FGFR) complex, a signaling axis that typically mediates
epithelial–stromal interactions (for brevity, henceforth called the “FGF
axis”), is central to prostate development and is commonly altered during
PCa progression. The FGF axis is also integral to normal bone development
and function,and it has been implicated in PCabone metastases via the
regulation of the cross-talk between PCa cells and bone cells.
Critical studies implicating FGFRs in the development and progression of
PCainclude those demonstrating thatin the prostate epithelium of mice,
conditional activation of FGFR1 leads to PCa and conditional deletion of
phosphorylated (p-)FRS2impairs prostatetumorigenesis induced by oncogenic
viral proteins. In addition, it has been shown that mesenchymal expression
of FGF10 leads to the formation of PCa through FGFR1 activation. Thus,
FGFR1- and FGF-mediated epithelial–stromal interactions are implicated in
the pathogenesis of PCa.
Correlative observations in clinical specimens have indicated that
abnormal expression of FGFs or FGFR isoforms are found in human PCa during
disease progression. The acquisition of ectopic expression of FGFR1 in PCa
epithelial cells, normally expressed by stromalcells, stands out as the
most remarkable change among the FGFR isotypes. Ectopic expression or
overexpression of multiple FGF ligands also has been observed in PCa
epithelial cells (including FGF1, FGF2, FGF6, FGF8, FGF9, and FGF17)(4,
5). Most of these studies were performed using tissue specimens derived
from primary tumors in men with localized or metastaticdisease. Recent
studies by our group and others have implicated the FGF axis (e.g., FGF9
and FGF8) in the pathogenesis of PCa progression in bone.
Taken together, these clinical and experimental observations support the
hypothesis that the FGF axis contributes to PCa progression in bone and is
thus a novel candidate target for therapy. To test this hypothesis, we
conducted parallel clinical and preclinical (i.e. co-clinical) studies
using dovitinib (TK1258, Novartis Pharma AG, Basel, Switzerland), a
receptortyrosine kinase inhibitor (TKI) with potent activity against FGFR
and vascular endothelial growth factor receptor (VEGFR), at clinically
achievable dose concentrations. For co-clinical studies, we used a
previously described patient-derived xenograft (PDX)mouse model that
reflects the biology of PCa progression in bone. On the basis of the
results from these studies, we report here that dovitinib is an active
therapeutic agent in some men with castration-resistant PCa and bone
metastases and that blockade of FGFR-mediated stromal–epithelial
interactions in the bone microenvironment (rather than a direct cytotoxic
effect on epithelial cells) plays an important role in this effect. The
integration of mouse and human results provides insights into FGF/FGFR
biology and into the mechanismunderlying the clinical activity that would
not have been evident using either model in isolation.

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Traigan su almuerzo y nosotros invitamos el café. Los esperamos!

Martín Edreira
Diego Grinman
Diego Laderach
Claudia Sepúlveda

Organizadores de los Seminarios del Dpto Química Biológica, FCEN-UBA.


Puede consultarse la agenda de próximos seminarios en
http://www.qb.fcen.uba.ar/seminarios.html