Disruption of Follicular Dendritic Cells–Follicular Lymphoma Cross-talk by the Pan-PI3K Inhibitor BKM120 (Buparlisib)

Abstract

Purpose: To uncover the signaling pathways underlying follicular lymphoma-follicular dendritic cells (FL-FDC) cross-talk and its validation as new targets for therapy.Experimental Design: FL primary cells and cell lines were cocultured in the presence or absence of FDC. After 24 and 48 hours, RNA was isolated from FL cells and subjected to gene expression profiling (GEP) and data meta-analysis using DAVID and GSEA softwares. Blockade of PI3K pathway by the pan-PI3K inhibitor BKM120 (buparlisib; Novartis Pharmaceutical Corporation) and the effect of PI3K inhibition on FL-FDC cross-talk were analyzed by means of ELISA, RT-PCR, human umbilical vein endothelial cell tube formation, adhesion and migration assays, Western blot, and in vivo studies in mouse FL xenografts.Results: GEP of FL-FDC cocultures yields a marked modulation of FL transcriptome by FDC. Pathway assignment by DAVID and GSEA software uncovered an overrepresentation of genes related to angiogenesis, cell adhesion, migration, and serum-response factors. We demonstrate that the addition of the pan-PI3K inhibitor BKM120 to the cocultures was able to downregulate the expression and secretion of proangiogenic factors derived from FL-FDC cocultures, reducing in vitro and in vivo angiogenesis. Moreover, BKM120 efficiently counteracts FDC-mediated cell adhesion and impedes signaling and migration induced by the chemokine CXCL12. BKM120 inhibits both constitutive PI3K/AKT pathway and FDC-or CXCL12-induced PI3K/AKT pathway, hampers FDC survival signaling, and reduces cell proliferation of FL cells in vitro and in mouse xenografts.Conclusions: These data support the use of BKM120 in FL therapy to counteract microenvironmentrelated survival signaling in FL cells. Clin Cancer Res; 20(13); 3458-71. Ó2014 AACR.

A Population of Heterogeneous Breast Cancer Patient-Derived Xenografts Demonstrate Broad Activity of PARP Inhibitor in BRCA1/2 Wild-Type Tumors

“…The growth inhibitory effect of buparlisib and TAK228 on the 2 metaplastic PDXs with PTEN alterationssupports the clinical findings of the utility of targeting PI3K/MTOR pathway in metaplastic breast cancer (34,35) and offers an opportunity to find combinations that will further enhance this effect. These findings support the idea that these combinations are well-suited for tumors with aberrant PI3K/MTOR signaling but do not rule out similar effects in non-PI3K/mTOR activated TNBC, potentially by non-cancer cell autonomous effects such as inhibiting angiogenesis (36,37). …”

Differential expression of long non‐coding RNAs are related to proliferation and histological diversity in follicular lymphomas

“…The t(14;18) positive WSU‐FSCCL cell line was selected for functional experiments as a representative model of FL tumour cells based on their phenotype, genetic alterations and behaviour in co‐culture models with follicular dendritic cells. (Mohammad et al , ; Matas‐Céspedes et al , ). To silence the expression of the lncRNA RP4‐694A7.2 in this cell line we used locked nucleic acid (LNA ™ ) oligos named Gapmers (Exiqon, Woburn, MA, USA) that are spontaneously incorporated into the cells (gymnosis) (Stein et al , ).…”

The role of G protein-coupled receptors in lymphoid malignancies

“…Multiple therapeutic possibilities involving CXCR4 have been attempted including monoclonal antibodies [139], the pan-PI3K inhibitor BKM120 [146] and crosslinking of LLT1 [147]. …”