Abstract LB-361: The novel PI3K kinase inhibitor NVP-BKM120 shows in vitro and in vivo efficacy in follicular Lymphoma by disrupting microenvironment survival signaling
Authors: Matas Alba , Roue Gael , Campo Elias , Lopez-Guillermo Armando , Colomer Dolors , Perez-Galan Patricia 
Published: August 2012

Follicular lymphoma (FL) is the second most common B- cell non Hodgkin Lymphoma and is characterized by the t(14;18)(q32;q21), leading to over expression of Bcl-2. However, this genetic alteration is not sufficient for tumor development and progression, and it is accepted FL pathogenesis as the result of a functional cross talk between the genetic alterations and the influence of its immune microenvironment in the bone Marrow (BM) and lymph nodes (LN). Although FL is an indolent tumor, up to one-third of cases can progress to a more aggressive disease leading to short survival. The immune microenvironment in the LN plays an important role in tumor development and progression and two outcome-related signatures IR1 and IR2, have been identified by gene expression profiling. IR1, composed of genes expressed by T-cells associated with a more favorable clinical course, and IR2, enriched for genes expressed by macrophages and follicular dendrytic cells (FDC) associated with an inferior clinical course. Recently, PI3K has become an attractive target in cancer therapy. In FL, PI3K/AKT pathway is constitutive activated as a consequence of survival signals coming from tumor microenvironment through cytokine/chemokine secretion (IL4/IL4R, CXCR4/CXCL12) and ligand-receptor interactions that include B-cell receptor (BCR) and CD40/CD40L.Thus, we have evaluated the potential interest of the novel and specific PI3K inhibitor NVP-BKM120 (Novartis) as a new therapy in FL. We found that NVP-BKM120 induces variable cytotoxic and cytostatic effect in FL cell lines, and limited toxicity in FL primary samples (10-20%) in accordance with results with other specific PI3K inhibitors in different models. NVP-BKM120 efficiently blocks constitutive activation of PI3K/AKT pathway in FL cells, and completely abrogates AKT activation derived from co-culture with BM stromal cells or FDCs or consequent to BCR ligation. NVP-BKM120 interferes with tumor cell-microenvironment interactions by blocking SDF1α/CXCL12-induced migration and significantly reduces the secretion of several cytokines (p&lt;0.01), including GM-CSF, G-CSF, CCL2, CCL7, CCL8, IL1, IL7, IL8 and IL10 in a FL-FDC co-culture model. Finally, we have evaluated the in vivo efficacy of this compound in a xenograft mouse model (subcutaneous injection of the FL cell line RL), and NVP-BKM120 reduced tumor size by 35%. Immunohistochemistry analysis revealed a marked decreased in the expression of pAKT and its downstream target pS6rp in tumors from NVP-120-treated mice. These results warrant further studies of NVP-BKM120 in FL. We are now trying to increase its therapeutic index by combination with the BH3-mimetic ABT-263 which is able to antagonize the over expression of Bcl-2, not affected by NVP-BKM120 action, or anti-CD20 antibodies, commonly present in FL current regimens.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-361. doi:1538-7445.AM2012-LB-361