ABSTRACT
Purpose: Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types, and pharmacologic inhibition of the PI3K/mTOR pathway has shown activity in lymphoma patients. Here, we extensively characterized the in vitro and in vivo activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models.Experimental Design: This study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on in vivo models and primary cells, proteomics and gene-expression profiling, and comparison with other signaling inhibitors.Results: PQR309 had in vitro antilymphoma activity as single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab. Sensitivity to PQR309 was associated with specific baseline gene-expression features, such as high expression of transcripts coding for the BCR pathway. Combining proteomics and RNA profiling, we identified the different contribution of PQR309-induced protein phosphorylation and gene expression changes to the drug mechanism of action. Gene-expression signatures induced by PQR309 and by other signaling inhibitors largely overlapped. PQR309 showed activity in cells with primary or secondary resistance to idelalisib.Conclusions: On the basis of these results, PQR309 appeared as a novel and promising compound that is worth developing in the lymphoma setting. Clin Cancer Res; 24(1); 120-9. ©2017 AACR.
Subject(s)
Antineoplastic Agents/pharmacology , Lymphoma/metabolism , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Drug Resistance, Neoplasm , Humans , Lymphoma/drug therapy , Lymphoma/genetics , Lymphoma/pathology , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Purines , Quinazolinones , Xenograft Model Antitumor AssaysABSTRACT
Cancer of the ampulla of Vater is an uncommon disease that leads to death in 60% of affected patients. There is general agreement that local spread of the tumour (T stage) is the only significant and independent prognostic factor for this cancer. Although the genetic mechanisms underlying the development of ampullary tumors are still mostly unknown because of their rarity, the genetic anomalies involved in tumor development might serve as additional prognostic markers. Cytogenetic studies may be helpful in identifying specific chromosome regions involved in these cancers. We studied two cases of poorly differentiated ampullary adenocarcinomas using conventional and molecular cytogenetics on direct preparations. The cytogenetic analysis revealed complex chromosome complements in both cases with different cell lines, rearrangements, chromosome markers, and aneuploidies. Interestingly, the involvement of the 1p36 region was a feature of both cases. The molecular studies showed an absence of high microsatellite instability (MSI) and the morphologic and immunohistochemical pattern did not suggest MSI. This study may help to characterized ampullary adenocarcinomas showing complex karyotypes, poor differentiation and poor prognosis. In these tumors, the 1p36 region may play a relevant role in the progression towards a high grade of anaplasia.
