Protein Kinase C Inhibitor Sotrastaurin Selectively Inhibits the Growth of CD79 Mutant Diffuse Large B-Cell Lymphomas

Abstract

The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) correlates with poor prognosis. The ABC subtype of DLBCL is associated with constitutive activation of the NF-kB pathway, and oncogenic lesions have been identified in its regulators, including CARD11/CARMA1 (caspase recruitment domain-containing protein 11), A20/TNFAIP3, and CD79A/B. In this study, we offer evidence of therapeutic potential for the selective PKC (protein kinase C) inhibitor sotrastaurin (STN) in preclinical models of DLBCL. A significant fraction of ABC DLBCL cell lines exhibited strong sensitivity to STN, and we found that the molecular nature of NF-kB pathway lesions predicted responsiveness. CD79A/B mutations correlated with STN sensitivity, whereas CARD11 mutations rendered ABC DLBCL cell lines insensitive. Growth inhibitory effects of PKC inhibition correlated with NF-kB pathway inhibition and were mediated by induction of G 1 -phase cell-cycle arrest and/or cell death. We found that STN produced significant antitumor effects in a mouse xenograft model of CD79A/B-mutated DLBCL. Collectively, our findings offer a strong rationale for the clinical evaluation of STN in ABC DLBCL patients who harbor CD79 mutations also illustrating the necessity to stratify DLBCL patients according to their genetic abnormalities. Cancer Res; 71(7); 2643-53. Ó2011 AACR.

Reproducible, Quantitative, and Flexible Molecular Subtyping of Clinical DLBCL Samples Using the NanoString nCounter System

“…As preclinical data suggested that ABC-type cell lines may be preferentially sensitive to fostamatinib, COO segmentation of patient DLBCL tissue was considered key to a possible patient selection strategy (ref. 25; AstraZeneca unpublished data). Fresh, predose DLBCL tumor biopsies (core needle) were successfully collected from nearly all patients during prescreening.…”

“…We examined nine DLBCL cell lines with literature-established COO designations (24,25). To confirm that inhouse cell lines were representative of those in the literature, we used a previously described (18) RT-PCR method and applied a COO signature score (detailed in Materials and Methods); a high scoring sample (>0.7) signified an ABC subtype, low scoring samples (<0) a GCB subtype, and those in between (>0-<0.7) as unclassified.…”

Genome wide SNP array identified multiple mechanisms of genetic changes in Waldenstrom macroglobulinemia

“…Hypothesis of the existence of a crosstalk between BCR and MYD88 signalling via Bruton tyrosine kinase will have to be explored. Similarly, further study will also have to determine whether the BCR might represent a new therapeutic target in B cell lymphoma, including WM [24].…”

PKC-β as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL

“…Lastly, considering the importance of PKC-b to CLL development in Em-TCL1 mice 10 and the preliminary efficacy of AEB071 in preclinical models of DLBCL, 28 our laboratory is currently pursing in vivo studies using TCL1 transgenic mice. Our preliminary results from 2 different CLL mouse models reveal beneficial antitumor effects of AEB071, wherein AEB071 treatment resulted in reduction of CD5/CD19-positive peripheral blood lymphocytes and spleen size in leukemic mice (supplemental Figure 4).…”

“…Although AEB071 affects primarily PKC, biochemical profiling of .200 kinases revealed both isoforms of GSK3, as previously unappreciated direct targets of AEB071. 27 Preclinically, AEB071 has demonstrated in vivo activity in an activated B-cell diffuse large B-cell lymphoma (DLBCL) model 28 and is currently being tested in a phase 1 clinical trial for patients with CD79-mutant DLBCL (ClinicalTrials.gov NCT01402440). Given its ability to suppress T-cell activation, AEB071 has been studied in phase 2 clinical trials for psoriasis and solid organ transplantation.…”