Compared with follicular lymphoma, high PI3Kα expression was more prevalent in diffuse large B cell lymphoma (DLBCL), although both tumor types expressed substantial PI3Kδ. Simultaneous inhibition of PI3Kα and PI3Kδ dramatically enhanced the anti-tumor profile in ABC-DLBCL models compared with selective inhibition of PI3Kδ, PI3Kα, or BTK. The anti-tumor activity was associated with suppression of p-AKT and a mechanism of blocking nuclear factor-κB activation driven by CD79, CARD11, TNFAIP3, or MYD88. Inhibition of PI3Kα/δ resulted in tumor regression in an ibrutinib-resistant CD79B/MYD88 patient-derived ABC-DLBCL model. Furthermore, rebound activation of BTK and AKT was identified as a mechanism limiting CD79B-ABC-DLBCL to show a robust response to PI3K and BTK inhibitor monotherapies. A combination of ibrutinib with the PI3Kα/δ inhibitor copanlisib produced a sustained complete response in vivo in CD79B/MYD88 ABC-DLBCL models.
Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in de novo fatty acid synthesis, and its ACC1 isoform is overexpressed in pancreatic and various other cancers. The activity of many oncogenic signaling molecules, including WNT and Hedgehog (HH), is post-translationally modified by lipidation. Here, we report that inhibition of ACC by a small molecule inhibitor, BAY ACC002, blocked WNT3A lipidation, secretion, and signaling. In pancreatic cancer cells, where WNT and HH are key oncogenic drivers, ACC inhibition simultaneously suppressed WNT and HH signaling, and led to anti-proliferative effects. Treatment with ACC inhibitors blocked tumor growth and converted the poorly differentiated histological phenotype to epithelial phenotype in multiple cell line-based and patient-derived pancreatic cancer xenograft models. Together, our data highlight the potential utility of ACC inhibitors for pancreatic cancer treatment, and provide novel insight into the link between upregulated de novo fatty acid synthesis in cancer cells, protein lipidation, and oncogenic signaling.
Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two of the most common Non-Hodgkin Lymphoma (NHL) wordwide. Although the introduction of anti-CD20 monoclonal antibodies has improved the outcome of patients with follicular lymphoma, a curative treatment or an improved treatment strategy for relapsed FL are still to be developed. DLBCL is an incurable, aggressive subtype of NHL with a high unmet medical need for effective therapeutics. Activation of the PI3K-AKT pathway by B cell receptor signaling and its role in the pathogenesis of FL and DLBCL have been highlighted in a number of studies, however, the relative importance of PI3K isoforms and effective application of PI3K inhibitors for the treatment of FL and DLBCL have not been fully addressed. To answer this question, we selected and characterized a panel of cell lines representing major subtypes (e.g. ABC and GCB) and frequent mutations (e.g. CD79, Bcl2, MyD88, CARD11, or EZH2) in FL and DLBCL. Analyzing the expression of PI3K isoforms indicated that not only PI3Kδ, an isoform known to be enriched in lymphocytes, but also PI3Kα is highly expressed in DLBCL and a subset of FL cell lines. Sensitivity profiling of the PI3Kα/δ inhibitor BAY 80-6946 (biochemical IC50=0.5 nM and 0.7 nM against PI3Kα and PI3Kδ, respectively) and the PI3Kδ-selective inhibitor CAL-101 confirmed that inhibition PI3Kα/δ is more effective than inhibition of PI3Kδ, particularly PI3Kα/δ inhibition showed a broader anti-tumor spectrum in the cell line panel. For example, unlike CAL-101, BAY 80-6946 revealed potent anti-tumor activity in NFκB activating MyD88 or CARD11 mutated DLBCL cell lines both in vitro and in vivo. Further analysis of mutation status and pathway inhibition discovered an unknown PI3K isoform-dependent crosstalk to the NFκB pathway in DLBCL. The detailed molecular mechanism and the strategy of developing PI3Kα/δ inhibitor as a single agent and rationale-based combination in FL and DLBCL will be discussed. Taken together, these findings provide further insights into the mechanism of action of BAY 80-6946 and support ongoing Phase I studies in FL and DLBCL patients (Lotze et al., J Clin Oncol 30, 2012, suppl, abstr 3019, data to be updated in the presentation). Citation Format: Ningshu Liu, Katja Haike, Juliane Paul, Isabelle Genvresse, Antje M. Wengner, Dirk Laurent, Damian O'Connell, Dominik Mumberg, Karl Ziegelbauer. PI3Kα/δ inhibition has greater efficacy compared to PI3Kδ-selective inhibition in NHL with activated NFkB pathway . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4115. doi:10.1158/1538-7445.AM2013-4115
The Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has demonstrated promising efficacy in a variety of hematologic malignancies. However, the precise mechanism of action of the drug remains to be fully elucidated. Tumor-infiltrating macrophages presented in the tumor microenvironment have been shown to promote development and progression of B-cell lymphomas through cross talk mediated by secreted cytokines and chemokines. Because Btk has been implicated in Toll-like receptor (TLR) signaling pathways that regulate macrophage activation and production of proinflammatory cytokines, we investigate the immunomodulatory effects of Btk inhibitor on macrophages.Our results demonstrate that Btk inhibition efficiently suppresses production of CXCL12, CXCL13, CCL19, and VEGF by macrophages.
In service, refractory linings experience thermal stresses typically exceeding their mechanical strength. However, this does not lead to the catastrophic failure of modern well-designed refractory linings. They rather undergo a more or less stepwise wear process and typically retain their structural stability despite existing substantial damage. Classic mechanical tests, such as modulus of rupture measurements that solely consider the maximum strength right before catastrophic fracture occurs are thereby inappropriate to quantify the resistance to damage of refractory products. Despite significant advancements in the theoretical description of fracture process and resistance to damages of refractory materials, there is still a lack of empirical data and scientific studies regarding the fracture behavior of typical refractory materials, especially at high temperature. Wedge splitting measurements, which proved very efficient to investigate the fracture behavior of refractory materials, were performed up to 1500 • C on four typical refractory materials and supported by microscopic investigations.All investigated refractory materials display a rather brittle behavior below 900 • C. While the high alumina brick almost remains in this state up to at least 1500 • C but gets mechanically weakened above 1400 • C, the cement bonded high alumina castable displays a drastic increase of its specific fracture energy above 1100 • C and no substantial loss of strength. This strongly suggests a brittle-toductile transition. The andalusite and silica bricks also seem to experience a brittle-to-ductile transition, even at lower temperature than for the high alumina castable; however as the andalusite brick gets dramatically weakened by the formation of liquid phase, its specific fracture energy collapses as well above 1100 • C. Much more surprisingly, silica bricks see their specific fracture energy strongly rising at about 1000 • C, but falling again above 1100 • C while retaining substantial strength, hence coming back to a rather brittle state.
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