1. Biology Informs Treatment Choices in Diffuse Large B Cell Lymphoma
Matthew J. Butler, Ricardo C.T. Aguiar 
Trends in Cancer 
Volume 3, Issue 12, Pages (December 2017)
DOI: /j.trecan
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2. Figure 1
Targeting BCR Signaling in DLBCL. Upon activation, the BCR utilizes multiple intermediaries in a signal transduction cascade that results in proliferative and prosurvival effects. Many of these signaling molecules are kinases (e.g., SYK, BTK, PI3Kδ and PCKβ) for which clinical grade inhibitors (yellow boxes) are in advanced testing in DLBCL (reviewed in [42]). An alternative strategy to attack the BCR is to unleash the inhibitory effects of the second messenger cAMP. This can be achieved by pharmacologically suppressing PDE4 with the FDA-approved PDE4 inhibitor roflumilast. Preclinical and clinical data show that PDE4 inhibition downmodulates SYK and PI3K, and downstream to them BTK and AKT [34,43,44,47,48], thus exerting a broader inhibitory influence than any targeted kinase inhibitor used in isolation. Toll-like receptor signaling is also shown because gain-of-function mutations in MYD88 are frequently found in DLBCL and they may predict response to inhibitors of BCR signaling [40]. Abbreviations: BCR, B cell receptor; BTK, Bruton’s tyrosine kinase; CARD11, caspase-associated recruitment domain 11; DLBCL, diffuse large B cell lymphoma; IRAKS, interleukin-1 receptor-associated kinases; ITAM, immunoreceptor tyrosine-based activation motif; MALT1, mucosa-associated lymphoid tissue 1; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-κB; PKCβ, protein kinase C β; PDE4, phosphodiesterase 4; PI3K, phosphoinositide 3-kinase; SFK, Src family kinase; SYK, spleen tyrosine kinase.
Trends in Cancer 2017 3, DOI: ( /j.trecan )
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3. Figure 2
Targeting the DLBCL Microenvironment. Immune evasion: a significant subset of primary testicular, primary central nervous system, and primary mediastinal BCL displays amplification in the loci encoding PD-L1 and PD-L2 [59,60]. When expressed on the surface of the lymphoma cell, these ligands interact with the PD-1 receptor of activated T cells, hindering their antitumor response. This unwanted escape from immune surveillance can be reversed with immune checkpoint inhibitors directed at PD-1 or PD-L1 (yellow boxes). Early clinical data suggest that these agents are highly active in these anatomically discrete DLBCLs [61,62]. Angiogenesis: in DLBCL, alternative antiangiogenesis strategies are needed because the combination of bevacizumab with R-CHOP in DLBCL was toxic [69]. Lenalidomide is an agent in advanced clinical testing in DLBCL [70] that may have antiangiogenic activity, as it was shown preclinically to directly inhibit endothelial cell function [73]. Roflumilast, an FDA-approved PDE4 inhibitor was shown in an in vivo preclinical model of B cell lymphoma to significantly suppress microvessel density in the tumor microenvironment [46]. This antiangiogenic activity was associated with a phosphoinositide 3-kinase/AKT-dependent suppression of VEGF-A secretion by the lymphoma cell. In addition, PDE4 inhibition can also suppress endothelial cell proliferation and migration [76–78]. Abbreviations: DLBCL, diffuse large B cell lymphoma; PDE4, phosphodiesterase 4; PD-L, programmed death ligand; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; SYK, spleen tyrosine kinase; VEGF, vascular endothelial growth factor.
Trends in Cancer 2017 3, DOI: ( /j.trecan )
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4. Figure 3
Targeting MYC and BCL2 in DLBCL. Dual expression of MYC and BCL2 defines a highly aggressive subset of DLBCL (DE DLBCL) [3,5]. Novel rationally devised strategies are needed to treat patients diagnosed with DE DLBCL, and these approaches will likely include agents that directly or indirectly suppress these molecules. The most advanced BCL2 inhibitor is venetoclax, which is currently in clinical testing for several mature B cell malignancies, including DLBCL (recently reviewed in [82]). The targeting of MYC is more challenging. One direct and specific manner to inhibit MYC may be the disruption of its essential dimerization with MAX at promoter regions, thus interfering with MYC functionality [85]. There is also active research on various indirect approaches to suppress MYC. Notable among these initiatives is the use of Aurora kinase A inhibitors, which by disrupting Aurora kinase A–MYC interactions, favors MYC degradation by the proteasome [88]. CDK7 inhibitors abrogate phosphorylation of Pol II, thus disrupting several aspects of transcriptional regulation. Curiously, this transcription deregulation is most toxic to tumors that are addicted to super-enhancer-associated transcription factors and dependent on high levels of MYC for transcription [25]. The most advanced concept in regards to MYC targeting is the use of BET protein inhibitors [85,86], with early clinical data suggesting that these agents have acceptable toxicity profile and may have clinical activity in patients with advanced relapsed/refractory DLBCL [84]. The phenotypic outcomes from BCL2 and/or MYC inhibition are probably diverse but will likely include apoptosis and tumor growth suppression, as indicate in the figure. Abbreviations: BET, bromodomain and extraterminal; BRD4, bromodomain 4; CDK7, cyclin-dependent kinase 7; DE, dual expresser; DLBCL, diffuse large B cell lymphoma; MAX, myc-associated factor X; Pol II, RNA polymerase II.
Trends in Cancer 2017 3, DOI: ( /j.trecan )
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