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Ac personalized targets

Ac personalized targets

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Ac personalized targets -

Thus, constitutive expression of interferon response factor IRF -4 in ABC-DLBCLs contributes to unchecked proliferation of DLBCL tumors [ 90 , 91 ]. X-box binding protein 1 XBP1 is the master regulator of immunoglobulin secretion [ 35 , 92 ]. On the other hand, ABC-DLBCLs acquire genetic alterations that repress BLIMP1 expression and function, thereby blocking the differentiation into end stage plasma cells [ 92 — 94 ].

ABC-DLBCL is characterized by genetic abnormalities that play an important role in its pathogenesis. A summary of characteristic molecular features of ABC-DLBCL is shown in Table 4. ABC-DLBCLs express genes that are upregulated in B cells with activated BCR signaling [ 13 , 96 ] see also next sections.

BCR-mediated NF-κB-dependent survival signaling plays important roles in certain B-cell malignancies [ 97 — 99 ]. Similar to PMLBCL, a key feature of the more aggressive ABC-DLBCL subtype is the constitutive activation of NF-κB-dependent gene expression and its dependency on the activity of NF-κB family members for proliferation and survival [ 18 , 54 , 66 , 76 , ].

NF-κB is a family of inducible transcription factors consisting of five members, REL-A p65 , REL-B, c-REL, NF-κB1 p50 and its precursor p , and NF-κB2 p52 and its precursor p [ ].

Inhibition of this pathway using either a dominant active form of NF-κB inhibitory protein inhibitor of kappa B IκB -α or a specific IκB kinase inhibitor is toxic to ABC- but not to GCB-DLBCL cell lines [ 59 , ]. The NF-κB family members REL-A, REL-B and c-REL have the capacity to regulate transcription of various subsets of genes involved in cell proliferation and resistance to apoptosis [ ].

ABC-DLBCLs shows a more restricted, potentially developmentally regulated NF-κB target gene signature [ 54 , 76 , ]. Activation of NF-κB has been identified as a key driver in apoptosis resistance in ABC-DLBCL and PMLBCL leading to poor outcomes in patients with ABC-DLBCL [ 18 , 54 , ].

The most common MyD88 mutant, LP, spontaneously coordinates a signaling complex in which interleukin-1 receptor-associated kinase IRAK -4 phosphorylates IRAK1, leading to inhibitor of kappa B IκB kinase IKK and NF-κB activation [ ].

CARD11 is a key signaling adaptor that coordinates a BCR and CDmediated signaling complex that activates NF-κB pathways [ , ]. ABC-DLBCLs with wild-type CARD11 depend on constitutively active BCR signaling [ ]. Both wild-type and mutant CARD11 are essential for chronic active BCR signaling and survival in ABC-DLBCL [ ].

Oncogenic deregulated intracellular signaling pathways in ABC-DLBCL are summarized in Fig. Translocations of both BCL2 and c- MYC genes also occur in ABC-DLBCLs and contribute to the inferior survival of the ABC subtype of DLBCL [ ].

Both GCB-DLBCL and ABC-DLBCL share genetic lesions that lead to inactivation of chromatin modifiers, owing to mutations in CREBBP, EP and MLL2 [ 15 , 19 , 20 , 29 ], as well as to immune escape, owing to inactivation of β2 microglobulin B2M , CD58 and genes encoding human leukocyte antigens HLA-A, HLA-B and HLA-C [ 15 , 19 , 20 , 29 , ].

For a detailed description of the biology and pathology of ABC-DLBCL, the readers are referred to the recent excellent reviews [ 2 , 3 , 35 , 39 , 70 , 86 , , , ]. Oncogenic deregulated intracellular signaling pathways in activated B cell-like ABC diffuse large B-cell lymphoma DLBCL.

The oncogenic constitutive activation of canonical nuclear factor-kappa B NF-κB family members in activated B cell-like diffuse large B-cell lymphoma ABC-DLBCL , together with a blockade in terminal B cell differentiation, which is in part mediated by BCL6, represent the hallmarks of ABC-DLBCL pathogenesis [ 13 , 16 — 18 , ].

The different clinical behavior of these lymphomas may be strongly influenced by differences in the lymphoma microenvironment [ 42 ]. In the following sections we will mainly focus on the two molecular subtypes of DLBCL-NOS; GCB- and ABC-DLBCL. More recent GEP studies using multiple clustering methods revealed the existence of at least seven distinct DLBCL-NOS subsets with poor prognosis.

An overview of molecular signatures in DLBCL-NOS associated with poor prognosis is presented in Table 5. The first signature identified by Monti S. et al. OxPhos-DLBCL display enhanced mitochondrial energy transduction, greater incorporation of nutrient-derived carbons into the tricarboxylic acid cycle, and increased glutathione levels [ ].

Although the exact nature of survival pathways in this group of tumors is not known, - based on findings in other cancer models- it has been suggested that the increased fatty acid metabolism observed in OxPhos-DLBCL may serve as an alternative survival pathway that is triggered by glucose deprivation or lack of glucose uptake [ ].

Indeed, disturbing the fatty acid oxidation program and glutathione synthesis is selectively toxic to the OxPhos-DLBCL tumor subset [ ]. The second subtype signature identified by Monti S. In normal untransformed B cells, BCR signaling is activated in an active antigen-dependent manner that initiates the germinal center response [ 96 , — ].

Antigen-induced aggregation of the BCR activates BCR signaling through receptor oligomerization and phosphorylation of immunoreceptor tyrosine-based activation motifs ITAMS by SRC family kinases, including FYN and B lymphocyte kinase BLK [ , ]. Active antigen-dependent BCR signaling engages multiple downstream pathways, [ , , , ].

Normal untransformed B cells also exhibit tonic, ligand antigen -independent, ITAM-transmitted BCR signaling, that promotes subsequent development and survival of mature B cells in the periphery [ 96 , — ]. Tonic active BCR signaling engages the phosphoinositide 3-kinase PI3K pathway only and is also relevant to B-cell malignancies [ 96 , — , ].

A role for tonic BCR signaling has been postulated for GCB-DLBCL based on the sensitivity of certain cell lines of this lymphoma subtype to R, a broad range small molecule inhibitor of SYK [ 97 ]. However, genetic knockdown of proximal BCR subunits IgM, Ig-kappa, CD79A and CD79B killed only ABC-DLBCL with wild-type CARD11 but did not kill other lymphomas including various GCB-DLBCL cell lines [ 96 ].

Moreover, GCB-DLBCL tumors do not acquire highly recurrent mutations in the BCR signaling or canonical NF-κB pathways [ 96 ]. Thus it remains to be elucidated whether SYK is indeed essential in GCB-DLBCL or other receptors might be required for activation of the observed BCR-like signaling in GCB-DLBCL [ 31 ].

A third type of BCR signaling, termed chronic active BCR signaling, have been characterized in B-cell malignancies, which can involve mutations of BCR pathway components or be triggered by auto- antigens present in the tissue microenvironment [ 96 , — , ].

Chronic active BCR signaling is distinct from tonic BCR signaling, which stimulates the PI3K pathway but not the NF-κB signaling pathways [ 31 ]. LYN functions as a feedback inhibitor of BCR-stimulated signaling [ ]. LYN is frequently mutated and inactivated in ABC-DLBCL [ 21 ].

This new pathogenetic mechanism in ABC-DLBCL was therefore termed chronic active BCR signaling [ 96 ]. Certain BCR-dependent ABC-DLBCLs also exhibit constitutive PI3K activation, which modulates downstream NF-κB signaling [ 98 , ].

Several studies have shown that differences in the tumor microenvironment of DLBCL affect survival after treatment with rituximab-based chemotherapeutic regimens [ 85 , , , ]. The robust NF-κB target gene signature of HR-DLBCL partially overlaps with that of PMLBCLs, implicating the NF-κB survival pathway in this subtype [ 40 , 54 , ].

HR-DLBCL lack most of the common cytogenetic abnormalities seen in OxPhos-DLBCL or BCR-DLBCL and occur in younger patients who often have splenomegaly and bone marrow involvement [ ]. The c-MYC overexpressing subsets of DLBCL-NOS have been recently suggested to be sub-classified as c-MYC-driven MD subtype of GCB-, ABC and typeDLBCL-NOS [ ].

Double-hit cases harboring a c-MYC gene translocation and BCL6 rearrangements have also been reported, although at a much lower frequency than with BCL2 [ ]. In addition, in some cases with the t 8,14 translocation, there is a concurrent rearrangement of both anti-apoptotic BCL2 and BCL6 oncogene s , which are referred to as triple-hit lymphomas [ , ].

DLBCLs with high co-expression of c-MYC and BCL2 proteins have an aggressive clinical course and an inferior overall survival when treated with R-CHOP [ , , ].

The aggressive nature of double-hit and triple-hit lymphomas is likely due to the concurrent rearrangement of both the pro-proliferative c-MYC oncogene and the anti-apoptotic BCL2 oncogene [ , ]. Several studies indicate that the overexpression of the c-MYC protein might be a prognostic marker for poor survival in DLBCL, independent of BCL2 [ — ].

However, it is still controversial whether the high expression of c-MYC has prognostic significance as a sole marker, independent of BCL2 co-overexpression [ , — ]. Indeed, it has been recently suggested that only high co-expression of both c-MYC and BCL2 proteins may serve as an independent predictor of very poor survival in DLBCL [ , — ].

A large GEP study performed by Lenz G. identified an additional microenvironment stromal gene expression signatures associated with superior or inferior outcomes, respectively after treatment with rituximab-based chemotherapeutic regimens [ 85 ].

Three gene-expression signatures, - termed germinal-center B cell, stromal-I and stromal-II signatures - were identified that predicted survival in patients who received CHOP or R-CHOP, respectively [ 85 ].

The stromal-I-signature, related to extracellular matrix deposition and histiocytic infiltration was associated with a good outcome [ 85 , ].

By contrast the angiogenesis-related stromal-II signature reflected tumor blood-vessel density and was found to be highly associated with a poor outcome [ 85 ]. This stromal-II signature includes genes encoding key regulators of angiogenesis such as vascular endothelial growth factor VEGF receptor 2, growth factor receptor-bound protein GRB , which mediates VGFR2 signaling; integrin alpha 9, which enhances VEGF signaling and the endothelial receptor tyrosine kinase TEK, the receptor kinase for angiopoietin signaling [ 85 ].

DLBCLs with overexpression of the stromal-II gene expression are associated with increased tumor blood-vessel density [ 85 ]. The stromal-II gene expression signature has been therefore suggested to represent an angiogenic switch in which the progression of a hyperplastic lesion to a fully malignant tumor is accompanied by new blood-vessel formation [ 85 ].

Jardin F. A systematic integrative study of high-resolution genotyping arrays and RNA sequencing data of two independent large cohorts of homogenously R-CHOP-treated DLBCL patients identified novel focal and recurrent deletions in the chromatin regulator and transcriptional corepressor gene RCOR1 encoding CoREST1 that are associated with a novel prognostically significant risk-associated gene expression signature [ ].

RCOR1 deletions define a subgroup of DLBCL patients with unfavorable progression-free survival [ ]. The established Rcor1 loss-associated prognostic gene signature was independent of the cell of origin classification [ ].

This risk-associated gene expression signature comprises genes and is enriched for biological processes that includes upregulation of the proteasome, processing of capped intron-containing pre-mRNA as well as downregulation of signaling events mediated by HDAC class II [ ].

Interestingly, loss of RCOR1 was associated with deletions of the TRAF3 gene, which is located in close vicinity. TRAF3 is a negative regulator of the alternative non-canonical NF-κB signaling pathways in DLBCL, acting as a negative regulator of NF-κB-inducing kinase NIK [ 27 , , ].

Thus, it is very likely that the combination of transcriptional pattern changes mediated by RCOR1 loss and the downstream effects on constitutive NF-κB signaling may cooperate and contribute to the malignant phenotype of this subgroup of DLBCL [ ]. Until , the standard treatment for DLBCL was the anthracycline-based chemotherapy regimen of cyclophosphamide, hydroxyldaunorubicin, vincristine, and prednisone CHOP.

Relapsed CHOP-resistant lymphomas disseminate and are highly lethal without autologous stem cell transplantation [ 1 , , ]. DLBCL subtypes differently respond to the standard CHOP chemotherapy.

The ABC-DLBCL subtype is associated with a very poor prognosis when treated with CHOP only, the majority of ABC-DLBCL patients treated with CHOP alone will succumb to their disease [ 1 , , ].

In contrast, CHOP only treated patients with GCB-DLBCL and PMLBCL have a significantly better outcome with relatively favorable 5-year overall survival rates [ 1 , , ]. The constitutive activation of the NF-κB and BCR pathways has been suggested to be required for the anti-apoptotic phenotype and chemotherapy-resistance in ABC-DLBCL [ 35 , , ].

These groups of patients pose a particular urgent clinical need because of a very aggressive clinical course, high chemorefractoriness and inferior overall survival when treated with R-CHOP [ , , ]. The combination of rituximab with R-CHOP [ — ] or dose dense CHOP chemotherapy, every 14 or 21 days [ , ], is now the current standard treatment for most patients with newly diagnosed DLBCL and improves the outcome of DLBCL patients of all ages and risk groups [ 1 ].

An alternative standard regimen for first-line treatments is DA-EPOCH-R dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab [ , ]. Preliminary data from ongoing clinical studies suggest that DA-EPOCH-R therapy might have a superior outcome in some subtypes of DLBCL when compared to R-CHOP therapy [ , , ].

For a detailed description of chemotherapeutic regimens used for the first-line treatment of DLBCL, the readers are referred to the recent excellent reviews [ 1 , , — ].

Relapsed or refractory DLBCL is difficult to treat, with limited therapeutic options. After finding a significant improvement of survival outcomes in an international randomized phase III trial PARMA study , high-dose chemotherapy HDC followed by autologous stem cell transplantation ASCT has been suggested as the standard therapy for patients with relapsed or refractory DLBCL [ 1 , ].

In addition, a recently performed prospective randomized trial by the Dutch Belgian Hemato-Oncology Cooperative Group established the benefits of rituximab combined with salvage chemotherapy, demonstrating clear survival benefits of combining rituximab with HDC prior to ASCT HOVON study [ ].

On the other hand, rituximab maintenance appears to have no defined role in relapsed DLBCL after ASCT [ ]. Various salvage regimens are available such as R-DHAP rituximab, dexamethasone, high-dose cytarabine, and cisplatin R-DHAP-VIM-DHAP rituximab-cisplatin, cytarabine, dexamethasone, etoposide - ifosfamide, methotrexate - cisplatin, cytarabine, dexamethasone , R-ESHAP rituximab, etoposide, steroids, ara-C, and cisplatin , R-DHAX rituximab, dexamethasone, cytarabine, and oxaliplatin , R-ICE rituximab, ifosfamide, carboplatin, etoposide , DA-EPOCH-R etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab , R-GIFOX rituximab, gemcitabine, ifosfamide, oxaliplatin , R-GEMOX rituximab emcitabine, oxaliplatin , R-GDP rituximab plus gemcitabine, cisplatin, and dexamethasone , R-MINE rituximab mesna, ifosfamide, mitoxantrone, etoposide or R-BEAM rituximab plus carmustine, etoposide, cytarabine, and melphala [ , — ].

However, salvage therapy and transplant conditioning regimens are still suboptimal, as are therapeutic options for patients who relapse following ASCT [ 1 , ].

Thus, the optimal salvage chemotherapy regimen still needs to be determined. There were no significant differences reported between R-ICE and R-DHAP for ORR, 3-year EFS, or OS [ ].

However, a subsequent subgroup analysis performed on the CORAL database showed that salvage treatment with R-DHAP was superior to R-ICE in the GCB subtype and may improve outcome in patients with GCB-type DLBCL [ , ].

Unfortunately, not all patients are fit or eligible for the HDC-ASCT. Patients with aggressive non-GCB-DLBCL ABC-subtype or c-MYC-driven typeDLBCL-NOS respond poorly to treatment with classical R-ICE or R-DHAP based salvage therapy [ — ]. Relapsed DLBCLs resistant to rituximab alone or R-CHOP treatments are refractory to subsequent treatments with the initial chemotherapy regimen and may even exhibit cross-resistance to multiple chemotherapeutic anticancer drugs [ , ].

Three different types of drug resistance have been defined and are associated with adverse clinical outcomes: Drug resistance of DLBCLs can be inherent from the beginning innate, due to the genetic heterogeneity of DLBCL tumor cells [ , ].

This type is called intrinsic genetic resistance, which is associated with recurrent translocations and the presence of specific genetic abnormalities [ 12 , 18 , , ].

Inherited genetic variations can contribute to the risk of therapy-induced side effects [ 12 , 18 , ]. A second type, termed treatment acquired resistance, develops from prior exposure to chemotherapy [ 33 , , ]. Due to the extensive heterogeneous genetic nature of DLBCL, multiple drug-resistant molecular mechanisms are required for the intrinsic genetic resistance and acquisition of chemotherapy resistance in DLBCL.

Only a small number of high-risk subsets of DLBCL are associated with increased expression of multidrug pumps i. Downregulation of CD20 protein expression strongly correlates with rituximab resistance in vitro [ ]. However its clinical relevance is not yet fully understood [ — ]. Chemotherapy resistance has been mainly associated with down-regulation of intrinsic apoptosis pathways and activation of survival pathways in DLBCL [ , , — , , ].

For instance, repeated exposure to rituximab can generate a therapy-resistant phenotype by the upregulation of the anti-apoptotic BCL2 family proteins [ ] or downregulation of the pro-apoptotic BAK and BAX proteins [ ].

A summary of observed and postulated immuno -chemotherapy resistance mechanisms in DLBCL is presented in Table 7. Multiple driver mutations and aberrant signaling pathways suggested to be required for drug resistance in DLBCL have been recently identified in specific molecular subsets of DLBCLs through gene expression profiling GEP , transcriptome sequencing, RNA interference screens, and DNA sequencing and have increased our understanding of chemotherapy- resistance.

Numerous small molecule inhibitors acting as GCB- and ABC-DLBCL subtype-specific pathway inhibitors are now in various stages of investigation, including clinical trial phase III studies. Only a few of them have been already approved for the treatment of B-cell malignancies, none of them for the treatment of DLBCL Table 8.

These drugs are mainly targeting oncogenic factors regulating cell metabolism, proliferation, cell cycle, growth, migration, survival and angiogenesis in a subtype-specific manner. Completed and ongoing experimental clinical studies combining novel experimental agents with conventional immuno- chemotherapy i.

Most of these drugs are targeting the DLBCL subtypes according to their COO status GCB- or ABC-specific and CC status OxPhos-, BCR- or MD-specific. The most important of these novel drug targets currently under study are discussed below. As mentioned above chronic active BCR-mediated signaling was recently identified as a critically important pathway in the pathogenesis of ABC-DLBCL [ 96 , , , ].

Chronic active BCR signaling in DLBCL is mainly dependent on the BTK, SYK and PI3K kinases [ ]. SiRNA-mediated depletion of SYK or BTK as well as inhibition of SYK or BTK by small molecule inhibitors selectively decreased BCR signaling and induced apoptosis of BCR-dependent DLBCL cell lines [ 90 , 98 , — ].

Thus, ibrutinib efficacy is limited to ABC-DLBCL patients with a constitutively active BCR signaling pathway [ , , ]. Consistent with the cooperation between the BCR and MyD88 pathways observed in vitro , ABC tumors with concomitant BCR and MyD88 mutations responded to ibrutinib frequently [ ].

Ibrutinib is a selective and irreversible BTK inhibitor that binds covalently to a C residue in the BTK active site, preventing Y phosphorylation required for activation [ ]. Ibrutinib is very well tolerable both as single agent and in combination with R-CHOP [ — , ]. A multicenter phase II trial of fostamatinib has completed and is pending announcement of the results NCT Additional file 1 : Table S2.

Additional phase II trials have been proposed to determine whether fostamatinib may improve the response to rituximab [ ]. PKCβ-II overexpression is an adverse prognostic factor in DLBCL and associated with poor prognosis in BCR-subtypes of ABC-DLBCL and GCB-DLBCL deficient of phosphatase and tensin homolog PTEN [ — ].

Preclinical studies demonstrated that sotrastaurin AEB and enzastaurin, two adenosine triphosphate-competitive selective inhibitors of PKCβ, induce apoptosis and inhibit the proliferation of BCR-subtypes of ABC-DLBCL in vitro and in vivo [ , ].

Sotrastaurin selectively inhibited the growth of CD79 mutant BCR-subtypes of ABC-DLBCL in vitro and in vivo whereas the presence of CARD11 mutations resulted in resistance to the inhibitor [ ]. Moreover, a randomized phase III study of enzastaurin as single-agent in patients with newly diagnosed DLBCL did not meet its primary endpoint to improve progression-free survival NCT [ ] Table 9.

Two clinical phase II studies evaluating the efficacy and safety of enzastaurin in combination with R-CHOP or R-Gemox have been recently completed and are pending announcement of the results NCT, NCT Additional file 1 : Table S3. As already discussed in previous sections recent studies validated the NF-κB signaling pathways as an important therapeutic target in ABC-DLBCL.

The major fraction of oncogenic NF-κB activating mutations in DLBCL is predominantly related to the canonical NF-κB pathway [ 12 , 16 , 18 , 19 , 96 , , ]. The less well-studied non-canonical NF-κB pathway is not yet fully established as a drug target in DLBCL, see next section.

ABC-DLBCL and PMLBCL cell lines and primary tumors, including drug-resistant cases, can be sensitized in vitro and in vivo to chemotherapy by treatment with drugs, which can inhibit the canonical NF-κB pathway.

For instance, small molecule inhibitors of the IKK complex were found to be selectively toxic for ABC-DLBCL and PMLBCL cell lines, but had no effect on GCB-DLBCL cell lines [ 59 ]. Proteasome inhibitors such as bortezomib or carfilzomib, block the degradation of negative regulators of cell cycle progression as well as of NF-κB inhibitory protein IκBα thereby inducing cell cycle arrest and mitochondrial dependent apoptosis in ABC-DLBCL [ — ].

Unfortunately, not all ABC-DLBCL are bortezomib-sensitive, and patients may eventually develop bortezomib-resistant disease.

Preclinical studies showed that proteasome inhibitors not only trigger the accumulation of proapoptotic proteins, but can also up-regulate antiapoptotic proteins, particularly MCL1 [ ] and HSP90 [ ], which are implicated in bortezomib resistance [ — ]. Surprisingly, a recent preclinical study uncovered an unexpected profound regulatory role for the bromodomain and extraterminal domain BET proteins BRD2 and BRD4 in cytoplasmic signaling through IKK in ABC-DLBCL [ ].

Inhibition BET proteins by small molecules inhibitors CPI and JQ1 as well as siRNA-mediated depletion of BRD2 and BRD4 expression, attenuated oncogenic IKKβ signaling, thereby inhibiting downstream oncogenic NF-κB-driven transcriptional programs and killing ABC-DLBCL cells in vitro and in an ABC-DLBCL xenograft model [ ].

MALT1 is an enzymatically active signaling component essential for upstream activation of NF-κB upon antigen stimulation of BCR [ ]. MALT1-dependent cleavage of the non-canonical and tumor suppressive NF-κB family member RELB promotes canonical NF-κB activation in DLBCL [ ].

Recent preclinical studies demonstrated that selective inhibition of the proteolytic activity of MALT1 with small-molecule inhibitors blocks the anti-apoptotic NF-κB signaling pathway and elicits toxic effects selectively on MALT1-dependent subsets of ABC-DLBCL cells in vitro and in vivo with very little toxicity towards primary B cells [ , ].

As mentioned above, a recent clinical phase II study demonstrated that ibrutinib does not inhibit the growth and survival of BCR wild-type ABC-DLBCL tumors with MyD88 mutations [ , , ].

MyD88 is an initial adapter linker protein in the canonical NF-κB signaling pathway activated by Toll-like receptors TLRs , including the endosomal TLRs 7, 8, and 9 [ ]. In the presence of the most common MyD88 mutant LP, ligand activation of those TLRs results in markedly increased signaling with subsequent increased cell activation, cell survival, and cell proliferation in DLBCL [ ].

IMO is an antagonistic oligonucleotide specifically designed to inhibit ligand activation of TLRs 7, 8 and 9 [ ]. The scientific rationale for assessing the use of IMO to treat patients with DLBCL and the LP mutation is based on the observations that IMO inhibits ligand-based activation of DLBCL cell lines with the LP mutation and decreases the survival and proliferation of DLBCL cells unpublished data of preclinical studies performed by Idera Pharmaceuticals, Inc.

Several recent studies provided strong evidence for an important role of the non-canonical NF-κB signaling pathway in DLBCL, particularly in ABC-DLBCL [ ].

Non-canonical NF-κB signaling appears to be activated by a restricted number of ligands in DLBCL, such as CD30 ligand CD30L , CD40 ligand CD40L and B cell activating factor BAFF, belonging to the TNF superfamily.

Pham L. recently reported that NIK kinase is overexpressed and accumulates in both GCB-like and ABC-like DLBCL cell lines [ ]. CD30, CD40 and BR3 receptors have been suggested to form a multimeric complex with TRAF3, TRAF2, TRAF5 c-IAP1, and c-IAP2 in DLBCL cells [ 27 , , ].

Both TRAF2 and TRAF3 serve as negative regulators of non-canonical NF-κB signaling pathways and target NIK for constant ubiquitination and degradation [ ]. Loss of this quaternary inhibitory complex can lead to increased NIK protein accumulation and constitutive activation of the non-canonical NF-κB signaling pathway [ ].

Zhang B. Modeling these genetic events in mice, Zhang B. demonstrated a key oncogenic role for the non-canonical NF-κB pathways in DLBCL pathogenesis [ 27 ]. Most DLBCL tumors developed in their mice model resembled ABC-DLBCL [ 27 ]. Thus, NIK appears to be an attractive new therapeutic target for ABC-DLBCL treatment, particularly for patients with ABC-DLBCL that are refractory to bortezomib or to the BCR pathway inhibitor ibrutinib.

Of interest, proteasome inhibitors such as bortezomib or carfilzomib, can also block the constant ubiquitination and degradation of NIK, thereby upregulating the non-canonical NF-κB signaling pathways.

In addition, targeting both arms of NF-κB signaling may also improve the therapeutic outcome in patients with newly diagnosed high-risk DLBCL displaying mutations in both canonical and non-canonical NF-κB pathways [ 12 , 18 , 19 , 27 , ].

Dual targeting of NF-κB pathways has been successfully demonstrated for multiple myeloma in vitro and in a xenograft model [ , ].

Combination therapy simultaneously targeting NIK and IKKβ as a main kinase of the canonical NF-κB pathway , either using the selective NIK inhibitors AM or AM and a small molecule IKKβ inhibitor MLX [ ] or the promising dual inhibitor of NIK and IKKβ, PBS [ ], showed significant anti-multiple myeloma activity, associated with apoptosis and inhibition of both NF-κB pathways in tumor cells in vitro [ , ] and in a mouse xenograft model of human multiple myeloma [ ].

Recent preclinical study demonstrated that the thalidomide-like drug lenalidomide is preferentially suppressing the proliferation and survival of ABC-DLBCL subtypes with minimal effects on non- ABC-DLBCL [ 90 , 91 ].

Thalidomide-like immunomodulatory agents such as lenalidomide or pomalidomide, are clinically important drugs for multiple myeloma and other B-cell malignancies [ — ]. IRF4 overexpression has been shown to enhance NF-κB activation and BCR signaling [ 90 , 91 ].

The lenalidomide-mediated reduction of IRF4 requires the E3 ubiquitin ligase complex coreceptor protein cereblon CRBN [ 90 , 91 ]. CRBN a substrate receptor of the Cul4-Rbx1-DDB1-CRBN E3 ubiquitin ligase complex, is a direct target of the immunomodulatory drugs thalidomide, lenalidomide and pomalidomide [ , ].

Thalidomide-like drugs directly bind to CRBN and promote the recruitment of its common substrates such as transcription factors Aiolos and Ikaros to the E3 ubiquitin ligase complex, thus leading to substrate ubiquitinylation and degradation [ ] and subsequent repression of IRF4 and SPIB [ 90 , 91 ].

Repression of IRF4 and SPIB by lenalidomide induces a lethal type I interferon response in ABC-DLBCL by augmenting interferon β IFNβ production [ 90 ].

IRF4 and its regulatory partner SPIB prevent IFNβ production by repressing IRF7 in ABC-DLBCLs [ 90 ]. However, due to their high toxicities, IFNα and -β have not yet been accepted as clinically useful agents in patients with aggressive B-cell lymphoma.

A recent study performed by Hagner P. Surprisingly, CC emerges with features that differentiate it from family member of thalidomide analogs. The anti-lymphoma activity of CC was independent of the cell of origin and observed in both ABC- and GCB-DLBCL cell lines, in contrast to the ABC-subtype selective activity of lenalidomide [ ].

CC has therefore been suggested to belong to a new class of drugs: pleiotropic pathway modifiers [ , ]. These novel properties make CC potentially clinically active in the GCB- subtype of DLBCL in which its predecessor, lenalidomide, has only limited or even no activity [ ].

At least three possibilities have been suggested to explain the differential activity of CC and lenalidomide [ , ]. First, CC may promote the recruitment, ubiquitination and degradation of specific and unique substrates to mediate some of its biological effects distinct from lenalidomide [ ]. Secondly, Aiolos and Ikarus, both known co-repressors of ISG transcription may act independently of IRF4 and interferon secretion in GCB- and type-3 DLBCL [ ].

Moreover, other potential immunomodulatory mechanisms for its activity in GCB -DLBCL likely do exist and may impact the nonimmune environment in vivo , in patients as well []. CC has already demonstrated clinical activity as single-agent in DLBCL [ — , ].

Of interest, Shi C. recently demonstrated that proteasome inhibitors such as bortezomib and carfilzomib can block Ikaros degradation by lenalidomide in multiple myeloma, when concomitantly added to the lenalidomide treatment [ ].

These data suggest that administration of thalidomide-like agents concurrent with or shortly after proteasome inhibitor administration might be ineffective or at least strongly reduce the efficacy of thalidomide-like agents in DLBCL.

Constitutive STAT3 activation has been recently correlated with poor overall survival in patients with ABC-DLBCL subtype treated with R-CHOP [ — ]. Inhibition of constitutive STAT3 activity sensitizes resistant B-cell NHL cells to chemotherapeutic cytotoxic drugs, including CHOP, cisplatin, fludarabine, adriamycin, and vinblastine [ , ].

STAT3 is persistently phosphorylated pSTAT3-Y in most ABC-DLBCL in an autocrine and paracrine manner from the tumor microenvironment [ — ].

Inactivating STAT3 in ABC-DLBCL cells inhibits cell proliferation and triggers apoptosis in vitro [ — ]. Inhibition of IL10R signaling with an anti-IL10R-blocking antibody induced dose-dependent cell death in all tested ABC-DLBCL cell lines and primary DLBCLs [ , ].

In preclinical in vitro studies, inhibitors of PI3K, such as LY selectively targeted PTEN- deficient GCB-DLBCL cells [ , ]. In addition, inhibition of target of rapamycin complex 1 mTORC1 or PI3K blocks proliferation and induces cell death in BCR-subtype of ABC-DLBCL [ , , ].

Autophagy can also serve as a protective mechanism to survive from chemotherapeutic-induced genotoxic stress [ ]. Secondly, the weak activity of rapamycin analogues can also be explained by their mTORC1-selective inhibitor activity.

Both everolimus and temsirolimus target only the mTORC1 but not mTORC2. mTORC2 is generally considered to be unaffected by rapamycin and produces resistance at least partly via the induction of upstream receptor tyrosine kinase signaling and phosphorylation of AKT on S, a critical regulatory site that stimulates maximal activity of this important survival kinase [ — ].

A preclinical study performed by Mortensen D. provided preliminary evidence that CC can strongly inhibit the growth of GCB-, ABC- and type-3 DLBCL cell lines associated with high mTORC1 and mTORC2 activity in vitro [ ]. Of interest, these data suggest that ABC-DLBCL with high IRF4 tend to be less sensitive towards CC [ ].

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Published on personalizeed Authors of this article:. Background: Organic ingredients for healthy skin the health benefits Ac personalized targets physical activity are well established, Body image acceptance remains personalize for people to adopt a more active lifestyle. Mobile health mHealth interventions can be effective tools to promote physical activity and reduce sedentary behavior. Objective: In this study, we aim to evaluate the impact of personalized goal setting in the context of gamified mHealth interventions. Henry H. WuDimitrios Poulikakos persoanlized, Helen HurstDavid LewisRajkumar Chinnadurai; Delivering Personalized, Goal-Directed Personalizex Organic ingredients for healthy skin Older Patients Receiving Peritoneal Dialysis. Kidney Dis 2 October ; 9 5 : — Background: An aging population living with chronic kidney disease and progressing to kidney failure, subsequently receiving peritoneal dialysis PD is growing. A significant proportion of these patients are also living with multi-morbidities and some degree of frailty.

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