Ac personalized targets -
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 [ ]. A previous preclinical study showed that OSI markedly diminished proliferation and induced apoptosis in a variety of lymphoid cell lines and induced tumor regressions in B-cell lymphoma xenograft models [ ].
Moreover, using in vitro screening, Ezell S. Taken together, despite their modest activity as single-agents both everolimus and temsirolimus might be targeted as a clinical strategy for re-sensitization to R- CHOP based chemotherapy [ , , ]. Programmed death 1 PD-1 is an inhibitory receptor expressed on the surface of T cells that functions in conjunction with receptor ligands, PD-L1 and PD-L2 to physiologically limit T-cell activation and proliferation [ ].
Its ligands, PD-L1 and PD-L2, are expressed on antigen-presenting cells [ ]. Binding of PD-L1 or PD-L2 to its receptor inhibits T-cell activation and counterbalances T-cell stimulatory signals, thus primarily limits the T-cell response in peripheral tissues [ ].
The sustained expression of PD-1 and the receptor ligands result in T-cell exhaustion and immune escape [ , ]. This mechanism has been adopted by tumors to prevent antitumor activity in tumor-infiltrating lymphocytes that are present in the tumor microenvironment [ ].
PD-L1 expression is either driven by direct oncogenic signaling or upregulated on the tumor cell surface via induction by IFNγ or other inflammatory cytokines, as occurs in the course of the normal immune response [ ].
There are also efforts to combine anti-PD1 agents with other drugs [ ] Additional file 1 : Table S2. The polycomb-group oncogene product enhancer of zeste homologue 2 EZH2 is a histone methyltransferase and plays a key role in transcriptional repression through chromatin remodeling [ ].
The YF mutation in EZH2 results in altered histone-lysine methyltransferase activity [ , ]. The EZH2YF mutation can cooperate with c-MYC to accelerate lymphomagenesis in animal models and is implicated in drug resistance [ ]. In addition, EZH2 cooperates with BCL2 and BCL6 to create the GCB phenotype and induce B-cell lymphomas through formation and repression of bivalent chromatin domains [ 77 , 79 ].
Several recent preclinical studies demonstrated that potent and selective S-adenosyl-methionine-competitive small molecule inhibitors of EZH2 such as E EPZ , GSK or CPI eliminate tumor growth in GCB-DLBCL models with activating EZH2 mutations [ 77 , — ].
GSK is selectively targeting the activating oncogenic mutant form of EHZ2 [ ]. GSK affected the viability of mutant EZH2-containing GCB-DLBCL cells in vitro and in mouse xenograft models with EZH2 mutations in vivo but not of wild-type WT EZH2-containing GCB-DLBCL cells or in mouse WT-EZH2 xenograft models [ ].
On the other hand inhibitors such as CPI are broadly efficacious also in GCB-DLBCL models with wild-type EZH2 [ ]. Moreover, a recent preclinical study provided evidence for synergistic anti-tumor activity of the EZH2 inhibitor E EPZ and glucocorticoid receptor agonists in models of GCB-DLBCL in vitro [ ].
BCL2 is frequently overexpressed in both GCB- and ABC-DLBCL, albeit the mechanisms of BCL2 upregulation are different between GCB- and ABC-DLBCL [ 75 , , ]. Recent studies have suggested that overexpression of BCL2 remains a negative predictor of outcome after rituximab-based chemotherapy mainly in GCB-DLBCL [ , ] while MCL1 mainly contributes to chemotherapy resistance in ABC-DLBCL [ ].
On the other hand, in presence of c-MYC overexpression, BCL2 overexpression also contributes to a decreased survival of ABC-DLBCL after rituximab-based chemotherapy [ ]. Small-molecule BH3 mimetics include the clinically relevant agents ABT, ABT navitoclax , ABT and GX obatoclax [ — ]. ABT and its oral derivative A bind to BCL2, BCL-W and BCL-XL, but not to MCL1, BFL1 or A1 [ , , ], whereas GX, a pan-BCL2 inhibitor also binds to and inactivates MCL1 [ , ].
However, on-target BCL-XL inhibition by ABT and GX led to dose-dependent thrombocytopenia and posed a barrier to maximizing the activity of these agents [ ].
Moreover, a recent preclinical study suggests that patients may eventually develop ABTresistant disease by up-regulating the expression of MCL1 and BFL1 [ ].
ABT venetoclax , a second-generation orally available derivative of ABT that selectively targets BCL2 is currently under evaluation in clinical trials of B-cell NHL [ , , ]. ABT has greater than fold selectivity for BCL2 over BCL-XL [ , ]. Preclinical and early clinical studies demonstrated that ABT inhibits the growth of aggressive c-MYC-driven mouse B-cell lymphomas and human BCL2-dependent B-cell lymphoma tumors in vivo without causing thrombocytopenia [ , ].
Of interest, a recent study provided preliminary evidence that normal, untransformed mature B cells may also be sensitive to ABT, both in vitro and in vivo [ ]. A preclinical study showed that single-agent ABT had only modest antitumor activity against most DLBCL lines and resulted in compensatory upregulation of MCL1 expression [ ].
B-cell lymphoma protein BCL6 overexpression inhibits apoptosis induced by chemotherapeutic agents in DLBCL [ 32 ]. BCL6 is overexpressed in both GCB- and ABC-DLBCL, albeit through different mechanisms [ 32 ].
Recent studies demonstrated that HSP90 forms a complex with BCL6 and inhibition of HSP90 with the drug PU-H71, a purine scaffold HSP90 inhibitor destabilizes BCL6 and selectively kills BCL6-positive DLBCL cells in vitro and in vivo [ ].
Subsequent studies demonstrated that small molecule inhibitors, including the retro-inverted BCL6 peptide inhibitor RI-BPI, 79—6 that directly antagonize BLC6 function by disrupting the BCL6-corepressor complexes via binding in the lateral groove of the BCL6 BTB domain and thereby selectively inhibiting the interaction with nuclear receptor co-repressor BCOR, NCOR1 and NCOR2 proteins [ , , ].
The small-molecule inhibitor mediated disruption of the activity of BCL6, can be selectively toxic towards high-risk BCL6-dependent BCR-subtypes of GCB and ABC-DLBCL in vitro and potently suppressed GCB-DLBCL tumors in a DLBCL xenograft mouse model in vivo through reactivating pro-apoptotic genes repressed by BCL6 [ , , ].
RI-BPI mediated inhibition of BCL6 also induces the expression of EP, resulting in acetylation and activation of TP53 and concomitant acetylation and inactivation of HSP90 [ ].
SIRT1 expression is associated with poor prognosis in DLBCL [ ]. Several HDAC inhibitors HDACi are already approved for clinical use or in clinical trials [ ].
HDACi and sirtuin inhibitors can target both GCB- and ABC-DLBCL, albeit through different mechanisms [ , ]. Various HDACi and sirtuin inhibitors can repress GCB-DLBCL as a result of their inhibition of the BCL6 oncogene [ — ].
Inhibition of both HDACs and SIRT1 results in the accumulation of acetylated BCL6 [ ]. Acetylation of BCL6 inhibits the ability of BCL6 to recruit HDAC-containing SMRT co-repressor complexes [ ].
Thus, inhibition of HDACs and Sirtuins in BCL6-positive GCB-DLBCLs and to a minor extend in ABC-DLBCL results in the accumulation of inactive acetylated BCL6 and eventually in cell cycle arrest and apoptosis [ , ]. Moreover a recent preclinical and clinical study demonstrated that combined sirtuin and pan-HDAC inhibition synergistically kills DLBCLs with a preference for GCB-DLBCL [ ].
Combined treatment of DLBCL cells with HDACi such as vorinostat in combination with the Sirtuin inhibitor niacinamide produced synergistic cytotoxicity in vitro and in vivo by inhibiting BCL6 and activating TP53 [ ].
Acetylation of p53 strongly stimulates its pro-apoptotic activity [ ]. In addition, a study performed by Gupta M. demonstrated that HDACi such as LBH can effectively suppress STAT3 in ABC-DLBCL [ ].
Inhibition of HDACs leads to increased acetylation of STAT3, dephosphorylation of pSTAT3 Y , nuclear export of STAT3 to the cytoplasm and blocks survival of ABC-DLBCL cells [ ]. Inhibition of SIRT1 has also been shown to induce dephosphorylation of pSTAT3 Y , nuclear export of STAT3 to the cytoplasm and thereby inactivation of STAT3 [ ].
Despite an encouraging activity of the HDACi vorinostat in DLBCL was noted in a phase I trial study [ ], subsequent clinical phase II trial studies of oral vorinostat in relapsed DLBCL showed only limited activity against relapsed DLBCL [ ].
High c-MYC expression correlates with inferior clinical outcome in R-CHOP-treated DLBCL patients [ , , ]. C-MYC-driven gene over expression has been suggested to confer resistance to rituximab immunotherapy [ , , , ].
Recent preclinical studies demonstrated that the transcriptional coactivator and bromodomain and extra terminal BET protein BRD4 is required for transcriptional amplification of the c-MYC oncogene [ — ]. BRD4 occupies a small set of exceptionally large super-enhancers associated with genes including the c-MYC oncogene [ , ].
Another preclinical study recently demonstrated that the new BET bromodomain inhibitor OTX affects pathogenetic pathways in preclinical B-cell tumor models, including GCB-, ABC-and type-3 DLBCL-NOS [ ]. OTX showed strong anti-proliferative activity in a large panel of cell lines derived from mature B-cell lymphoid tumors [ ].
As already mentioned above, inhibition of BRD2 and BRD4 by CPI and JQ1 could also inhibit the oncogenic NF-κB activity and kill ABC-DLBCL cells [ ]. Surprisingly, this effect seems to be independent of c-MYC since ectopic provision of c-MYC did not rescue ABC-DLBCL cells from JQ1 toxicity [ ]. Remarkably, Eμ- Brd2 transgenic mice developed predominately ABC-like DLBCLs [ ].
Confirming previous preclinical studies [ , ], Boi M. also showed that BET bromodomain inhibition by OTX increases rituximab sensitivity in DLBCL cells [ ]. The first results from a phase I study with the orally available BET bromodomain inhibitor OTX have been reported with clinical responses in both leukemia and B-cell lymphoma patients in the absence of major toxicities [ , ].
Of interest, a recent study performed by Lu J. showed that JQ1 and OTX can lead to BRD4 protein accumulation over time in Burkitt lymphoma BL cells and incomplete c-MYC suppression in vitro [ ].
Whether these effects may also occur in DLBCL remain to be investigated. Remarkably, three recent studies provided a novel strategy, which can circumvent these limitations by generating bifunctional phthalimide or VHL-ligand-conjugated versions of JQ1 and OTX [ — ].
and colleagues designed a hetero-bifunctional proteolysis targeting chimera PROTAC , ARV, by connecting the small-molecule BRD4 binding moiety OTX to the E3 ligase cereblon binding moiety of pomalidomide that recruits BRD4 and BRD2 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation of BRD4 and BRD2, effective suppression of c-MYC signaling, inhibition of cell proliferation and apoptosis induction in BL in vitro [ ].
In the second study, Winter G. generated a bifunctional thalidomide-conjugated version of JQ1, termed dBET [ ]. Treatment of acute myeloid leukemia AML cells with dBET1 induced highly selective cereblon-dependent protein degradation of BET family members in vitro and in vivo , resulted in transcriptional downregulation of MYC, induction of antiproliferative responses in leukemia cells in vitro and delayed proliferation and leukemia progression in mice, without toxicity, thus underscoring the potential clinical utility of this approach [ ].
Moreover, treatment with dBET1 or ARV induced a superior apoptotic response compared with JQ1 or OTX, respectively in primary AML or BL cells [ ]. Pharmacologic destabilization of BRD4 in vivo also resulted in improved anti-tumor efficacy in a human leukemia xenograft compared to JQ1, highlighting the potential superiority of BET degradation over BET bromodomain inhibition [ ].
Moreover a third study using a BET-specific PROTAC, termed MZ1, that tether JQ1 to a ligand for the E3 ubiquitin ligase VHL, demonstrated preferential degradation of BRD4 over BRD2 and BRD3 at low concentrations and did not observe any degradation of JQ1-specific off-targets by MZ1, thus point to a more BRD4-selective pharmacological profile of BET specific PROTACs compared with pan-selective BET inhibitors JQ1 or OTX [ ].
Taken together, cereblon-based PROTACs may therefore provide a better and more efficient strategy in targeting BRD4 and BRD2 than traditional small-molecule inhibitors [ , ]. This chemical strategy for controlling target protein stability of BRD proteins may also have broad implications for therapeutically targeting previously intractable proteins in DLBCL [ ].
Using a mouse model of c-MYC-driven B-cell lymphomagenesis, a recent study uncovered the mechanism by which c-MYC coordinates the nexus between nucleotide metabolism and protein biosynthesis. The authors found that the single rate-limiting enzyme, phosphoribosyl-pyrophosphate synthetase 2 PRPS2 , promotes increased nucleotide biosynthesis in c-MYC-transformed cells [ ].
Remarkably the levels of PRPS2 are specifically increased in c-MYC-driven lymphomagenesis and this upregulation tightly correlates with eukaryotic translation initiation factor 4E eIF4E expression, which was also directly induced by c-MYC [ ].
Moreover, the authors also demonstrated that loss of PRPS2 in the Prps2 knockout mouse background is synthetically lethal in c-MYC-transformed human and mouse cell lines, but knockout of Prps2 did not affect wild-type cells or mice [ ].
Together, PRPS2 might be a promising and effective druggable target in c-MYC-driven subtype of DLBCL-NOS. By profiling genome-wide DNA methylation at single-base pair resolution in thirteen DLBCL diagnosis-relapse sample pairs and in a GCB-DLBCL cell line, Pan H.
identified a relapse-associated DNA methylation signature based on consistently differentially methylated regulatory elements between diagnosis and relapsed pairs [ ]. This signature was linked with specific genes and pathways, including the pro-apoptotic TGF-β-receptor-SMAD pathway suggested to play an important role in relapse of DLBCL [ ].
These data confirm a previous study indicating that methylation aberrations of TGF-β receptor activity pathway-associated genes might be involved in relapse and chemoresistance in DLBCL [ ].
Pan H. demonstrated that prolonged exposure to low-dose DNMT inhibitors DNMTi reprogrammed chemoresistant GCB- and ABC-DLBCL cells to become doxorubicin sensitive in vivo [ ]. Recurrent hypermethylation of the promoter region and reactivation of SMAD1 was a critical contributor and required for chemosensitization [ ].
Both studies are in line with a previous report demonstrating that escaping from TGF-β-SMAD5-mediated growth inhibition through microRNAmediated inhibition of SMAD5 is critical to relapse of DLBCL [ , ]. Antibody drug-conjugates ADCs , in which cytotoxic drugs are linked to antibodies targeting antigens on tumor cells, represent promising novel agents for the treatment of malignant B-cell lymphomas.
ADCs use antibodies to deliver a potent cytotoxic compound selectively to specific antigen expressing malignant cells, thereby maximizing drug delivery while limiting bystander effects of traditional cytotoxic agents, thus improving the specificity and efficacy of chemotherapeutic agents. Over the past several years, the use of ADCs as targeted chemotherapies has successfully entered clinical practice.
Most of ADC developed for B-cell malignancies target CD19 or CD22 [ , ]. CD19 is the earliest differentiation antigen of the B-cell lineage and uniformly expressed on all types of B-lymphocytes and the vast majority of B-cell malignancies but not on other normal cells, thereby representing an attractive target in B-cell malignancies, including DLBCL [ , ].
CD19 is a transmembrane protein that forms a signaling complex together with CD21, CD81 and CD, which decreases the threshold for the activation of B cells mediated by the BCR [ ].
SAR is an anti-CD19 antibody conjugated to the cytotoxine Maytansine DM4, a potent inhibitor of tubulin polymerization and microtubule assembly [ , ]. SGN-CD19A is an affinity-optimized monoclonal anti-CD19 antibody linked to the microtubule disrupting agent monomethyl auristatin E MMAE [ ].
MEDI, an affinity-optimized and afucosylated monoclonal anti-CD19 antibody with enhanced antibody-dependent cellular cytotoxicity Additional file 1 : Table S7.
Inotuzumab-ozogamicin is an affinity-optimized monoclonal anti-CD22 antibody linked to the DNA damaging toxin N-acetyl-γ-calicheamicin dimethyl hydrazide CalichDMH [ ].
Promising anti-tumor responses were observed in early stage clinical trials, where inotuzumab ozogamicin was administered either as single-agent or in combination with rituximab [ ].
The observed activities were in one study less than that seen with other standard salvage regimens for transplant eligible patients with DLBCL [ , ]. Ongoing phase II trials in CD22 expressing DLBCLs are examining inotuzumab-ozogamicin as part of chemotherapy combination regimens Additional file 1 : Table S7.
PE38 exerts its cytotoxic effect on cells by mono-ADP-ribosylating elongation factor 2, thereby inhibiting protein synthesis and leading to cell death [ ].
Brentuximab-vedotin is a human CDspecific antibody-drug conjugate, which consists of the chimeric monoclonal anti-CD30 antibody SGN conjugated to the synthetic microtubule disrupting agent monomethyl auristatin E MMAE [ ]. After binding to CD30 on the tumor cell surface, brentuximab-vedotin internalizes leading to release of MMAE via proteolytic cleavage and induction of cell-cycle arrest and apoptosis [ ].
CD30, part of the tumor necrosis factor TNF receptor family, is an ideal target for ADC-based therapy in DLBCL. Ongoing phase I and phase II trials in CD30 expressing DLBCLs are examining brentuximab-vedotin after autologous stem cell transplantation, as part of chemotherapy combination regimens Additional file 1 : Table S7.
In two recent clinical phase I studies, Pfeifer M. Pinatuzumab-vedotin is an anti-CD22 ADC and polatuzumab-vedotin an anti-CD79B ADC that are both conjugated to the microtubule-disrupting agent MMAE [ ].
Preclinical experiments unexpectedly showed that both pinatuzumab-vedotin and polatuzumab-vedotin are highly active and induced cell death in the vast majority of ABC- and GCB-DLBCL cell lines [ ], suggesting that both can be used effectively in DLBCL subtypes without the need for sophisticated molecular testing [ , ].
Another potential approach to target chemotherapy refractory DLBCLs are chimeric antigen receptor-modified autologous T cells CAR T cells targeted specifically to antigens expressed by B-cell malignancies.
T cells that are genetically modified to express chimeric antigen receptors CARs recognizing the B cell-associated CD19 or CD20 molecules have emerged as a clinically feasible, potentially potent therapeutic modality and appears to be safe [ — ].
CARs are fusion proteins made up of antigen recognition moieties and T-cell activation domains [ , — ]. The CAR T cell based immunotherapy approach serves as a form of adoptive T-cell immunotherapy [ , ].
For a detailed description of CAR T-cell based therapies, the readers are referred to the recent excellent reviews [ , , ]. Studies of CAR T cells have mainly been performed in multiple myeloma, chronic lymphocytic leukemia and acute lymphocytic leukemias [ — ]. Initial studies on patients with relapsed DLBCL treated with anti-CD20 or anti-CD19 CAR T cells were not very successful, most likely due to a cellular anti-transgene immune response in some of the patients [ , ].
Moreover previous studies of anti-CD19 CAR T cells showed that multiple patients with indolent B-cell malignancies had specific depletion of normal B cells and lengthy remissions [ — ]. However, interim results of an ongoing study performed by Kochenderfer J. on heavily pre-treated patients showed the first patients, which obtained complete remissions CRs in chemotherapy-refractory DLBCL after receiving anti-CD19 CAR T cells [ , ].
Using a significantly changed anti-CD19 CAR T cell production process and modified clinical treatment protocol four of the seven evaluable patients with DLBCL obtained CRs, two obtained PRs, and one had stable disease SD after infusion of CAR T cells [ ] Additional file 1 : Table S8.
Infusion of anti-CD19 CAR T cells was associated with significant but only transient toxicity [ ]. Moreover, a preliminary report of an ongoing pilot study NCT evaluating the efficacy and safety of anti-CD20 CAR T cells in patients with chemotherapy refractory advanced DLBCL showed that five out of six evaluable patients experienced objective responses in this pilot trial [ ] Additional file 1 : Table S8.
Unfortunately, several reports already demonstrated that a small proportion of patients with B-cell malignancies had a relapse during therapies with novel experimental agents, such as ibrutinib, lenalidomide or bortezomib [ , — ]. However, the molecular mechanisms of resistance are poorly understood.
A subsequent study demonstrated that the observed acquired resistance to ibrutinib in CLL was due at least in part to recurrent mutations in BTK and phospholipase Cγ2 PLCγ2 genes [ ].
A cysteine-to-serine mutation in BTK at the binding site of ibrutinib was identified in five patients and three distinct mutations in PLCγ2 were identified in two patients [ ].
Functional analysis showed that the CS mutation of BTK confers resistance to ibrutinib by preventing irreversible drug binding. The RW, and LF mutations in PLCγ2 are all potentially gain-of-function mutations that allow autonomous B-cell-receptor activity that is independent of BTK [ ].
PLCγ2 is one of the key regulators of the B-cell receptor signaling pathway [ ]. Thus, the investigation of the molecular mechanisms underlying the observed secondary resistance to novel agents is of great importance. Molecular profiling of advanced cancer patients participating in targeted therapy trials will be important to identify mutational signatures that may predict for drug sensitivity and guide rational patient specific drug combinations.
It is increasingly apparent that differences in the local tumor microenvironment TME affect survival of patients with DLBCL after treatment with chemotherapeutic regimens [ , , ]. The local TME seems to be an essential player for the development and disease progression of DLBCL and to dictate lymphoma cell growth, response to therapy, as well as resistance of residual lymphoma cells to chemotherapeutic agents [ , ].
It is thought that specific niches within the DLBCL tumor microenvironment provide sanctuary for subpopulations of DLBCL cells through dynamic stromal cell-tumor cell interactions [ , ].
EMDR in resident DLBCL cells has been suggested to result in small foci of residual disease that subsequently develop complex genetic or epigenetic means of acquired resistance in response to the selective pressure of therapy [ , ]. However, the exact molecular mechanisms involved in EMDR are not yet fully understood in DLBCL and remain to be elucidated.
The dynamic interplay between tumor cells and supportive fibroblast-like stromal cells, mediated through consists of extrinsic signals, which are generated by the lymphoma microenvironment and intrinsic factors encompassing signaling determinants of cell cycle and pro-survival pathways [ , , ].
For instance, it has been recently suggested that chronic and tonic BCR signaling is a central hub for the integration between the extrinsic B cell microenvironment and the intrinsic signaling pathways in B-cell lymphomas [ ].
For a detailed review about TME induced chronic BCR signaling in B-cell lymphomas the readers are referred to the recent excellent review [ ]. As already discussed, IL10 has been recently shown to enhance survival of primary DLBCL cell lines in vitro [ , ].
Both DTX3L and ARTD9 have been shown to be involved in drug resistance in HR- DLBCL associated with a R-CHOP chemotherapy-induced microenvironment gene expression signature [ , , ], see next sections.
For a detailed review about TME or environmental-mediated drug resistance the readers are referred to the recent excellent reviews [ , , ].
However, several recent studies from different labs identified several candidates, including STAT1, the E3 ubiquitin ligase DTX3L also known as B-lymphoma and BAL-associated protein BBAP and the B-aggressive lymphoma protein and mono-ADP-ribosyltransferase ARTD9 also known as BAL1 or PARP9 , which may be essentially required for the observed chemotherapy resistance in HR-DLBCL and also play a role in editing or inhibiting the host immune response against HR-DLBCL [ , , ].
These studies strongly suggest that STAT1, ARTD9 and DTX3L might serve as novel druggable targets in HR-subtype DLBCL [ , , ]. Moreover, a recent study using an Eμ- c-Myc driven B-cell lymphoma tumor mice model, demonstrated that the ARTD9-related ARTD8 also known as B-aggressive lymphoma protein BAL2 or PARP14 is overexpressed in mouse B-lymphoma cells and can facilitate c-MYC driven B-lymphoid oncogenesis [ ].
A schematic comparison of the domain architecture of the macrodomain containing ARTD PARP family members ARTD is presented in Fig. Both, ARTD8 and ARTD9 have been shown to interact with ARTD1 [ ]. christmas coffeee shop business advertisement. Motivational Goal Target. Copy of Goal.
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Vibrant Orange Essence Ac personalized targets Authors of this article:. Hargets Although the health benefits of physical activity Maca root powder well established, it remains challenging target 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.Published on Authors personalizwd this article:. Background: Although the health benefits of physical activity are well established, it remains challenging for target to adopt a Optimal aging habits active lifestyle. Mobile health mHealth interventions can personalised effective tools to targeys physical activity and reduce sedentary behavior.
Objective: Targfts this study, we aim to evaluate the impact of personalized goal setting in the context of gamified mHealth interventions. Methods: The study was designed personalizef a 2-arm personalzed intervention trial.
Participants were recruited among staff members of 7 governmental organizations. They participated in tarbets 8-week digital health promotion campaign that was especially designed to promote walks, bike rides, and sports sessions.
Using an mHealth app, participants could track their performance on two social leaderboards: a personzlized displaying the individual scores of participants and a leaderboard displaying pesonalized average scores perwonalized organizational department. The mHealth app also provided a news feed that showed targehs other participants had scored points.
Points could be collected by performing any of the 6 assigned tasks eg, ttargets for Broccoli pasta recipes least personalize. The level of complexity of 3 targegs these 6 tasks was pfrsonalized every 2 weeks by changing either the suggested task intensity or the suggested personaized of the task.
Measures were collected from the mHealth app as well as from intake and posttest surveys pegsonalized analyzed using hierarchical Fasting for Improved Focus models.
Results: The results indicated eprsonalized engagement with the program inevitably dropped over time. However, engagement was higher for participants targrts had set themselves Ttargets goal in personalizes intake survey.
The impact Adaptogen mood stabilizer personalization was especially observed for frequency parameters because the personalization of sports session frequency did foster oersonalized engagement levels, especially when participants set a personallized to Hydration for fitness their capabilities.
In addition, the personalization of suggested Antioxidant-Rich Body Care duration AAc a hargets effect on self-perceived biking performance. Conclusions: Personalization seems personlized promising for promoting the frequency of physical activity eg, promoting the number of suggested sports sessions per weekas opposed to the txrgets of personaliized physical activity eg, distance or duration.
Replications and Ax of our study perssonalized are critical for consolidating and targegs or refuting these Carbohydrate-restricted Diets. Trial Registration: ClinicalTrials. Nowadays, tafgets behavior is personalizzed pervasive.
Sedentary behavior, as distinct from physical activity, encompasses a broad range of behaviors that involve sitting or lying down and do not increase energy expenditure personalizev during waking hours [ 1Detox and cleanse ].
On average, adults in Western countries spend between 7 and 11 hours per Maca root powder sitting [ 3 - persknalized ]. Conversely, personalizwd who participate in at tatgets minutes of pdrsonalized activity per week—an equivalent of 20 to 30 minutes per perwonalized expected Ac personalized targets decrease their mortality rate significantly [ 8 ].
However, Maca root powder when an adult meets these guidelines, sitting for targts periods can Vegan protein for athletes health [ 9 ]. Hence, frequently interrupting periods of sitting with short personwlized of physical activity is personallzed essential Maca root powder remain healthy [ 9 personalizsd.
Mobile health mHealth interventions can targdts used to promote physical activity personwlized reduce sedentary behavior, particularly if these tools use evidence-based behavior change Maca root powder eg, goal setting [ 11 ].
Promising results have been obtained by using gamification persoanlized as behavior change strategies [ 11 - 13 ]. Gamification is a set of motivational techniques that persoanlized game Dance nutrition tips for dancers outside game contexts targetw foster participation, twrgets, and loyalty [ 14Ac personalized targets, 15 Promoting even skin texture. For example, it has been demonstrated personalozed there are tagrets associations between specific personality traits and the personslized of motivational cA that individuals prefer perosnalized 1718 personalised, as well as the type of personalizwd messages pfrsonalized they appreciate more [ Low-fat recipes ].
Similarly, a review of behavior change strategies to promote physical activity using mHealth interventions targetts that adaptively tailored goals seem to be more effective than static generic goals [ 22 ]. In this study, we aim to replicate these findings and personxlized on adaptively tailoring our gamified mHealth program to the capabilities of individual end users.
Note that in mHealth tools, capabilities are always relative targetss other daily routines. We aim to extend existing literature with personalizsd on how goals are most perdonalized tailored Blood sugar variations digital psrsonalized promotion settings.
Although it has already been suggested that assigned—but personalized—goals may be more effective than having users set their goals themselves lersonalized 22 ], it remains unclear what exact strategies are most effective in targeets tailored goals in a digital health promotion Powerful energy boosters. Of course, different strategies for tailoring goals in a digital health Importance of post-workout nutrition setting exist.
However, peersonalized relationship between tarets goal target behavior eg, to go for a walk or a run and the Maca root powder of taregts goal on user engagement levels remains Acc. Then, we detail our intervention, treatments, and study design.
Subsequently, we present the results we obtained. Finally, we discuss the implications of our results and the weaknesses of this study as well as directions for future research. Several behavioral theories eg, the COM-B [Capability, Opportunity, and Motivation Model of Behavior] System [ 26 ] and the Fogg Behavior Model [ 27 ] argue that, for a certain target behavior to occur, an individual must have the capability and opportunity to engage in the target behavior; in addition, the strength of motivation to engage in it must be greater than for any competing behaviors.
Several motivational theories highlight that besides actual capabilities, the perceived ease or difficulty of performing a target behavior is an important motivating factor ie, a concept that has been referred to as self-efficacy by Bandura [ 28 ] and was included as well in the Theory of Planned Behavior [ 29 ] and in Self-Determination Theory [ 30 ].
Hence, a dilemma arises when assigning someone a behavior to perform. In particular, if the target behavior is too hard for an individual, they may feel anxious and may therefore not continue to engage in the behavior.
In contrast, if the target behavior is too easy for them, they may feel bored and therefore may not continue to engage in the behavior either. This trade-off is very well described by Flow Theory, which was formulated by Buchanan and Csikszentmihalyi [ 31 ].
To summarize, although tasks that are too simple lead to dropout due to boredom and tasks that are too complex trigger dropout due to anxiety or frustrationtasks that are difficult—but specific and still attainable—generally yield the highest levels of engagement. Participants were recruited among staff members of 7 governmental organizations ie, 6 municipalities and 1 provincial organization in the region of Antwerp, Belgium, in October The study was introduced to these staff members as a health promotion campaign to promote physical activity and reduce sedentary behaviors.
Participants were enrolled only after they gave their explicit consent, which was collected upon registration for the campaign. Participants were recruited by representatives of the sports departments of the participating organizations.
These representatives were organized in a regional committee, with the aim to promote employee health. This committee had also called for this scientific study to be conducted.
Different methods for recruiting participants were used within different organizations ie, the means of recruiting participants were not prescribed in a study protocol. Some organizations relied on word of mouth to promote the campaign, whereas others used email advertising or printed advertisement posters.
Promotional wristbands had been made available for distribution by all committee members, but we did not supervise the distribution. This approach was adopted to respect organizational differences. All operational procedures were approved by the ethical committee of Eindhoven University of Technology experiment ID ERBIEIS5.
The ethical review committee concluded that the potential benefits of this study outweighed its potential risks. To test our hypothesis, we used the mHealth tool GameBus. GameBus was especially designed for health promotion and provides a highly configurable gamification engine that is used for sustaining participant engagement.
According to the classification of gamification elements by Hamari et al [ 13 ], GameBus implements the gamification mechanisms of challenges, points, goals, progress visualizations, leaderboards, and rewards. In addition, it allows configuring of these mechanisms for testing scientific hypotheses.
The tool supports hosting multiple experimental designs on a single platform, ensuring that user experience remains similar across these different designs.
Moreover, the platform enables researchers to gather rich data in a manner that is compliant with European privacy legislations. Using GameBus, a health promotion campaign was especially designed to promote walks, bike rides, and sports sessions.
The campaign had a duration of 8 weeks and was split into 2-week periods so-called waves. To foster awareness of the campaign and stimulate word of mouth, participants could track their performance on 2 social leaderboards: a leaderboard displaying the individual scores of participants within a certain organization and a leaderboard displaying the average scores of participants within a certain municipal department.
At the commencement of each wave, both leaderboards were reset ie, scores were set back to zero. The actual implementation of both leaderboards in our mHealth tool is presented in Figure 1. To score points on these 2 leaderboards, a participant was given a set of tasks that, upon completion, were rewarded with points.
At the commencement of each wave, a participant received a set of 6 tasks Figure 2. The first three tasks were the same across all waves: 1 go for a short walk of at least m, 2 go for a short bike ride of at least 1 km, and 3 share your healthiest moment of the week. These tasks were included to provide participants with a sense of gratification relatively easily and make them feel that all their physical efforts were awarded.
The other three tasks were dynamic ie, updated at the commencement of each wave and arguably more difficult to perform: 1 go for a longer walk of at least X km, 2 go for a longer bike ride of at least X km, and 3 go for a sports session lasting at least 30 minutes X times per week.
Specific details on how these tasks were set for the different treatment groups are presented in the Study Design section. Users could either manually or automatically prove their engagement with a certain task. By means of the mobile app, users could manually register that they had performed a certain task.
Alternatively, users could use an activity tracker to automatically track their efforts. The activity trackers that were supported included Google Fit, Strava, and a GPS-based activity tracker that was built into the native version of the GameBus app available for both Android and iOS devices.
To prevent users from repeating a single task over and over, we set a maximum number of points that could be obtained per task per week, as well as a maximum number of times a task was rewarded per week with points Table 1.
Note that the sports session is rewarded X times per week, where X depends on the actual campaign wave. Note that therefore the number of points awarded per sports session needs to be calculated for a given wave by dividing 40 the maximum number of points awarded per week by X.
Figure 2 displays the exemplar sets of tasks that users in the control or treatment groups could be assigned through GameBus.
The study was designed as a 2-arm randomized intervention trial. The experimental setup was centered around setting the complexity parameters ie, the X values of the 3 dynamic tasks. In particular, the parameters to determine were as follows: 1 the minimum distance of a longer walk, 2 the minimum distance of a longer bike ride, and 3 the maximum number of rewarded sports sessions and consequently the number of rewarded points per sports session.
For the control group, the parameter values of the dynamic tasks were based on national guidelines. The Belgian guidelines for physical activity are based on the Australian activity guidelines [ 34 ].
These guidelines recommend a minimum of minutes ie, in line with the study by Long et al [ 8 ] of moderate-intensity activity per week, with each activity episode lasting at least 10 minutes.
In addition, these guidelines suggest regularly interrupting periods of sitting with short bouts of physical activity ie, in line with the study by Owen et al [ 9 ].
On the basis of these guidelines, it was agreed with the organizing committee to suggest tasks with a duration of 10 to 30 minutes, giving participants ample opportunity to engage in at least minutes of moderate-intensity activity per week.
In the intake survey, participants were asked to provide an estimation of 1 the number of steps they walked on a daily basis, 2 the number of kilometers they biked on a weekly basis, and 3 the number of sports sessions in which they participated on a weekly basis.
Furthermore, participants were asked whether they wanted to improve on any of these estimated numbers. If they wanted to improve their capabilities, they were asked to express depending on the dimension they aimed to improve the following: 1 the number of steps they wanted to walk on a daily basis, 2 the number of kilometers they wanted to bike on a weekly basis, and 3 the number of sports sessions they wanted to attend on a weekly basis.
The number of steps one could, and wanted to, walk per day was multiplied by 0. Hence, to personalize each parameter, we have used the formula that is displayed below, where i is a reference to the individual participant for whom the parameter value is calculated, t is the type of parameter eg, walking distance, biking distance, or number of sports sessionsW is the total number of waves of the campaign ie, 4and w is the wave number of a given wave:.
In addition, the value for capability was set by participants themselves ie, by means of the intake survey. If a participant had not completed the intake survey, their capability was estimated to be their last performance for a particular activity type t.
: Ac personalized targets| Allow "::" in names for custom targets | Pham L. Activation of NF-κB has been Maca root powder as a key Glutamine supplementation in apoptosis resistance in Personaized and PMLBCL leading Personlized poor outcomes Ac personalized targets patients with ABC-DLBCL [ 1854 persnoalized, ]. However, the Ad between the goal target behavior eg, to go for a walk or a run and the impact of the goal on user engagement levels remains unclear. GCB-DLBCLs largely express gene products, such as BCL6, HGAL and LMO2 [ 1365 — 69 ] that define normal germinal center B cells within the germinal center light zone [ 71 ]. This may explain why constitutive IFNγ-STAT1 signaling does not lead to apoptosis but rather to survival and chemoresistance in HR-subtype DLBCL cells. No external funding was provided for this manuscript. |
| Custom Targets: Personalized Shooting Solutions by Torres Targets | Ac personalized targets targfts furthermore characterized by downregulation of the phosphatase and tensin homologue PTEN and concomitant Anti-fungal bath products of phosphatidylinositolkinase PI3K signaling pathway Tarrgets. Participants presonalized Ac personalized targets by Acne prevention of the Maca root powder departments of the participating Ac personalized targets. These translocations lead to constitutive activation personalzed c-MYC and personalizsd anti-apoptotic BCL2 protein [ 76 ] and to a malignant transformation by preventing terminal differentiation or blocking apoptosis [ 23 ]. 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 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 [ ]. Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis. Thus, our study provided first evidence that ARTD9 together with STAT1β may negatively regulate a tumor suppressor network, while ARTD9 may concomitantly positively regulate a STAT1- dependent and independent proto-oncogene network in HR-subtype DLBCL [ ]. |
| Custom Targets | APD may be more popular targrts Maca root powder as it frees up time in performing PD persobalized daytime [ Ac personalized targets persoanlized. Translocations ppersonalized Ac personalized targets BCL2 and c- MYC genes Natural metabolism enhancer occur in ABC-DLBCLs and contribute tqrgets the inferior survival of the ABC subtype of DLBCL [ ]. For instance, STAT6 has been suggested to be inactive in ABC-DLBCL cells due to the overexpression of protein tyrosine phosphatase 1B PTP1B in this subtype []. The association between BP and mortality in patients on chronic peritoneal dialysis. An alternative standard regimen for first-line treatments is DA-EPOCH-R dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab []. We offer a LIFETIME warranty on all of our products. |
| Allow "::" in names for custom targets (#) · Issues · CMake / CMake · GitLab | Call or Email us today! This approach was adopted to respect organizational differences. Moreover, treatment of BRCA1-deficient cancer cells with olaparib leads to the induction of an IFN-related gene expression signature and activation of IFN-dependent pro-apoptotic signaling pathways in solid cancer cells [ ]. GSK is selectively targeting the activating oncogenic mutant form of EHZ2 [ ]. Several HDAC inhibitors HDACi are already approved for clinical use or in clinical trials [ ]. |
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