BCL2 overexpression

BCL2 overexpression equally blocks cell death, documenting for the first time induction of mitochondrial apoptosis downstream of extra centrosomes. Our findings demonstrate context-dependent effects of centrosome amplification during transformation and ask to adjust current belief that extra centrosomes are intrinsically pro-tumorigenic.

Impressively, the concurrent application of miR15-a and miR16-1 demonstrated a robust capacity to induce apoptosis through the reduction in Bcl-2 expression levels. This technology, employing RNA-loaded ferritin nanoparticles, hints at promising directions in the battle against CLL, bridging the substantial gap left by traditional transfection agents and indicating a pathway that may offer hope for more effective treatments.

Recent evidence suggests that this chronic BCR signaling drives FL polarization toward a dark-zone phenotype and promotes clonal evolution. Since both epigenetic and post-transcriptional modifications of B cells have been implicated in the early stage of FL development, it may be possible to use novel non-chemotherapeutic approaches that interfere with the immunobiology in treatment or early prevention of FL.

We also argue how some cancers, with the major focus on diffuse large B-cell lymphoma (DLBCL) are difficult to treat, although theoretically prime marked for Bcl-2-targeting therapeutics. Further work is needed to understand the non-canonical functions of Bcl-2 also at organelles beyond the mitochondria, the interaction partners outside the Bcl-2 family as well as their ability to target or exploit these functions as therapeutic strategies in diseases.

Lastly, we show for the first time in primary MM patient samples, that 5-azacytidine enhances the response to venetoclax ex-vivo, across diverse anti-apoptotic dependencies (BCL-2 or MCL-1) and diverse cytogenetic backgrounds. Overall, our data identifies 5-azacytidine and venetoclax as an effective treatment combination and this could be a tolerable steroid-sparing regimen, particularly for elderly MM patients.

BFC1108 suppresses the growth of triple negative breast cancer xenografts with high Bcl-2 expression and inhibits breast cancer lung metastasis. This study demonstrates a novel approach to targeting Bcl-2 using BFC1108, a small molecule Bcl-2 functional converter that effectively induces apoptosis in Bcl-2 expressing cancers.

Overall, we successfully develop a proof-of-concept workflow employing a robust cell preparation protocol for intracellular markers combined with cell enrichment using the cellenONE platform, providing an alternative to droplet-based technologies when cellular input is low or requires prior enrichment to detect rare populations. This workflow has wider prognostic and therapeutic potential to study residual cells in a pan-cancer setting.

BCL-2 overexpression abolished the impacts of LOXL2/LOXL3 knockdown on LC cells. In conclusion, CEBPA boosts LOXL2 and LOXL3 transcription to facilitate BCL-2 stability by recruiting Tip60 and thus contributes to LC cell growth and metastasis.

Moreover, in vitro and in silico research identified Paclitaxel as a promising natural substance that targets Bcl2. Overall, this work shows that Bcl2 overexpression accelerates the development of BC, and that targeting Bcl2 in combination with other drugs will dramatically improve BC patient's response to treatment and prevent the emergence of drug resistance.

Accordingly, this article reviews key research on the molecular pathogenesis of nodal FL and novel therapies targeting the causative genetic mutations. Moreover, the results of clinical trials are summarized, with a particular focus on treating nodal and gastrointestinal FLs.

Venetoclax demonstrates promising results. When given with drugs like dexamethasone, daratumumab and carfilzomib, a synergistic effect is seen in treating translocation (11:14) positive relapsed/refractory MM. The use of venetoclax in clinical practice can potentially improve outcomes and quality of life in RRMM patients, and future research should continue to explore this promising treatment option.

The analysis of the data collected in this paper highlights several key parameters with prognostic value and statistical significance: the EBV infection at diagnosis, its association with low-intensity BCL2(+), the presence of CD68 with rosette formation, and the identification of specific vascularization patterns. The development of prognostic systems that take into account the integration of biological prognostic markers seems essential for a better risk stratification.

Diffuse Large B-cell Lymphoma (DLBCL) represents a challenging disease as only 60% of DLBCL can be cured with R-CHOP...In conclusion, R-CODOX-M/IVAC may be a good first line treatment for younger patients with aggressive DLBCL. Figure 1.

This is the first comprehensive analysis of expression and prognostic role of BCL2 family proteins in MBC. Our data suggest a strong association of higher expression of PMAIP1 with worse MTNBC patient survival, potentially attributed to higher immune checkpoint, stem cell-related genes expression, and higher frequency of PD-L1 positivity in PMAIP1-H tumors. These findings indicate PMAIP1 as a potential prognostic biomarker candidate in MTNBC but needs further validation in large prospective studies Table 1.

These cell lines serve as a preclinical tool to test novel therapeutic strategies and develop a deeper understanding of the molecular mechanisms driving lymphomagenesis, therapeutic response, and resistance in genetically defined subtypes of GC-derived B-cell lymphomas. Most importantly, this resource meets a critical need in the field for syngeneic models of lymphoma to study disease progression and precision therapy in immunocompetent mice.

In an effort to further confirm these results, and examine the extent to which peptide-based BH3 profiling predicts sensitivity to selective BH3 mimetics in MTCL, cell lines were treated with venetoclax, A1155463 (a BCL-xL selective antagonist), navitoclax (a BCL-2/BCL-xL antagonist), or S63845 (MCL-1 antagonist), and cell viability determined. These findings suggest that BCL-xL is a therapeutic vulnerability for MTCL subsets, particularly non-ALCL subtypes that are TCR dependent, and provide a robust pre-clinical rationale for future studies investigating navitoclax in these lymphomas.

Furthermore, from the list of SNPs associated with BCP ALL-related traits from the GWAS catalog (NHGRI-EBI), we identified 11 SNPs overlapping some of our OCRs. In summary, we are presenting the most comprehensive publicly available atlas of early B cell regulation (B-rex; https://brex.shinyapps.io/brex/), and therefore a powerful resource for understanding early B cell differentiation in health and disease.

Therefore, SUPT11 cells (used as a model of T-PLL) were exposed to venetoclax (25 and 50nM; BCL-2inh), fadraciclib (25 and 50nM; CDK2/9inh – indirect inhibitor of MCL-1 as it decreases mRNAs with high decay rates including MCL1 and MYC) or a combination of venetoclax and fadraciclib. In conclusion, preclinical evaluation of a T-PLL cell line and primary patient samples demonstrate BCL2-family dependency that can be effectively targeted with small molecule inhibitors of BCL2 and CDK2/9. In vivo studies in PDX models of T-PLL are underway to form the basis for clinical trials to study these combinations.

In conclusion, our results provide a high-resolution view of events spanning FL progression and indicate a major role of early TME remodeling in establishing a suitable niche for progression. Early intervention aimed to target the B cell-tumor microenvironment interactions driving intra-tumoral heterogeneity may represent a promising therapeutic avenue against early disease and prevention of FL recurrence.

In summary, our single cell RNAseq analysis in the frame of a clinical trial provide the first longitudinal map of FL heterogeneity in the BM and characterize putative CPCs resistant to Rituximab-therapy. Ongoing efforts are now focusing on the microenvironment drivers of this intra-patient BM diversity and on specific molecular features of BM residual cells that could represent therapeutic vulnerabilities in this particular low-tumor burden FL population.

The addition of 14 days of VEN at 400 mg daily dose to a pediatric-inspired regimen during IND and CONS was safe in adults with newly diagnosed B-ALL and did not delay counts recovery. The addition of VEN led to a promising higher than expected MRD- CR rate in high-risk B-ALL, including for pts with Ph-like subtype. The study is actively enrolling on the expansion cohort, and BH3 profiling on pre-treatment and post relapse samples will be performed to determine BCL-2 dependency and correlates to early MRD- response.

It showed strong anti-leukemia activity in preclinical stage, but its clinical efficacy as a single drug for AML was limited.Nl-101 (also known as EDE-S101)is a new small molecule compound formed by covalently linking the DNA damage core group of Bendamustine hydrochloride with the inhibition core group of histone deacetylase of the histone inhibitor Volinostat (also known as SAHA).Our previous study found that NL-101 single drug can reduce tumor load and prolong survival of AML mice in vivo.In this study, we used Venetoclax in combination with NL-101 to understand its efficacy and safety in vitro and in vivo, and to explore the synergies and mechanisms of action between the two drugs, providing new effective options for the treatment of AML patients...In vivo experiments demonstrated that Venetoclax combined with NL-101 can synergistically reduce tumor load and prolong survival time in AML mice. These results suggest that Venetoclax in combination with NL-101 is effective in the treatment of acute myeloid leukemia.

Tagraxofusp was able to effectively eliminate pDCs and blasts to a lesser extent as a single agent. High expression of BCL-2 in blasts supports the consideration of tagraxofusp in combination with venetoclax as an effective combination therapy to eradicate both blasts and pDCs in AML-PDC patient samples.

The formation of these complexes depended on active BTK, as treatment with the BTK inhibitor ibrutinib reduced complex formation to levels found in Cd79b WT lymphomas. Consequently, we investigated the effects of ibrutinib treatment in Cd79b-mutant and wildtype MCD DLBCL mouse models and found Cd79b-mutant lymphomas to be significantly more sensitive to ibrutinib treatment than their Cd79b WT counterparts.

Background: The Phase II CAVALLI study assessed the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (Ven; 800mg for 10 days [Ds]) + rituximab (R), cyclophosphamide (C), doxorubicin (H), vincristine (O) and prednisolone (P; R-CHOP), for first line treatment of diffuse large B-cell lymphoma (DLBCL)...In the Phase III POLARIX study, polatuzumab vedotin (Pola)-R-CHP had a prolonged PFS vs R-CHOP, establishing Pola-R-CHP as standard of care for untreated DLBCL (Tilly et al... Ven 800mg/D for 5 Ds/cycle + Pola-R-CHP has been determined as the RP2D; early results show acceptable safety and promising efficacy for untreated BCL-2 IHC+ DLBCL. High CR rates were observed across all cohorts at EOT, including pts with DHL/THL. Updated results, including circulating tumor DNA, will be presented.

Myeloid sarcoma shows distinct molecular evolution and microenvironmental composition compared to medullary disease, including location-specific evolution necessitating personalized management consideration. Leukemia cutis is distinct from MS tumorous lesions and should be considered a separate entity. High BCL2 expression in extramedullary disease might represent a promising targetable vulnerability in patients with isolated MS.

Recognition of this unique subtype may provide clues for solving the long-standing issues of NEC and appropriate therapeutic stratification. It is important to accurately identify POU2F3-expressing carcinomas by immunohistochemistry and to analyze their clinicopathological features.

Collectively, we conclude that MHME provokes TNBC cell apoptosis through the blockade of the SRC/STAT3/BCL-2 pro-survival axis. Our findings suggest the potential of applying MHME as a TNBC chemotherapy agent.

This was circumvented by exchanging the CMV promoter to the cardiac-specific NCX1 promoter, leading to the successful production of a lentiviral vector which could induce cardioprotective expression of Bcl-2. In conclusion, reduced expression of Bcl-2 driven by a weaker promoter improved vector yield, and led to the production of functional cardioprotective Bcl-2 in primary cardiomyocytes.

In addition, we discuss the known prognostic and predictive factors in MCS. Finally, we present the novel trends, including targeted therapies and ongoing clinical trials using protein kinase inhibitors and the death receptor 5 (DR5) agonist, which may be the focus of future MCS treatment studies.

Venetoclax targeting of BCL-2 increased while the spautin-1-mediated inhibition of BECLIN-1-dependent autophagy reversed doxorubicin sensitivity in the former and in the latter, respectively. Notably, patients with high BECN1 expression displayed longer survival. Our data reveal, for the first time, that the modulation of BECLIN-1-dependent autophagy influences the prognosis of DLBCL patients and provide a mechanistic explanation supporting the therapeutic use of drugs that, by stimulating autophagy, can sensitize lymphoma cells to chemotherapy.

Knowing that BCL-xL inhibition in the clinic has been limited by platelet toxicity, PROTACs PZ18753b and WH25244 were synthesized from navitoclax (BCL-2/BCL-xL dual inhibitor) linked to a VHL E3 ligase ligand to target Bcl-2 and Bcl-xL for degradation, with improved specificity to cancer cells while sparing platelets. PZ18753b and WH25244 have preclinical efficacy in baseline CLL and can degrade, both, Bcl-xL and mutant Bcl-2 proteins, which are known to confer venetoclax resistance. This translational study supports the development of novel therapeutics for the treatment of CLL subgroups with adverse clinical prognosis and will open new frontiers as we better understand the biology of this disease.

Introduction: The drug-resistant mechanisms of the first-generation Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib, has been extensively explored in Chronic Lymphocytic Leukemia (CLL) patients. Integrated multi-omics were performed in our zanubrutinib-resistant CLL patients’ cohort. BTK Cys481 and Leu528 were two main BTK resistant mutations in zanubrutinib resistant CLL patients. Due to spatial heterogeneity and clonal evolution among patients, deep targeted-gene NGS and ddPCR should be used comprehensively to evaluate the emergence of resistant clones.

To circumvent these problems, we loaded the Bcl-2 inhibitor ABT-737 in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) that were wrapped with phospholipid membranes derived from 4T1 murine mammary cancer cells, which mimic the growth and metastasis of human TNBC...We posit that increasing the dose of ABT CCNPs, altering the treatment schedule, or encapsulating a more potent Bcl-2 inhibitor may yield more robust effects on tumor growth and metastasis. With further development, drug-loaded biomimetic NPs may safely treat solid tumors such as TNBC that are characterized by Bcl-2 overexpression.

Finally, we demonstrate that SUFU promotes GLI1 activity without affecting its protein stability. Through our findings, we propose a novel role of SUFU as a positive regulator of GLI1 in PDAC, adding a new mechanism of Hh/GLI signaling pathway regulation in cancer cells.

In non-endometrioid forms of MCH+, ECs had a significantly higher expression of Bcl 2 in combination with a high level of Ki 67 and low (RP) or absence (RE) hormone receptors, which reduces the prognostic significance of the MSI-negative tumor phenotype.Conclusion For endometrioid forms of EC, it is advisable to use a complex of markers, including MSN, ER, RP, and Ki 67. For non-endometrioid forms, the markers Ki 67 and Bcl 2 are more informative.

Nude mice experiments demonstrated that compared to the lenvatinib-alone group, the combination group of lenvatinib and secukinumab better inhibited the in vivo tumorigenesis of HepG2 cells and enhanced autophagy in xenotumor tissues. In conclusion, the antagonism of IL-17A with secukinumab, due to the upregulation on BCL2-related autophagic cell death, can cooperate with starvation therapy in inhibiting HCC carcinogenesis. Our data suggested that secukinumab can become an effective adjuvant for the treatment of HCC.

Furthermore, Nrh-R confers higher sensitivity towards Thapsigargin-induced cell death compared to the Nrh-L isoform, due to altered interactions with IPR1 Ca channels in the former case...Overall, this study supports the notion that the rs2231292 Nrh SNP could be used as a predictive tool regarding chemoresistance, improving therapeutic decision-making processes. Moreover, it sheds new light on the contribution of the BH4 domain to the anti-apoptotic function of Nrh and identifies the IPR1/Nrh complex as a potential therapeutic target in the context of breast cancer.

Presently, concurrent radiation plus cisplatin (CDDP)-based chemotherapy is the standard treatment for CxCa patients...Poly (ADP-ribosyl) polymerase-1, an effective mediator of nucleotide excision repair pathway, is involved in DNA repair as well as maintaining genomic stability and is significantly expressed in malignant lymphomas, hepatocellular-, cervical- and colorectal carcinoma, which has been approved effective in maintenance therapy and may serve as an effective target to enhance CDDP sensitivity in CxCa. Here, we summarize the etiology and epidemiology of and treatment for CxCa, the mechanism responsible for chemotherapy resistance, PARP inhibitor as a possible therapy for CxCa, and other possible chemotherapeutic options for CxCa treatment.

Dithiocarbamates in previous studies have shown to inhibit the calcium-binding protein S100A4 relative to the metastasis of hepatocellular carcinoma. To that end, we turn to the anticipated synthesis of a dithiocarbamate analogue in respect to inhibiting the anti-apoptotic Bcl-2 oncoprotein commonly overexpressed in many malignant cancers.

Among 52 patients with hematological malignancies the maximum tolerated dose (MTD) was not reached and no clinical TLS was observed.20 In this study of 22 evaluable patients with RR CLL there was an overall response rate (ORR) of 63.6% (14/22).20 A larger study of 114 patients with RR CLL evaluated lisaftoclax in combination with either the Bruton's tyrosine kinase inhibitor (BTKi) acalabrutinib or the anti CD20 monoclonal antibody rituximab (NCT04215809)...In CLL an overall response rate (ORR) to BGB-1147 of 100% as monotherapy was observed among 8 patients with RR disease.25 In 12 patients with RR MM, the ORR to BGB-1147 in combination with dexamethasone varied from 0–68% depending on the dose cohort.26 In combination with azacytidine in AML the ORR to BGB-11417 was 74% among those with treatment naïve (TN) disease (n=20/27) and 65% (n=13/20) in the cohort with RR disease.27 BGB-11417 monotherapy in 23 patients with RR NHL demonstrated responses in 2 patients with diffuse large B cell lymphoma (DLBCL) and one patient with marginal zone lymphoma (MZL).28 In 11 patients with RR MCL treated with BGB-11417 in combination with zanubrutinib there was a 55% (6/11) ORR.28 S55746 is a potent BAX/BAK dependent BCL2 inhibitor administered orally.18,29 Developed by Servier, it has been tested in phase I studies in CLL, NHL and AML. In a study of S55746 among 37 patients with RR NHL, no dose limiting toxicities (DLT) or TLS was observed after a medium duration of treatment of 42 days.30 FCN-338 is another orally available selective BCL2 inhibitor developed by Fochon currently undergoing phase I testing in RR CLL.18,31 Clinical outcomes with this drug are yet to be publicly reported...More recently navitoclax has been tested in RR myelofibrosis (MF) in combination with ruxolinitib with evidence of clinical response to the combination.35 AZD0466 by Astrazeneca is a nanomedicine potent dual BCL2/ BCLxL inhibitor that mediates BAX/BAK induced apoptosis36,37 and is administered intravenously...Among 9 patients reported undergoing testing for RR hematological malignancy the DLT had not yet been reached.38 Pelcitoclax or APG1252 by Ascentage is a more recent BAX/BAK dependent dual BCL2 and BCLxL inhibitor18,39,40 currently in phase I trials in RR NHL (NCT05186012)...There are multiple emerging BCL2 inhibitors currently undergoing clinical trial testing in hematological malignancies, and it remains too early to appreciate the differential efficacy and toxicity profiles that these agents may carry compared with venetoclax. It is hoped that the results seen with venetoclax can be improved upon across a raft of disease groups over the coming years.

These data suggest Tfl regulates Cxcl13 in B220IgM cells in the bone marrow, and a very high concentration of serum Cxcl13 arising from these cells may contribute to early death in lymphoma-bearing mice. Since several reports have suggested the association of CXCL13 expression with lymphoma, these findings provide new insights into cytokine regulation via TFL in lymphoma.