- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, HitGen, navitoclax (ABT 263) / AbbVie
Targeting antiapoptotic Bcl-2 proteins with highly specific BH3 mimetics in solid tumors (Hall Bordeaux) - Jan 31, 2023 - Abstract #ESMOTAT2023ESMO_TAT_131;
Conclusions Our findings indicate that among antiapoptotic Bcl-2 proteins, targeting Bcl-x L might break resistance to radiation in NSCLC, CCA and breast cancer in vitro. Especially for breast cancer, Mcl-1 could also be a promising target that needs to be further investigated.
- |||||||||| S63845 / Servier, Novartis, HitGen
Targeting tumour-associated Treg to improve response to immunotherapy in non-small cell lung cancer () - Jan 13, 2023 - Abstract #LCC2023LCC_228;
However, further validation is necessary to evaluate the effects of combination anti-PD1 and S63845 treatment on the depletion of tumour- associated Treg cells and infiltration of functional immune cells. Nevertheless, we anticipate our preliminary work will provide a foundation to uncover new avenues to targeting tumour Treg cells and improve patient outcomes to immunotherapy.
- |||||||||| JQ-1 / Roche, S63845 / Servier, Novartis, HitGen, A-1331852 / AbbVie
Activating programmed cell death pathways to improve therapy in glioblastoma multiforme (GBM) () - Jan 13, 2023 - Abstract #LCC2023LCC_35;
We found that a BCL-XL plus an MCL-1 inhibitor potently cooperate with inducers of ferroptosis in killing U251 cells. Overall, these findings demonstrate the potential of dual targeting of distinct programmed cell death pathways in GBM and may guide the utility of BCL-XL inhibitors and inducers of ferroptosis with standard of care treatment for improved therapies for GBM.
- |||||||||| S63845 / Servier, Novartis, HitGen
Preclinical, Journal, IO biomarker: Expression Ratios of the Antiapoptotic BCL2 Family Members Dictate the Selective Addiction of Kaposi's Sarcoma-Associated Herpesvirus-Transformed Primary Effusion Lymphoma Cell Lines to MCL1. (Pubmed Central) - Nov 24, 2022
In this context, PEL cells become resistant to MCL1 knockdown or MCL1 inactivation by the MCL1 inhibitor S63845, indicating that the main function of MCL1 in PEL cells is to prevent BAX/BAK1-mediated apoptosis...Consistent with this model, shifting these expression ratios changes the requirement away from MCL1 and toward the dominant BCL2 family gene. Together, our results indicate that although MCL1 is an attractive chemotherapeutic target to treat PEL, careful consideration must be taken, as resistance to MCL1-specific inhibitors easily develops through BCL2 family overexpression.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, onametostat (JNJ-64619178) / J&J
Inhibition of PRMT5 Increases Sensitivity to BH3 Mimetics in Aggressive B Cell Malignancies (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_5790;
P1
The DLBCL cell lines (HBL1, TMD8, RI-1, OCI-Ly1, Karpas 422, SUDHL4, Toledo), double hit lymphoma (DHL) patient-derived xenograft (PDX) cell lines (DW19), mantle cell lymphoma (MCL) cell lines (Mino, Jeko-1), T cell acute leukemia (T-ALL) cell line (Jurkat) and Burkitt lymphoma (BL) cell line (Raji) were used to investigate the in vitro anti-cancer activity of JNJ-64619178 (Janssen Pharmaceuticals) and BH3 mimetics (venetoclax [BCL2i], S63845 [MCL-1i] and A1331852 [BCL-xLi], Selleckchem). The combination of a PRMT5 inhibitor with BH3 mimetics, especially venetoclax, is worthy of further exploration as a potential therapeutic strategy for DLBCL and MCL.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, IACS-010759 / UT MD Anderson Cancer Center, navitoclax (ABT 263) / AbbVie
LP-118, a Novel BCL2 Inhibitor, Shows Potent in Vitro Anti-Myeloma Activity (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_4548;
P1
However, best results were seen when targeting the compensatory upregulation of MCL-1 with S63845, an MCL-1 inhibitor...An ongoing phase 1 dose-escalation trial (NCT04771572) is underway evaluating safety and tolerability in patients with relapsed or refractory hematological malignancies. Future in vitro and in vivo animal studies will continue to evaluate drug combinations that best overcome drug resistance to anti-apoptotic treatment.
- |||||||||| Comparison of Data from Fresh and Frozen AML Samples for Functional Drug Testing (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_4229;
Additionally, fresh samples were more sensitive to paclitaxel than frozen ones across the paired samples.The cell composition of paired samples was also affected by cryopreservation, with a reduction in the frequency of cells expressing c-KIT (CD117) and a reduction of cells with high granularity (side scatter)...However, careful consideration should be given to the specific drugs and cell populations of interest before deciding on sample handling methodology. This may be of particular importance when investigating specific drugs and phenotypes affecting cell proliferation and maturation stage, as sample handling may induce systematic differences and confound interpretation.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie
The Flavonoid Brusatol Induces Apoptosis in Aggressive Lymphoma Cells and Exhibits Synergistic Effect with Venetoclax (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_3037;
Despite the available chemoimmunotherapy R-CHOP, one third of DLBCL patients still have primary refractory disease or relapse, and the incidence of these lymphomas continuously increases...Furthermore, co-treatment of Brusatol with inhibitors of Bcl-2 (Venetoclax), Bcl-XL (A-1331852), Mcl-1 (S63845), BTK (Ibrutinib), PI3K (Idealisib), Myc (EN4, JQ1), respectively, was performed in the same four cell lines and Annexin V levels were measured after 24h...Additionally, the combination of Brusatol with Venetoclax results in enhanced induction of apoptosis. Thus, our study suggests that Brusatol, alone or in combination with Venetoclax, represents a very interesting agent for further development of novel anti-lymphoma therapies.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Nutlin-3 / EMD Serono, S63845 / Servier, Novartis, HitGen
TP53 CRISPR/Cas9 Reveals Strict BAX Dependence in the Response to BH3 Mimetic Targeting MCL1 (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_2690;
Materials and Methods To knockout the expression of all p53 isoforms in two TP53wt t(4;14)+ 1q+ myeloma cell lines, NCI-H929 and XG7 cells were sequentially transduced with 2 lentiviruses expressing Cas9 and a doxycycline-inducible TP53-specific sgRNA targeting exon 5...Results RNAseq analysis was performed in triplicate in the 12 clones of the two MM cell lines: analysis of the 6 TP53-/-clones versus the 6 control clones showed significant changes (log2FC>0.4, p>0.05) in the expression of 92 genes under steady-state conditions (and of more than 3000 upon nutlin3a-induced p53 accumulation) : 27% of the genes were known to be direct p53 target genes, 39% were known to be indirectly regulated, and 35% of the genes were not identified as p53 targets in solid cancer cell lines (Andrysik Z Genome Res 2017)...To analyze the response to the combination of S63845 and Venetoclax at the single cell level, we performed scRNASeq analysis in t(4;14)+ 1q+ del17p+/- patients and determined the transcriptomic profile of cells surviving the combination: we show that BH3 mimetics combination heterogeneously induced death in and between patient's samples and we identified a resistance signature that is under evaluation. All these results support the S63845 / Venetoclax combination for patients with double (1q+, del17p) to triple (t(4;14), 1q+, del17p) hit.
- |||||||||| Clinical, Preclinical, Journal: AML-266 Optimization of a Drug Screening Platform in Acute Myeloid Leukemia. (Pubmed Central) - Sep 29, 2022
P=N/A
During this study, we validated and upscaled our NEXT platform on 49 patients. The prospective application of our niche-like drug screening platform is now being investigated in relapsed/refractory AML patients accrued to the multicenter study ALFA-PPP (NCT04777916).
- |||||||||| Optimization of a Drug Screening Platform in Acute Myeloid Leukemia () - Sep 22, 2022 - Abstract #SOHO2022SOHO_480;
P=N/A
During this study, we validated and upscaled our NEXT platform on 49 patients. The prospective application of our niche-like drug screening platform is now being investigated in relapsed/refractory AML patients accrued to the multicenter study ALFA-PPP (NCT04777916).
- |||||||||| Novel Agents in Chronic Lymphocytic Leukemia (CLL) () - Sep 21, 2022 - Abstract #SOHO2022SOHO_373;
BH3-mimetics which target Bcl-xL, such as navitoclax, are not being developed in CLL due to concerns of thrombocytopenia.14 However, AZD4320, an alternative Bcl-2/xL inhibitor, is being studied in lymphoid malignancies as an intravenous formulation, with hope to mitigate its effect on platelets.15 Therapeutic Antibodies Targeting surface receptors and inducing both direct and immunemediated apoptosis has been a success story in CLL with use of anti-CD20 agents...Lanalumab (VAY-736), a humanized defucosylated engineered antibody directed against BAFF-R, antagonized pro-survival effects of BAFF in CLL cells.16 In a phase 1 study in combination with ibrutinib in 32 patients with CLL, CR was achieved in 38% of patients, and 42% demonstrated undetectable minimal residual disease (uMRD) in the blood/bone marrow, a promising result not expected with ibrutinib alone.17 Alternative targets for therapeutic antibodies include ROR1 (cirmtuzumab) and CD19 (tafasitamab)...A recent report of a phase 1/2 study of lisocabtagene maraleucel, an autologous CD19-directed CAR T-cell therapy (TRANSCEND CLL 004), confi rmed effi cacy in patients with relapsed/refractory CLL.18 In this study, patients had a median of 4 prior therapies, including ibrutinib and venetoclax...In a Phase 1/2 trial, HLA-mismatched CD19-targeting CAR NK cells induced CRs in patients with CLL after a single infusion and without CRS or neurotoxicity attributable to the cellular product.19 Finally, bi-specifi c antibodies have demonstrated impressive effi cacy in non-Hodgkin lymphoma and are also an off-the-shelf product which boasts high tolerability. Development of bi-specifi c antibodies in CLL is still in early stages, however epcoritamab (a subcutaneously administered CD3xCD20 Duobody) demonstrated responses in an ongoing Phase 1 study.20 In sum, targeted therapy replaced chemo-immunotherapy in treatment of CLL, and emerging small molecule and cell therapy approaches auger an expansion of the therapeutic armamentarium for CLL in the next decade.
- |||||||||| Journal: Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells. (Pubmed Central) - Sep 14, 2022
In an attempt to uncover the mechanism of such synergy, we revealed that the surviving subpopulation of cells resistant to individually applied ABT-737/ABT-263, MIK665, ABT-199, and S63845 BCL-2 family inhibitors showed elevated MCL-1 compared to untreated control cells indicating the presence of a subset of cells expressing high MCL-1 levels and, therefore, resistant to BCL-2 inhibitors within the original population of senescent cells. Overall, we found that combining BCL-2 inhibitors can be beneficial for eliminating senescent cells, thereby enabling use of lower, potentially less toxic, doses of drugs compared to monotherapy, thereby overcoming the resistance of the subpopulation of senescent cells to monotherapy.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, HitGen
Biomarker, Journal, IO biomarker: Bcl-x as prognostic marker and potential therapeutic target in cholangiocarcinoma. (Pubmed Central) - Aug 21, 2022
Correlation between Bcl-2 protein expression and survival was analyzed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-x in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-x as a key protein in cell death resistance of CCA and may pave the way for clinical application.
- |||||||||| S63845 / Servier, Novartis, HitGen, Blincyto (blinatumomab) / Astellas, Amgen, Koselugo (selumetinib) / Merck (MSD), AstraZeneca
Use of luciferase-labeled target cells to explore immune cell killing in high throughput format () - Aug 6, 2022 - Abstract #ITOC2022ITOC_114;
And finally, we show an ADCC example using NK as cytotoxic cells. Our data supports the outstanding usefulness of this methodological approach for the exploration of bispecific cytotoxic immune cell engager agents.
- |||||||||| Review, Journal: Anticancer effects of putative and validated BH3-mimetic drugs in head and neck squamous cell carcinomas: An overview of current knowledge. (Pubmed Central) - Jul 28, 2022
The remaining 39 preclinical studies investigated cell lines and/or xenograft models involving the use of six validated BH3-mimetics (A-1210477, A-1331852, ABT-737, navitoclax, S63845, venetoclax) and six putative BH3-mimetics (ApoG2, gossypol, obatoclax, sabutoclax, TW-37, and YC137)...In conclusion, although clinical data are still insufficient to evaluate the anticancer effects of BH3-mimetics in head and neck squamous cell carcinomas, promising results in preclinical settings were observed concerning induction of cell death and inhibition of tumour growth. Therefore, further clinical trials are highly encouraged.
- |||||||||| Mekinist (trametinib) / Novartis, S63845 / Servier, Novartis, HitGen
Sequential combinations with BH3 mimetics enhance rhabdomyosarcoma treatment (Poster Area) - Jun 28, 2022 - Abstract #EACR2022EACR_508;
Conclusion Functional DBP assay can rapidly predict the efficacy of targeted therapies and their anti-apoptotic adaptations in RMS. We found a new sequential combination of trametinib with S63845 that could improve RMS treatment and avoid side effects in the clinic.
- |||||||||| carfilzomib / Generic mfg.
CARFILZOMIB RESISTANCE IS ASSOCIATED WITH SIGNIFICANT DEREGULATION OF THE BH3 FAMILY PROTEINS () - May 13, 2022 - Abstract #EHA2022EHA_1953;
Decreased sensitivity to the BCL-2 inhibitor venetoclax as well as to the BCL-xL inhibitor A1331852 was observed in resistant KMS12PE cells...This is further emphasized by the coherent deregulation of BCL-xL and BAK throughout carfilzomib exposed carfilzomib resistant cell lines when compared to their sensitive cell line variants. Moreover, BH3 profiling indicates a change in dependency on anti-apoptotic BH3 protein in carfilzomib resistant vs. sensitive MM cell lines.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, HitGen, A-1331852 / AbbVie
PREDICTING THE RESPONSE OF DLBCL CELLS TO BH3-MIMETICS USING SYSTEMS BIOLOGY () - May 13, 2022 - Abstract #EHA2022EHA_1690;
Using a combination of in silico and in vitro experiments, we show that a computational model can predict the sensitivity of a cell to targeted therapies. Future work will test the ability of the model to predict patient responses to targeted therapies in order to enable a personalised medicine approach.
- |||||||||| AZD4320 / AstraZeneca
THE DUAL BCL-2 AND BCL-XL INHIBITOR AZD4320 SHOWS ON-TARGET ACTIVITY IN ALL AND ACTS SYNERGISTICALLY WITH MCL-1 INHIBITION () - May 13, 2022 - Abstract #EHA2022EHA_596;
Aims In this study, the anti-leukemia activities of the dual BCL-2 and BCL-XL inhibitor AZD4320 and of MCL-1-selective AZD5991 were evaluated and compared to the effects of other BH3-mimetics (BCL-2-selective venetoclax, BCL-XL-selective A-1331852 and MCL-1-selective S63845)...Importantly, the highest synergism was found at low concentrations of both inhibitors, suggesting efficacy at moderate concentrations, which could potentially be achieved in vivo . Conclusion In summary, our study demonstrates sensitivity, on-target activity and synergism of the dual BCL-2 and BCL-XL inhibitor AZD4320 with inhibition of MCL-1, thereby providing strong evidence for further clinical evaluation in ALL.
- |||||||||| S63845 / Servier, Novartis, Ligand, A-1331852 / AbbVie
Smac mimetic and BH3 mimetics sensitize rhabdomyosarcoma spheroids towards NK cell killing () - May 9, 2022 - Abstract #CIMT2022CIMT_260;
Using the related BH3 mimetic compound A1331852, only RH30 spheroids showed an increased killing by NK cells...The killing seems to be independent of TRAIL but highly dependent on caspase activation. Therefore, combining a cell death sensitizing agent with cytotoxic immune cells, opens the possibility for a novel cellular immunotherapeutic approach.
- |||||||||| S63845 / Servier, Novartis, Ligand, Blincyto (blinatumomab) / Astellas, Amgen, Koselugo (selumetinib) / Merck (MSD), AstraZeneca
Use of luciferase-labeled target cells to explore immune cell killing in high throughput format () - May 9, 2022 - Abstract #CIMT2022CIMT_233;
Depending on compound combination, we observe synergistic but also antagonistic effects. Our data support the outstanding usefulness of this methodological approach for the exploration of bispecific cytotoxic immune cell engager agents.
- |||||||||| S63845 / Servier, Novartis, Ligand, navitoclax (ABT 263) / AbbVie
Journal: Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer. (Pubmed Central) - Apr 29, 2022
While treatment with the Bcl-2 inhibitor Navitoclax results in the reduction of metastases in tumor bearing mice, treatment with the Mcl-1 inhibitor S63845 leads to complete elimination of senescent tumor cells and metastases. These findings provide insights on the mechanism by which senescent tumor cells survive and reveal a vulnerability that can be exploited for cancer therapy.
- |||||||||| S63845 / Servier, Novartis, Ligand, navitoclax (ABT 263) / AbbVie
Journal: SFPQ-ABL1 and BCR-ABL1 utilize different signalling networks to drive B-cell acute lymphoblastic leukaemia. (Pubmed Central) - Apr 14, 2022
SFPQ-ABL1 was sensitive to navitoclax and S-63845 and promotes cell survival by maintaining expression of Mcl-1 and Bcl-xL. SFPQ-ABL1 has functionally distinct mechanisms by which it drives ALL, including subcellular localisation, proliferative capacity, and activation of cellular pathways, highlighting the role that fusion partners have in mediating the function of ABL1 fusions.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, Ligand, IACS-010759 / UT MD Anderson Cancer Center
Journal, IO biomarker: Targeting mitochondrial respiration and the BCL2 family in high-grade MYC-associated B-cell lymphoma. (Pubmed Central) - Apr 9, 2022
In BCL2-negative lymphoma cells, instead, killing by IACS-010759 was potentiated by the Mcl-1 inhibitor S63845. Thus, combining an OxPhos inhibitor with select BH3-mimetic drugs provides a novel therapeutic principle against aggressive, MYC-associated DLBCL variants.
- |||||||||| Mekinist (trametinib) / Novartis, S63845 / Servier, Novartis, Ligand
Journal: MEK and MCL-1 sequential inhibition synergize to enhance rhabdomyosarcoma treatment. (Pubmed Central) - Apr 9, 2022
Indeed, we found that the MCL-1 inhibitor S63845 synergistically enhanced trametinib cytotoxicity in rhabdomyosarcoma cells in vitro and in vivo. In conclusion, our findings indicate that the combination of a BH3 mimetic targeting MCL-1 with trametinib improves efficiency on rhabdomyosarcoma by blocking tumor adaptation to treatment.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, Ligand, A-1331852 / AbbVie
Journal: Synergistic activity of combined inhibition of anti-apoptotic molecules in B-cell precursor ALL. (Pubmed Central) - Apr 7, 2022
The effect of combining BCL-2 and MCL-1 inhibition by venetoclax and S63845 was evaluated in vivo and strongly enhanced anti-leukemia activity was found in a pre-clinical patient-derived xenograft model. Our study offers in-depth molecular analysis of mutual substitution of BCL-2 family proteins in acute lymphoblastic leukemia and provides targets for combination treatment in vivo and in ongoing clinical studies.
- |||||||||| doxorubicin hydrochloride / Generic mfg.
Journal, IO biomarker: Synergistic apoptotic effect of Mcl-1 inhibition and doxorubicin on B-cell precursor acute lymphoblastic leukemia cells. (Pubmed Central) - Apr 1, 2022
Our study offers in-depth molecular analysis of mutual substitution of BCL-2 family proteins in acute lymphoblastic leukemia and provides targets for combination treatment in vivo and in ongoing clinical studies. Our data declared that MCL-1 inhibition alone or in combination with a chemotherapeutic agent is considered an appealing strategy for the induction of apoptosis in BCP-ALL cells.
- |||||||||| S63845 / Servier, Novartis, Ligand
Journal, IO biomarker: Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function. (Pubmed Central) - Mar 23, 2022
We show that MCL-1 is essential in established tumours with genetic deletion inducing tumour regression and inhibition with the MCL-1-specific BH3-mimetic drug S63845 significantly impeding tumour growth...This strongly supports the idea that the key function of MCL-1 in breast cancer is through its anti-apoptotic function. This has important implications for the future use of MCL-1-specific BH3-mimetic drugs in breast cancer treatment.
- |||||||||| S63845 / Servier, Novartis, Ligand
Moonlighting function of mitochondrial protein VDAC2 provides a potent pharmacological strategy against selective killing of hepatocellular carcinoma (Section 5) - Mar 9, 2022 - Abstract #AACR2022AACR_6147;
We found that combination of an inhibitor of the anti-apoptotic proteins (S63845, a selective Mcl-1 inhibitor), which normally suppresses Bak activation, with an activator of the tBid pathway (TRAIL) enhanced the death of hepatocarcinoma cells with little effect on normal hepatocytes...Thus, we postulate that increased VDAC2 expression in HCC leads to elevated Bak recruitment to the OMM, which in turn sensitizes HCC to tBid. Therefore, this differential expression provides an excellent opportunity for selective elimination of HCC cells.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, Ligand
Intracellular redox milieu regulates Mcl-1 and decreases overall mitochondrial priming in hematopoietic cancers (Section 23) - Mar 9, 2022 - Abstract #AACR2022AACR_6143;
Oncogenic activity of O2.- is mediated by increased Mcl-1 stability through Thr163 phosphorylation, which resulted in a reduction in overall mitochondrial priming and increased binding of Mcl-1 to NOXA and Bak. Scavenging O2.- reduces Mcl-1 levels and sensitizes resistant cells to venetoclax-induced apoptosis thereby demonstrating that manipulation of the redox microenvironment could be a potential vulnerability to be exploited in venetoclax resistant cancers
- |||||||||| S63845 / Servier, Novartis, Ligand, Blincyto (blinatumomab) / Astellas, Amgen, Koselugo (selumetinib) / Merck (MSD), AstraZeneca
Exploring the combinatorial potential of bispecific T-cell engagers in high throughput format (Section 38) - Mar 9, 2022 - Abstract #AACR2022AACR_4824;
Depending on compound combination, we observe synergistic but also antagonistic effects. Our data support the outstanding usefulness of this methodological approach for the exploration of bispecific cytotoxic immune cell engager agents.
|
