AZD5991 / AstraZeneca - LARVOL DELTA

AI-enabled multi-omics pharmacogenomic modeling guides resistance-aware multitarget optimization of venetoclax therapy in acute myeloid leukemia. (PubMed, NPJ Precis Oncol) - "Translating these findings into therapy design, network-based modeling and in silico perturbation prioritized rational combinations expected to block escape routes, including venetoclax plus MCL1 inhibition (e.g., AZD5991-class inhibitors), venetoclax plus FLT3 inhibition (e.g., gilteritinib-class agents) in signaling-driven disease, and venetoclax plus p53-axis modulation (e.g., MDM2 inhibition) in TP53-altered contexts. Structural candidate evaluation using ensemble docking provided supportive drug-target interaction evidence for prioritized dependencies. Together, these results establish a clinically interpretable, resistance-aware AI framework for precision optimization of venetoclax-based combination therapy in AML."

Biomarker • IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • FLT3

Dysregulated RAS Signaling Modulates Apoptotic Dependencies and Therapeutic Response in Multiple Myeloma (IMS 2026) - "Our previous work showed that dysregulated RAS signaling can influence apoptotic priming and dependencies on BCL2 family proteins, as well as sensitivity to venetoclax (ven)...Cells were treated with increasing concentrations (1-1000 nM) of a pan RAS(ON) inhibitor (RMC-7977) alone and in combination with 5 µM lenalidomide (len)...Cell death was assessed after treatment with ven alone or in combination with 500 nM dexamethasone (dex), MCL1 inhibitor, AZD5991 (1-1000 nM), melphalan (1-30 µM), or bortezomib (1-1000 nM) MM1s cells exhibit limited induction of apoptosis with RAS inhibition (~10% of cells), and the addition of len increased sensitivity (~20%)... These studies demonstrate that dysregulated RAS signaling can modulate apoptotic dependencies in MM, shifting away from BCL2 and towards alternate survival pathways. This shift can also alter therapeutic response to both novel targeted agents and select standard of care therapies suggesting that rational..."

IO biomarker • Hematological Malignancies • Leukemia • Multiple Myeloma • ANXA5 • BCL2 • KRAS • NRAS

A PHASE 1 FIRST-IN-HUMAN STUDY OF THE MCL-1 INHIBITOR AZD5991 IN PATIENTS WITH RELAPSED/REFRACTORY HEMATOLOGIC MALIGNANCIES. (PubMed, Clin Cancer Res) - "Treatment with AZD5991 was associated with high incidence of laboratory troponin elevation and a low overall response rate."

Journal • P1 data • Acute Myelogenous Leukemia • Cardiovascular • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Oncology • Respiratory Diseases • Septic Shock

Beat AML: Study of Biomarker-Based Treatment of Acute Myeloid Leukemia (clinicaltrials.gov) - P2/3 | N=3000 | Recruiting | Sponsor: Beat AML, LLC | Phase classification: P1/2 ➔ P2/3 | Trial completion date: Dec 2028 ➔ Dec 2032 | Trial primary completion date: Dec 2028 ➔ Dec 2032

Biomarker • Phase classification • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • NPM1

Therapeutic development of the clinically active compound ACT001 with Mcl-1 inhibitors for the treatment of paediatric diffuse midline glioma (ISPNO 2026) - P1 | "Mcl-1 inhibitors (MIK665 and AZD5991) showed the strongest synergy consistent with ACT001-mediated suppression of anti-apoptotic signalling...In vivo, ACT001, the Mcl-1 inhibitor S63845, and their combination each extended survival without evidence of synergy in orthotopic DMG models and reduced Ki67-positive tumour cells...Collectively, these findings indicate that ACT001 is a multi-targeted agent that disrupts NF-κB and apoptotic signalling while promoting oxidative stress and the unfolded protein response. Combining ACT001 with inhibitors of anti-apoptotic proteins represents a promising therapeutic strategy for patients with DMG."

Clinical • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • Pediatrics • Solid Tumor • NQO1 • RELA

Docirbrutinib is a pan-mutant BTK inhibitor and inhibits B-cell receptor signaling in chronic lymphocytic leukemia cells in preclinical and early clinical investigations. (PubMed, Blood Cancer J) - P1 | "Covalent BTKi (cBTKi) such as ibrutinib, acalabrutinib, and zanubrutinib are effective but alterations in the kinase domain at C481 or BTK gatekeeper residue T474 mutations result in development of resistance...We evaluated the efficacy of a new ncBTKi, docirbrutinib (AS-1763), against 14 BTK mutants, including C481S, T474x, and L528x, as well as gatekeeper and kinase domain double mutants, using biochemical assays, cell-line models, and primary CLL lymphocytes. Docirbrutinib potently inhibited BTK autophosphorylation and mutant BTK-driven cell proliferation, with greater effects than ibrutinib and pirtobrutinib against certain mutants. In treatment-naïve and relapsed/refractory CLL samples, docirbrutinib disrupted B-cell receptor signaling and sensitized cells to apoptosis induced by venetoclax and AZD5991. In a dose-escalation trial (NCT05602363), docirbrutinib decreased CCL3/CCL4 biomarkers and inhibited the B-cell receptor pathway signaling in longitudinal..."

Journal • Preclinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • CCL3

Mcl-1 inhibitors and antidepressants as enhancers of chemotherapy response in pleural mesothelioma (AACR 2026) - "Chemotherapy with cisplatin (CDDP) and pemetrexed provides modest benefit which is limited by primary resistance mechanisms involving dysregulated apoptotic signaling...Mitochondrial and glycolytic metabolic parameters were quantified by Seahorse XF. CDDP + AZD-5991 exhibited robust synergy (HSA = 10.51, p < 0.0001 in H2452; HSA = 9.06, p < 0.0001 in H28)... These findings support that complementary mechanisms of DCMI blocking autophagy and MCL-1 promoted apoptosis will enhance the response to cisplatin. This cooperative mechanism reveals metabolic and anti-apoptotic vulnerabilities that could be exploited to overcome chemoresistance in mesothelioma. Further investigation is warranted to assess whether blocking autophagy will increase patient's response to chemotherapy."

IO biomarker • Hematological Malignancies • Leukemia • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • BCL2

Assessing cancer drug combination efficacy across 900+ PRISM cell lines in a multiplexed screening assay (AACR 2024) - "In the first combination, temozolomide+O6-benzylguanine (alkylating agent + MGMT inhibitor), we found that cell lines expressing MGMT were sensitized to temozolomide in the presence of O6-benzylguanine, thus illustrating synergy. In the second combination, we screened two anti-apoptosis compounds A-1331852+AZD5991 (BCL-xL + MCL1 inhibitor) and found that BCL-xL and MCL1 inhibition were also synergistic. In the third combination, ML210+ferrostatin-1 (GPX4 inhibitor inducing ferroptosis + ferroptosis inhibitor), we found that ferrostatin-1 antagonized the effects of ML210. Our analysis also reveals the importance of appropriate dose selection and analytical metrics for reliably measuring combined effects. In conclusion, the PRISM platform's multiplexed cell line screening is a robust method for characterizing rationally designed drug combinations, offering a systematic approach to enhance the precision of combination therapy development in cancer care."

Preclinical • Oncology • BCL2L1 • GPX4 • MGMT

Genomic amplification of MCL1 as a therapeutic target for osteosarcoma (AACR 2025) - "The treatment for OS that combines surgery with chemotherapy, which consists of a four-drug combination of doxorubicin (DOX), cisplatin (CDDP), high-dose methotrexate (MTX), and ifosfamide, was established in 1970s, and it is still used as a standard therapy...Additionally, the combination of MIK665 with IGF-1R inhibitors, including OSI906, AEW541, and AZD3463, induced synergistic cell death by overcoming drug tolerance conferred by the activation of IGF signaling in OS cells...Moreover, the combination therapy of AZD5991 with OSI906 also reduced tumor growth in the NOS-10 xenograft model. These results suggest that genomic amplification of MCL1 in the 1q21.2-3 region, observed in nearly half of OS patients, may act as a predictive biomarker for combination therapy with an Mcl-1 inhibitor and an IGF1-R inhibitor."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • IGF1 • NOS1 • PIP5K1A

Combined inhibition of MCL-1 and MEK reduces tumor growth in a triple-negative/inflammatory breast cancer, MEK-resistant xenograft mouse model (AACR 2024) - "Further, we treated resistant cells with MEKi AZD6244 and an MCL-1i (AZD5991) that confirmed restoration of MEK sensitivity in both resistant cell lines, resulting in decreased cell viability, colony formation and increased apoptosis. Our results suggest that MCL-1 is important for inducing acquired MEK resistance and combining an MCL-1i with a MEKi could improve treatment outcomes of patients with TNBC or IBC who have developed resistance to single-agent MEKi."

Preclinical • Breast Cancer • Hematological Malignancies • Inflammatory Breast Cancer • Leukemia • Mantle Cell Lymphoma • Oncology • Solid Tumor • Triple Negative Breast Cancer • ALDH1A1 • BBC3

Potential novel interventions of oncohistones, epigenetic modifications, and RNA processing machinery in betel-nuts related HNSCC in Taiwan (AACR 2025) - "PI3K/AKT/mTOR interventions, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, AT2AR inhibitor, Mcl-1 inhibitor, MEK1/2 inhibitor, JAK2 inhibitor, CXCR4 inhibitor, FAK inhibitor, p53 reactivator, MDM2 inhibitor, SHP2 inhibitor, PARP7 inhibitor, IAP inhibitor, GLS1 inhibitor, eribulin, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT /mTOR signaling and modulation of stemness & PD1/PDL1 pathway...Disrupting NSD1 in HNSCC cell lines led to CpG hypomethylation & enhanced cisplatin sensitivity. TW2.6 used to test (1)in vitro drug sensitivity to (a)Chemical Modulators of Splicing; (b)PRMT5 inhibitor; (c)CDK9 inhibitor, EZH2i, DNMT3i, BRD/BET4i, and HDACi; (d)NSD1/SETD2 inhibitor; (e)METTL3 inhibitor; (2)synergistic effects with other therapies by MTT assay, colony..."

IO biomarker • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck • AKT1 • ALK • ARID1B • ATM • AXL • BRD4 • CCND3 • CDK12 • CXCR4 • DDR2 • EPHB1 • FAT1 • FGF10 • FGFR • FLCN • HRAS • KDM5A • KDR • METTL3 • MITF • NSD1 • PDGFRB • PIK3CA • RICTOR • RPS6KB1 • SDHA • SETD2 • SOX9 • STK11 • TERT • TIPARP • TMB • TNFAIP3

Therapeutic potential of BH3-mimetics and NK cell-mediated immunotherapy in T-ALL. (PubMed, Cell Death Dis) - "Here, we analyzed the sensitivity of T-ALL to inhibitors of BCL-2 (venetoclax), BCL-XL (A1331852), MCL-1 (AZD5991) and dual inhibition of BCL-2/BCL-XL (AZD4320) and evaluated their combination effects with natural killer (NK) cells. Importantly, NK cell-mediated killing could be further enhanced by combining NK cells with AZD4320, proposing this combination as a potential effective treatment. Taken together, we demonstrated promising potential of BH3-mimetics and NK cells for the treatment of T-ALL alone and in combination, warranting further preclinical and potential clinical evaluation."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • BCL2L1

KS18, an Mcl-1 inhibitor, triggers cell death and enhances the therapeutic efficacy of venetoclax in bortezomib-resistant multiple myeloma cells (AACR 2024) - "KS18 outperforms other Mcl-1 inhibitors such as S63845, VU661013, and AZD5991, according to the findings of our research, which shows that it is extraordinarily effective against MM cells that have become resistant to bortezomib. These intriguing findings highlight the potential value of KS18 as an adjunct to therapies aimed at overcoming bortezomib resistance in MM and other associated cancers. Bortezomib-resistant malignancies provide a challenge for patients, but additional research into the clinical value of KS18 holds the potential to improve treatment outcomes and broaden the range of therapeutic alternatives available to these patients."

Clinical • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • BCL2

AZD4573 in combination with CHOP increases combination benefit in preclinical peripheral T-cell lymphoma models (AACR 2024) - "Using MCL-1 inhibitor AZD5991, we showed statistically significant benefit in survival when combined with CHOP in MCL-1 dependent preclinical pTCL PDX models (Koch et al. CHOP treatment in vitro resulted in a decrease in c-MYC levels but not MCL-1, suggesting that combination benefit may be driven through c-MYC. This data suggests that treatment with AZD4573 as a monotherapy or in combination with CHOP regimen ­would be an effective therapeutic strategy in pTCL."

Combination therapy • IO biomarker • Preclinical • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • BCL2 • BCL2A1 • BCL2L1 • CASP3 • CASP7 • MYC

Discovery of novel sophocarpine derivatives as potential dual Bcl-2 and Mcl-1 inhibitors: design, synthesis and anti-hepatocellular carcinoma evaluation. (PubMed, Bioorg Med Chem Lett) - "Herein, guided by the structural features of Sorafenib, the selective Bcl-2 inhibitor Venetoclax, and the selective Mcl-1 inhibitor AZD5991, we designed and synthesized a series of novel Sophocarpine-derived analogues bearing a pyridylethyl moiety via a molecular-hybridization strategy. In parallel, a 3D-QSAR (CoMFA) model was constructed to rationalize the structure-activity relationship and to inform further lead optimization. Collectively, these findings identify S6 as a promising Sophocarpine derivative with a putative dual Bcl-2/Mcl-1 targeting profile, with significant anti-HCC activity and potential for preclinical development."

IO biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • BCL2 • CASP3

Molecular decoupling of lineage identity and morphology in aggressive variant prostate cancer. (PubMed, medRxiv) - "Pathway and perturbation analyses suggested that NCI-LYM-1 harbored a strong dependency on apoptotic pathways, which was confirmed by in vitro organoid testing with the BCL-2/BCL-xL inhibitor navitoclax (IC 50 : 0.27 µM) and the MCL-1 inhibitor AZD-5991 (IC 50 : 0.060 µM). Overall, NCI-LYM-1 recapitulates the clinical aggressiveness and heterogeneity of AVPC, providing a tractable platform to identify novel precision therapies."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • ASCL1 • BCL2 • BCL2L1 • BRCA2 • PTEN • RB1 • TP53

Molecular subtypes and BH3 mimetic synergy with anti-leukemia agents in T-cell acute lymphoblastic leukemia (ASH 2025) - "In this study, we evaluated the ex vivo cytotoxicity of threeinvestigational BH3 mimetics, namely AZD4320 (BCL2/BCL-XL dual inhibitor), AZ'3202 (BCL-XL inhibitor),and AZD5991 (MCL1 inhibitor), using an imaging-based cell viability assay in a panel of 58 patient-derivedxenograft (PDX) models of T-ALL...These findings highlightthe interplay between molecular subtype and apoptotic signaling and their effects on BH3 mimeticsensitivity in T-ALL.Next, to investigate the therapeutic potential of BH3 mimetics in combination settings for T-ALL, weevaluated the interactions between AZD4320 and key anti-leukemic agents, i.e., asparaginase,prednisolone, nelarabine, and an LCK inhibitor, dasatinib, across 40 T-ALL PDX samples ex vivo...In three T-ALL PDX models, the combination of AZD0466 (a drug-dendrimer conjugateof AZD4320) with asparaginase consistently exhibited greater efficacy compared to monotherapy (vsAZD0466, P = 0.0007, P = 0.015, and P = 0.0006; vs asparaginase, P =..."

Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • BCL2 • BCL2L1

Beat AML: Study of Biomarker-Based Treatment of Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=3000 | Recruiting | Sponsor: Beat AML, LLC | N=2000 ➔ 3000 | Trial completion date: Dec 2026 ➔ Dec 2028 | Trial primary completion date: Dec 2026 ➔ Dec 2028

Biomarker • Enrollment change • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Epitranscriptomic signatures define prognosis and therapeutic vulnerabilities in large B-cell lymphoma (ASH 2025) - "The first-line treatment consists of a R-CHOP-like regimen,where 20-40% of patients are refractory to the treatment or will relapse (R/R)...The results showed asynergic effect between the anti-apoptotic protein inhibitors tested and YTHDC1i, particularly with at alow dose of venetoclax (0.01 µM, BCL-2 inhibitor), with a mean of 17% of viability of OCI-LY1 cells, incomparison to venetoclax alone (mean of 35% viability). Interestingly, when the MCL-1 inhibitor (0.1 µM,AZD-5991) was combined with YTHDC1i, we reached a mean of 8% of viability in comparison to MCL-1ialone (mean of 62%)... Our study reveals that specific epitranscriptomic modifications and the expression of theirregulatory enzymes are significantly associated with overall survival in patients with LBCL. Among these,i6A and its writer, TRIT1, correlate with a better prognosis, while m1G and m1A, along with theirassociated enzymes, predict poorer outcomes. Functional assays identified YTHDC1 as a..."

IO biomarker • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • ALKBH5 • ANXA5 • BCL2L1 • CASP3 • METTL1 • METTL3 • TRMT6 • WDR4 • YTHDC1

CSF1R-CSF1 axis blockade with axatilimab effectively targets leukemia stem cells and monocytes in AML resistant to BH3 mimetics (ASH 2025) - "Background : The BCL2 inhibitor venetoclax (VEN), in combination with hypomethylating agents, ishighly effective in inducing remissions in AML...The effects on cytokine production, AML blasts, stem cells, andmonocytes were evaluated. MV4-11 cells with acquired resistance to BH3 mimetics targeting BCL2 or MCL1,peculiarly to VEN and VEN plus MCL-1 inhibitor AMG176, exhibited elevated levels of cytokinesincluding CSF1, TGF-1ß, IL-4, and IL-10 compared to parental cells... CSF1, TGF-1ß, IL-4, IL-10, and numerous other cytokines are increased in BH3mimetic resistant AML cell lines and patient samples. Inhibition of CSF1R targets ERK and AKTsignaling and significantly enhances the cytotoxic effects of BH3 mimetics against AML cells,stem/progenitor cells, and monocytes resistant to VEN. Furthermore, blockage of CSF1R-CSF1axis suppresses multiple cytokines in vitro and in vivo, and markedly improves the therapeuticefficacy of BH3 mimetics in a VEN/AZD5991/Decitabine..."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • ANXA5 • CSF1R • IL10 • IL4 • TP53

Inhibition of NSD2 in t(4; 14) myeloma induces changes in mitochondrial priming (ASH 2025) - "Dynamic profilingof KMS11 indicated increased priming on BCL-XL and potentially BCL2 with delta priming of 14-21% withBAD and 14% with HRK peptides (targets BCL-XL), as well as increased sensitivity to AZD4320 and DT2216(BCL-XL PROTAC)...Additionally, we found these cells were less sensitive to AZD5991 and AZD4320 thanthe control cells, suggesting loss of NDS2 in KMS18 leads to decreased priming. Dynamic mitochondrial profiling post-NSD2 inhibition in t(4; 14) myeloma displayed cell linespecific patterns, perhaps owing to the heterogenous baseline priming in this high-risk subtype... Dynamic mitochondrial profiling post-NSD2 inhibition in t(4; 14) myeloma displayed cell linespecific patterns, perhaps owing to the heterogenous baseline priming in this high-risk subtype. Themolecular basis for these differences is under current investigation and could be related to thedifferences in genes influenced by NSD2 activity in these cells. RNAseq analysis of 3 myeloma cells..."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Targeted Protein Degradation • ANXA5 • BCL2L1 • FGFR3 • NSD2 • TP53

FLT3L-based conjugate targets chemoresistant leukemia stem cells via cell cycle re-entry in Acute Myeloid Leukemia [WITHDRAWN] (ASH 2025) - "FL-Fc-DM1 outperformed unconjugated DM1 in vitro, remained effective inthe presence of physiological FLT3L, induced FLT3 internalization, and activated the p53 pathway.Cytarabine treatment induces a senescence-like phenotype in AML characterized by G1 arrest andupregulation of senescence-associated genes, which confer resistance...Co-treatment with the MCL1 inhibitor AZD-5991 or the BCL2inhibitor venetoclax synergistically enhanced cell death, particularly in FLT3-ITD-positive AML cells...Serial transplantation and limitingdilution assays demonstrated that FL-Fc-DM1 selectively depleted LSCs, impairing leukemia-initiatingpotential.Importantly, at therapeutically relevant concentrations, FL-Fc-DM1 selectively suppressed colonyformation of AML-derived CD34⁺ cells while sparing healthy donor CD34⁺ hematopoietic stem cells exvivo. Consistently, in a humanized mouse model reconstituted with healthy human CD34⁺ cells, FL-Fc-DM1 treatment preserved normal hematopoiesis, immune..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • CD34 • FLT3 • PTPRC

Synergy between enzalutamide and selective Bcl-2 family inhibitors in metastatic castration-resistant prostate cancer (ESMO Asia 2025) - "While venetoclax (Bcl-2 inhibitor) combinations with enzalutamide have entered clinical evaluation, the relative benefit of inhibiting different Bcl-2 family members under identical experimental conditions has not been directly compared. DU145 mCRPC cells were treated for 48 h with enzalutamide (ENZA) alone or in combination with ABT-199 (Bcl-2 inhibitor), A-1331852 (Bcl-xL inhibitor), or AZD5991 (Mcl-1 inhibitor). In a direct comparison under uniform conditions, Mcl-1 inhibition with AZD5991 emerged as the most effective partner for ENZA in DU145 cells, followed by Bcl-xL inhibition, while Bcl-2 inhibition was less impactful. These findings support further evaluation of Mcl-1-targeting strategies as a means to overcome AR-independent resistance in mCRPC, while underscoring the need for cautious interpretation of large in-vitro dose-reduction estimates."

IO biomarker • Metastases • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ANXA5 • BCL2L1

Proteasome inhibition as a potential therapeutic target in thymic cancer. (PubMed, Cell Death Dis) - "Carfilzomib synergized with BCL2 family protein inhibitors (navitoclax or AZD5991), suggesting that drug combinations could be used to reduce the dose of each drug to minimize toxicity. Notably, thymic carcinomas differed from squamous cell carcinomas in other organs by higher levels of β5i (PSMB8) and constitutive proteasome β5 (PSMB5). We hypothesize that TC (and probably many TH) are uniquely suited for treatment with proteasome inhibitors alone or in combination with selective BH3 mimetics."

IO biomarker • Journal • Oncology • Solid Tumor • Squamous Cell Carcinoma • Thymic Carcinoma • Thymic Epithelial Tumor • Thymoma • Thymus Cancer • BCL2 • PSMB10 • PSMB5 • PSMB8 • PSMB9

The development of ACT001 with Mcl-1 inhibitors as a novel combination therapy for the treatment of paediatric diffuse midline glioma (SNO 2025) - P1 | "Among the strongest were Mcl-1 inhibitors (Mcl1i-MIK665, Mcl1i-AZD5991) consistent with ACT001's mechanism of downregulating anti-apoptotic signaling...In vivo, single-drug treatment of ACT001 or Mcl1i-S63845 extended survival in orthotopic DMG models and significantly reduced the number of Ki67-positive tumor cells...Our findings suggest that ACT001 is a multi-targeted agent acting on NF-κB and apoptotic signalling while inducing oxidative stress. The combination of ACT001 with anti-apoptotic protein inhibitors represents a promising treatment strategy for DMG patients."

Combination therapy • IO biomarker • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • Pediatrics • Solid Tumor • BCL2 • NQO1 • SLC7A11 • SOD2