SRA515 / AstraZeneca, GSK - LARVOL DELTA

Anti-tumor effects following BET inhibition in preclinical models of pediatric and AYA osteosarcoma (AACR 2025) - "Effect of BETi (AZD5153, BMS-986378, ZEN-3694) in clinical trials for pediatric and adult solid tumors were investigated...To interrogate mechanisms of action, RNA-seq analysis of BET/BRD4 inhibition via AZD5153, PROTAC (ARV-825), and BRD4 siRNA in OS cell lines revealed distinct and overlapping patterns of alterations in gene expression...At the transcript level, increased DHRS2 was evident with no changes in TMPRSS9. These data sets reveal the promise of BETi for treatment of OS PDX derived from treatment naïve patients some of which go on to relapse, and in OS PDX derived from metastatic sites."

Preclinical • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • BRD2 • BRD4 • DHRS2 • H2AX

Simultaneous targeting of CDK4/6 and BETs is independent of RB status in osteosarcoma (AACR 2025) - "In comparison to wildtype (WT) clones, KO clones were 2-10-fold more resistant to palbociclib and at most 2-fold more resistant to abemaciclib; with differences attributed to broader selectivity profile of abemaciclib...Additionally, RB monoallelic OS PDX models TT2 (pretreated) and PDX96 (naïve), were treated for 6 weeks with CDK4/6i (palbociclib, 40mg/kg, BETi (AZD5153,1 mg/kg), or their combination and significantly reduced tumor growth compared to single agents in both models (p<0.05) and was well tolerated...Future studies will extend dosing duration and focus on metastatic and RB- variant models. These findings provide rationale for further study of novel therapeutic options which may expand the clinical utility of CDK4/6i regardless of RB status."

Eye Cancer • Oncology • Osteosarcoma • Retinoblastoma • Sarcoma • Solid Tumor • ANXA5 • CDK4 • PARP1

The role of endothelial cell remodeling in driving immunotherapy resistance of hepatocellular carcinoma (AACR 2025) - P2 | "We aim to delineate the microenvironmental cue and transcriptional network that direct EC remodeling for tumor immunosuppression and their role in promoting ICB resistance. Single-cell transcriptomic profiling was performed on samples from a Phase II trial of pembrolizumab (anti-PD-1) in hepatitis B-related HCC patients (NCT03419481). Our study reveals that the dynamic trans-differentiation from LEC to MaVEC is associated with ICB resistance in HCC, which can be reversed by BRD4 inhibition and possibly mediated by TCF4 transcriptional regulation, targeting their expression in ECs showed improved therapeutic outcomes.Keywords: Hepatocellular carcinoma, Immune-checkpoint blockade, Endothelial cells, Transcriptional network."

IO biomarker • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • BRD4 • TCF4

In vivo screening reveals therapeutic vulnerabilities in a patient-derived xenograft established from an intraosseous TFCP2-rearranged rhabdomyosarcoma (AACR 2025) - "PDX174 was derived prior to ALKi treatment (lorlatinib) and PDX199 from the same patient following disease progression after 16 months of lorlatinib therapy...In addition, while CDK4/6 inhibitor, palbociclib, and CHK1 inhibitor, SRA737, induced moderate inhibition of tumor growth, drug resistance quickly followed within 2 weeks. Global kinome analysis indicated a significant increase in the mitogen- and stress-activated kinase 1 (MSK1) in AZD5153-resistant tumors compared to the vehicle group, revealing a potential therapeutic vulnerability in the BETi-resistant tumors. IORMS models such as PDX174/PDX199 are crucial for revealing actionable molecular signatures before and after targeted therapy and will increase our mechanistic understanding of tumor adaptive responses and aid in designing therapies that mitigate the emergence of therapeutic resistance."

Preclinical • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • ALK • FUS • TERT • TFCP2

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

Tumor lineage plasticity blockade by therapeutic targeting of an epigeneticregulator (AACR 2025) - "Further study revealed thatsuppression of tumor expression of LP programs through reduction of local chromatinaccessibility is a primary mechanism of action (MOA) by AZD5153. Together, ourfindings demonstrated that BRD4 plays a fundamental role in directly activating tumorLP programs and that its inhibitor AZD5153 is highly promising in effective treatment ofthe lethal forms of the diseases."

Genito-urinary Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor • ASCL1 • BRD4 • RUNX1 • SOX2 • SOX9

Targeting Dysregulated Epigenetic Modifiers With Kidney-Targeted Nanotherapeutics for Polycystic Kidney Disease. (PubMed, J Biomed Mater Res A) - "The one small molecule drug available to patients, tolvaptan, is associated with off-target side effects and high discontinuation rates, necessitating the development of new therapeutic strategies...We found Brd4 and BMi1 are upregulated and observed that their inhibition using small molecule drugs, AZD-5153 and PTC-209, significantly slowed the proliferation of ADPKD patient cells...These findings were also consistent in murine in vitro models using Pkd1 null renal proximal tubule cells. In summary, we demonstrate Brd4 and BMi1 as novel targets in ADPKD and targeting the epigenome using kidney nanomedicine as a novel therapeutic strategy in ADPKD."

Journal • Autosomal Dominant Polycystic Kidney Disease • Chronic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • BMI1 • BRD4 • PKD1 • PRKD1

Functional combinatorial precision medicine for predicting and optimizing soft tissue sarcoma treatments. (PubMed, NPJ Precis Oncol) - "From a panel of approved and investigational agents, QPOP identified AZD5153 (BET inhibitor) and pazopanib (multi-kinase blocker) as the most effective combination with superior efficacy compared to standard regimens. Validation in a panel of established patient lines and in vivo models supported its synergistic interaction, accompanied by repressed oncogenic MYC and related pathways. These findings provide preliminary clinical evidence for QPOP to predict STS treatment outcomes and guide the development of novel therapeutic strategies for STS patients."

Journal • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Blocking the BRD4-MYC signalling axis overcomes chemoresistance among HPV-driven malignancies (LCC 2025) - "Collectively, our data demonstrate that AZD5153 could potentially serve as a novel therapeutic option for the treatment of HPV-mediated malignancies."

Cervical Cancer • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • BRD4

High-risk neuroblastoma: ATRX and TERT as prognostic markers and therapeutic targets. Review and update on the topic. (PubMed, Rev Esp Patol) - "We highlight the promising results of the clinical trial involving the combination of adavosertib and irinotecan, which encourages further clinical trials with adavosertib targeting NB with ATRX mutations. Preclinical results with BET inhibitors (OTX015 and AZD5153) and with 6-thio-2'-deoxyguanosine, targeting NB with TERT mutations, are promising. Both represent future therapeutic targets, emphasizing the need to prioritize research using these models."

Biomarker • Journal • Review • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • ATRX • MYCN • TERT

Lipid metabolism-related gene signature predicts prognosis and unveils novel anti-tumor drugs in specific type of diffuse large B cell lymphoma. (PubMed, Mol Med) - "Our results provide the first lipid metabolism-based gene signature for predicting the survival of patients with DLBCL. Furthermore, by determining novel subtypes with our lipid metabolism prognostic model we illustrated that drugs that compromising MYC target genes rather than immune checkpoint inhibitors may be beneficial to DLBCL patients with certain lipid metabolism profiles."

Gene Signature • IO biomarker • Journal • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Metabolic Disorders • Non-Hodgkin’s Lymphoma • Oncology • BCL6 • CD3E • CTTN • FABP4 • LAYN • MMP9 • SLC2A3 • SLIT2

CDK9 inhibition inhibits multiple oncogenic transcriptional and epigenetic pathways in prostate cancer. (PubMed, Br J Cancer) - "Our work demonstrates that CDK9 inhibition disrupts multiple oncogenic pathways and positions CDKI-73 as a promising therapeutic agent for prostate cancer, particularly aggressive, therapy-resistant subtypes."

IO biomarker • Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • BCL2 • BRD4

Targeting CDK4/6 and BET proteins for the treatment of RB+ and RB- osteosarcoma (AACR 2024) - "In OS cell lines, combination index and Bliss analysis indicated additive-to-synergistic growth inhibition using CDK4/6i (abemaciclib or palbociclib) and BETi (AZD5153). In-vivo efficacy of dual CDK46i+BETi is underway. This data provides rationale for further study of novel therapeutic options which may expand the clinical utility of CDK4/6i regardless of RB status."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CDK4 • CDKN2A

BET inhibitor increases DNA damage, modulates Wnt signaling, and suppresses osteosarcoma growth in naïve and metastatic disease models (AACR 2024) - "Combination index and Bliss independence analyses of bivalent BET inhibitor (BETi) AZD5153 or PROTAC ARV825 in combination with salvage agents demonstrated additive-to-synergistic cell growth inhibition in OS lines. TT2 PDX was resistant to commonly used salvage agents ifosfamide and irinotecan; however, combination BETi+ topotecan increased the probability of survival compared to each agent alone (p<0.05) and was well tolerated. These data collectively suggest that BET inhibition alone or in combination with low-dose salvage therapy holds promise as novel treatment strategies in aggressive OS."

Metastases • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • EPHA2 • EPHA4 • TCF7 • TXNIP

Beat AML: Study of Biomarker-Based Treatment of Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=2000 | Recruiting | Sponsor: Beat AML, LLC | Trial completion date: Dec 2023 ➔ Dec 2026 | Trial primary completion date: Dec 2023 ➔ Dec 2026

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

First-in-Human Study of AZD5153, A Small Molecule Inhibitor of Bromodomain Protein 4, in Patients with Relapsed/Refractory Malignant Solid Tumors and Lymphoma. (PubMed, Mol Cancer Ther) - "This first-in-human, phase 1 study investigated AZD5153 alone or with olaparib in patients with relapsed/refractory solid tumors or lymphoma. These results show AZD5153 was tolerable as monotherapy and in combination at the RP2Ds; common toxicities were fatigue, hematologic AEs, and gastrointestinal AEs. Strong evidence of peripheral target engagement was observed."

Journal • P1 data • Fatigue • Gastrointestinal Cancer • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Hepatology • Lymphoma • Oncology • Pancreatic Cancer • Solid Tumor • Thrombocytopenia • BRD4 • HEXIM1

Epigenetic remodeling of endothelial cells underlying immune checkpoint resistance in hepatocellular carcinoma (IDDF 2023) - P2 | "Methods Single-cell RNA sequencing (scRNA-seq) was performed in Phase II clinical trial of pembrolizumab (anti-Programmed cell death 1(PD-1)) in hepatitis B virus-related HCC patients ( NCT03419481 ). Notably, a clinically-trialed BRD4 specific inhibitor AZD5153 synergized with PD-L1 antibody to suppress tumor growth and ameliorated immunosuppressive microenvironment, which was accompanied by significant reduction and increase in MaVEC and LEC densities, respectively. Conclusions Our data demonstrated that epigenetic reversion of LEC-to-MaVEC trans-differentiation by BRD4 inhibition may be a potential strategy for improving HCC immunotherapy."

IO biomarker • Gastrointestinal Cancer • Hepatitis B • Hepatocellular Cancer • Hepatology • Immune Modulation • Infectious Disease • Oncology • Solid Tumor • BRD4

Blocking the BRD4-MYC signalling axis as a novel approach for the treatment of HPV-driven malignancies (EACR 2023) - "To date, AZD5153 has not been explored as a therapeutic option for treating HPV-driven cancer patients.Results and DiscussionsUpon challenged with AZD5153 in vitro, we observed HPV+ve cancer cells to be significantly sensitive compared to HPV-ve cancer cells. In addition, low dose of AZD5153 induced chemo-sensitivity in HPV+ve cancer cells and demonstrated high synergism and demonstrated cell death in Caspase-3 dependent manner.ConclusionOur preliminary data highlights that inhibition of BRD4-MYC axis could potentially serve as novel therapeutic option against treatment of HPV-driven malignancies."

Oncology • BRD4 • CASP3 • MYC

BET inhibition targets ABC-DLBCL constitutive B-cell receptor signaling through PAX5. (PubMed, Blood Adv) - "Adding IFNß1 to cells treated with acalabrutinib partially rescued PAX5 activation. Our results demonstrate AZD5153 enhances the efficacy of acalabrutinib through PAX5 and BCR mechanisms that are critical for ABC-DLBCL."

IO biomarker • Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BRD4 • NF-κβ • PAX5

BRD4 inhibition impairs DNA mismatch repair, induces mismatch repair mutation signatures and creates therapeutic vulnerability to immune checkpoint blockade in MMR-proficient tumors. (PubMed, J Immunother Cancer) - "We demonstrated that BRD4 inhibition suppressed expression of genes critical to MMR, dampened MMR, and increased dMMR mutation signatures both in vitro and in vivo, sensitizing pMMR tumors to ICB. Importantly, even in BRD4 inhibitors (BRD4i)-resistant tumor models, the effects of BRD4i on MMR function were maintained rendering tumors sensitive to ICB. Together, these data identified a strategy to induce dMMR in pMMR tumors and further, indicated that BRD4i sensitive and resistant tumors could benefit from immunotherapy."

Checkpoint block • Checkpoint inhibition • IO biomarker • Journal • Mismatch repair • Tumor mutational burden • Immune Modulation • Oncology • Ovarian Cancer • Solid Tumor • BRD4 • CD4 • CD8 • FOXP3 • HAVCR2 • MLH1 • MSH2 • MSH6 • PD-L1 • PMS2 • TMB

Therapeutic targeting of BET bromodomain proteins increases DNA damage and potentiates salvage therapy in osteosarcoma xenografts derived from patients with replication stress signatures (AACR 2023) - "Treatment with PROTAC ARV825 that degrades BET proteins, resulted in similar growth inhibitory effects...Combination treatments of BETi+topotecan/ifosfamide indicated that AZD5153 potentiated the anti-cancer effect of salvage therapy in TT2 OS PDX, was well tolerated, and increased the probability of survival in mice. Efficacy in an OS RS+ metastatic lesion model is in progress. These data collectively suggest that BET inhibition as a single agent and in combination with low-dose salvage therapy holds promise as novel treatment strategies for inducing RS-mediated cell death in aggressive OS."

Clinical • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • BRD2

Synergistic effect of PARP inhibitor and BRD4 inhibitor in multiple models of ovarian cancer. (PubMed, J Cell Mol Med) - "To solve this problem, we found that BRD4 inhibitor AZD5153 and PARP inhibitor olaparib had a widespread synergistic effect in multiple models with different gene backgrounds. The similar results of these models further proved that the mechanism identified was consistent with the biological process occurring in ovarian cancer patients after drug treatment. This consistency between the results of different models suggests the possibility of translating these laboratory research findings into clinical studies towards developing treatments."

Journal • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • BRD4 • PTEN

RADIOSENSITIZATION BY BRD4 INHIBITION IN DIFFUSE INTRINSIC PONTINE GLIOMA (SNO 2022) - "We tested two BRD4 inhibiter (BRD4i: AZD5153 and JQ-1) and genetic BRD4 depletion enhances radiation-induced DNA damage, making it a potential radiosensitizer in the treatment of DIPG. In vivo studies revealed increased survival of animals treated with combination therapy of RT and BRD4i in compared to either monotherapy. Together, these results highlight BRD4i as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG."

Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • BRCA1 • BRD4 • RAD51 • TP53BP1

Evaluation of the Synergistic Potential of Simultaneous Pan- or Isoform-Specific BET and SYK Inhibition in B-Cell Lymphoma: An In Vitro Approach. (PubMed, Cancers (Basel)) - "We evaluated the anti-lymphoma activity of the isoform-specific bivalent BET inhibitor AZD5153 (AZD) and the pan-BET inhibitor I-BET151 (I-BET) as single agents and in combination with SYK inhibitor Entospletinib (Ento) in vitro. Genes such as ADGRA2, MYB, TNFRSF11A, S100A10, PLEKHH3, DHRS2 and FOXP1-AS1 were identified as possible key regulators. Simultaneous inhibition of BET and SYK enhanced the anti-proliferative effects, and induced a combination-specific gene expression signature."

Journal • Preclinical • Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • DHRS2 • FOXP1 • SYK • TNFRSF11A

Identification and characterisation of multiple strategies to enhance cancer cell death in preclinical models of head and neck cancer (EACR 2022) - "Functional Assays : RNA interference and inhibitors that selectively target GLS (CB-839), DHODH (Teriflunomide, Leflunomide, Vidofludimus, Brequinar and BAY 2402234) or BRD4 (MZ-1; JQ1; AZD5153; Mivebresib and Birabresib) potently and specifically diminish the clonogenic potential of several SCCHN cell lines. However, none of these treatments induce comparable apoptosis in the ex vivo SCCHN tumour tissue. Conclusion The challenges presented by the tumour microenvironment in diminishing the potential of several promising therapies will have to be characterised further, which is the primary focus of our current studies."

IO biomarker • Preclinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • BCL2 • BRD4