SRA515 / AstraZeneca, GSK - LARVOL DELTA

Targeting Dysregulated Epigenetic Modifiers with Kidney-Targeted Nanotherapeutics for PKD (KIDNEY WEEK 2025) - "Currently, tolvaptan, is the only FDA-approved therapy...To improve kidney-specific delivery, we encapsulated the small molecule inhibitors AZD-5153 (Brd4 inhibitor) and PTC-209 (BMi1 inhibitor) into kidney-targeting micelles (KMs) and evaluated their efficacy in human and murine ADPKD models...Conclusion We identified the epigenome as a therapeutic target for ADPKD and evaluated the efficacy of inhibiting Brd4 and BMi1 in ADPKD. We observed improved response upon loading inhibitors of the dysregulated epigenetic regulators into kidney-targeting nanoparticles and present a novel nanomedicine-based combinatorial therapeutic approach for ADPKD."

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

The chordoid glioma PRKCA D463H mutation is a kinase inactive, gain-of-function allele that induces early-onset chondrosarcoma in mice. (PubMed, Sci Signal) - "D463H expression reduced the sensitivity of cells to the BET inhibitors JQ1 and AZD5153, indicating the functional importance of these pathways. The findings indicate that D463H is a dominant gain-of-function oncogenic mutant that operates through a noncatalytic allosteric mechanism."

Journal • Preclinical • Brain Cancer • Glioma • Oncology • Sarcoma • Solid Tumor • BRD4 • PRKCA • TGFB1

AZD5153 enhances the chemo-sensitivity of gemcitabine on pancreatic cancer cells in vitro and in vivo. (PubMed, Cancer Cell Int) - "In conclusion, these results suggested that AZD5153 might be an excellent GEM sensitizer in pancreatic cancer."

Journal • Preclinical • Oncology • Pancreatic Cancer • Solid Tumor • MUC2 • PARP1

Combination of PSMA targeting alpha-emitting radioligand [212Pb]Pb-AB001 with BET bromodomain inhibitors in in vitro prostate cancer models. (PubMed, Med Oncol) - "Bromodomain and extra-terminal (BET) protein inhibitors, such as AZD5153 and JQ1, disrupt oncogenic transcriptional programs by altering chromatin structure. In 3D spheroids, combination treatment led to synergistic growth suppression. In conclusion, these findings indicate that therapeutic inhibition of BET bromodomain in combination with the alpha-emitting radioligand [212Pb]Pb-AB001 could significantly enhance tumour control and should be further evaluated in metastatic prostate cancer models."

Journal • Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

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

Effective therapeutic targeting of tumor lineage plasticity in neuroendocrine prostate cancer by BRD4 inhibitors. (PubMed, Acta Pharm Sin B) - "Significantly, we demonstrated that BRD4 inhibitor AZD5153, currently at clinical development, possesses potent activities in complete blockade of tumor growth of both de novo neuroendocrine prostate cancer (NEPC) and treatment-induced NEPC PDXs and that suppression of tumor expression of LP programs through reduction of local chromatin accessibility is the primary mechanism of action (MOA) by AZD5153. Together, our study revealed that BRD4 plays a fundamental role in direct activation of tumor LP programs and that its inhibitor AZD5153 is highly promising in effective treatment of the lethal forms of the diseases."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • ASCL1 • BRD4 • DLL3 • FOXA1 • NEUROD1 • RUNX1 • SOX2

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

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

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

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