SRA515 / AstraZeneca, GSK - LARVOL DELTA

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

3D Epigenomic Remodelling Mediated by Foxa1 Drives Gemcitabine Resistance in Pancreatic Cancer. (PubMed, Cancer Lett) - "Notably, the clinical-stage BET inhibitor AZD5153, in combination with gemcitabine, achieves robust tumor suppression and overcomes resistance in cell-derived xenograft (CDX) models by dismantling the Foxa1-mediated resistant transcriptome and reinvigorating drug sensitivity. Our findings establish Foxa1-orchestrated enhancer reprogramming as a fundamental mechanism of gemcitabine resistance and unveil a promising epigenetic therapy to restore treatment efficacy in PDAC."

Journal • Gene Therapies • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • FOXA1 • RRM1 • USP7

The role of endothelial cell remodeling in driving immunotherapy resistance of hepatocellular carcinoma (AACR 2026) - P2 | "Hence, we aim to delineate the microenvironmental cue 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 clinical trial of pembrolizumab in HCC patients (NCT03419481)...BET inhibitor AZD5153, administered in nanoparticle formulations, was used to suppress BRD4 and TF expression selectively in ECs... Our study reveals that the dynamic trans-differentiation from LEC to MaVEC is related with ICB resistance in HCC. Blocking this EC transformation shifts the TME from immunosuppressive to stimulatory, re-sensitizing tumors to anti-PD-L1 therapy. This project may yield new strategies to counter adaptive immune resistance in HCC.Keywords: Hepatocellular carcinoma, Immune-checkpoint blockade, Endothelial cells remodeling."

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

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

BET inhibition potentiates salvage chemotherapy response through TXNIP upregulation in osteosarcoma (AACR 2026) - "In vitro combination studies showed additive-to-synergistic effects between AZD5153 and a variety of salvage agents (etoposide, SN38, and topotecan)...In vivo, dose finding studies indicated that PDX77-TT2 was resistant to salvage agents ifosfamide and SN38 but moderately sensitive to topotecan. Furthermore, AZD5153 alone or in combination with topotecan improved survival compared to single agents (p<0.05) and was well tolerated. Collectively, these data support BET inhibition alone or with salvage therapy as a promising therapeutic approach for aggressive OS, potentially mediated through TXNIP upregulation and AKT pathway suppression."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • BRD2 • BRD4 • PARP1 • PDGFRA • RPA2 • TXNIP

A PLK1-OCT4 regulatory axis controls lineage plasticity and neuroendocrine differentiation in prostate cancer (AACR 2026) - "We observed a similar plasticity pattern in 16D cells treated with enzalutamide, and in a DOX-inducible LNCaP Rb/p53 knockdown model, where DOX induction likewise promoted a shift toward neuroendocrine features...To test this, we performed in vivo xenograft studies using pre-castrated NSG mice bearing N2P1 tumors and treated animals with vehicle, the PLK1 inhibitor Onvansertib, the BET inhibitor AZD5153, or the combination...Collectively, our findings reveal a critical role for the PLK1-OCT4 axis in prostate cancer plasticity and neuroendocrine differentiation. These results support a therapeutic strategy that simultaneously inhibits PLK1 and BET proteins as a promising approach to slow NEPC progression and improve patient outcomes."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Genitourinary Neuroendocrine Carcinoma • Oncology • Prostate Cancer • Solid Tumor • BRD2 • PLK1 • POU5F1

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

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

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

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

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

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

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 • Genitourinary Neuroendocrine Carcinoma • Lung Cancer • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor • ASCL1 • BRD4 • RUNX1 • SOX2 • SOX9

The Effect of AZD5153 on Radiosensitivity in Pancreatic Cancer Cells Through ATM-chk1 Pathway. (PubMed, Drug Des Devel Ther) - "Further molecular mechanism study revealed that AZD5153 inhibited radiotherapy-activated ATM-chk1 pathway, suggesting that AZD5153 may enhance radiosensitivity by impairing DNA damage repair. Collectively, these results suggested that AZD5153 might be a promising radiosensitizing agent, and targeting the ATM-chk1 pathway may offer a novel therapeutic strategy to overcome radioresistance in pancreatic cancer."

Journal • Hematological Malignancies • Lymphoma • Oncology • Pancreatic Cancer • Solid Tumor • BRD4

Lactylation-related genes signature panel in hepatocellular carcinoma reveals the prognostic and therapeutic optimization. (PubMed, Mol Cell Oncol) - "Conversely, the high-LRGS group demonstrated heightened sensitivity to several antitumor agents, including AZD5153, cediranib, foretinib, and vorinostat, relative to the low-LRGS group. Our findings establish a robust LRGS model, offering a clinically actionable tool for prognostic assessment and precision therapy in HCC."

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

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

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

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

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