SRA515 / AstraZeneca, GSK - LARVOL DELTA

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

Trial of Selumetinib and AZD5153 With Durvalumab for Sarcomas (clinicaltrials.gov) - P1/2 | N=41 | Not yet recruiting | Sponsor: University of Alabama at Birmingham | Initiation date: Jul 2022 ➔ Oct 2022 | Trial primary completion date: Jul 2026 ➔ Oct 2026

Trial initiation date • Trial primary completion date • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor

Trial of Selumetinib and AZD5153 With Durvalumab for Sarcomas (clinicaltrials.gov) - P1/2 | N=41 | Not yet recruiting | Sponsor: University of Alabama at Birmingham | Trial completion date: May 2027 ➔ Aug 2027

Trial completion date • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor

MUS81 Inhibition Enhances the Anticancer Efficacy of Talazoparib by Impairing ATR/CHK1 Signaling Pathway in Gastric Cancer. (PubMed, Front Oncol) - "In conclusion, these data suggested that MUS81 regulated ATR/CHK1 activation, a key signaling pathway in the G2M checkpoint, and targeting MUS81 enhanced the antitumor efficacy of talazoparib. Therefore, AZD5153 combined with talazoparib may represent a promising therapeutic strategy for patients with MUS81 proficient gastric cancer."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CHEK1 • MUS81

BRD4 inhibition enhances the acalabrutinib tumor response by modulating PAX5 and interferon signaling in ABC-DLBCL (AACR 2022) - "In summary, our results demonstrate AZD5153 enhances the efficacy of acalabrutinib, and our in vitro data suggest adding AZD5153 to acalabrutinib concentrations much lower than the clinical equivalent dose results in a similar biomarker response. We show that this drug combination attenuates interferon signaling, which supports the mechanism of AZD5153 and acalabrutinib inhibiting PAX5 signaling in ABC-DLBCL."

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

Therapeutic induction of replication stress in the context of salvage therapy in osteosarcoma (AACR 2022) - "The effects of BET inhibitors (BETi), AZD5153 and OTX-015, as single agents and in combination with drugs used in salvage therapy such as topotecan were evaluated for effects on OS cell growth, PARP cleavage, and the DNA damage repair network. In vivo combination treatments of BETi+topotecan are in progress. These data collectively suggest that BET inhibition alongside salvage therapy holds promise as a novel treatment strategy for inducing RS-mediated cell death in aggressive OS."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • BRD2 • BRD4 • CHEK1

AZD5153, a Bivalent BRD4 Inhibitor, Suppresses Hepatocarcinogenesis by Altering BRD4 Chromosomal Landscape and Modulating the Transcriptome of HCC Cells. (PubMed, Front Cell Dev Biol) - "This may explain why AZD5153 acted in concert with FK866, a potent NAMPT inhibitor, in reducing HCC cell proliferation and clonogenic survival. In conclusion, our results identified novel targets of BRD4 in the HCCLM3 cell genome and demonstrated anti-HCC efficacy of AZD5153, which was potentiated in combination with an NAMPT inhibitor."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • BRD4 • MYC • NAMPT • RAD51B • TRIB3 • YAP1

Inhibition of histone readers bromodomain extra-terminal proteins alleviates skin fibrosis in experimental models of scleroderma. (PubMed, JCI Insight) - "Blockade of BETs was done using a pan BET inhibitor JQ1, BRD2 inhibitor BIC1, or BRD4 inhibitors AZD5153 or ARV825. The anti-fibrotic effect of BRD4 inhibition was at least in part mediated by downregulation of Ca2+/calmodulin-dependent protein kinase II α (CaMKII-α) and reduction of intracellular calcium concentrations. These results suggest that targeting calcium pathways or BRD4 might be novel therapeutic approaches for progressive tissue fibrosis."

Journal • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis • BRD2 • BRD4

Trial of Selumetinib and AZD5153 With Durvalumab for Sarcomas (clinicaltrials.gov) - P1/2 | N=41 | Not yet recruiting | Sponsor: University of Alabama at Birmingham

New P1/2 trial • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor