A5002091193- Cytokine Signaling Pathways and Interactions
- Mathematical Biology Tumor Growth
- Cancer-related Molecular Pathways
- Chromosomal and Genetic Variations
- Immune Cell Function and Interaction
- Cancer-related molecular mechanisms research
- Cancer, Hypoxia, and Metabolism
- Chronic Myeloid Leukemia Treatments
- RNA modifications and cancer
- Protein Degradation and Inhibitors
- Telomeres, Telomerase, and Senescence
- Genomics and Phylogenetic Studies
- Cancer Mechanisms and Therapy
- Lung Cancer Treatments and Mutations
- Phagocytosis and Immune Regulation
- Cancer Research and Treatments
- Genomics and Chromatin Dynamics
- Cell death mechanisms and regulation
- CAR-T cell therapy research
- interferon and immune responses
- CRISPR and Genetic Engineering
- Chronic Lymphocytic Leukemia Research
- Advanced Breast Cancer Therapies
- PARP inhibition in cancer therapy
- Ubiquitin and proteasome pathways
AstraZeneca (United States)
2018-2025
AstraZeneca (United Kingdom)
2023
AstraZeneca (Brazil)
2021
John Brown University
2019-2020
Brown University
2012-2019
Summary Replicative cellular senescence is an important tumor suppression mechanism and also contributes to aging. Progression of both cancer aging include significant epigenetic components, but the chromatin changes that take place during are not known. We used formaldehyde assisted isolation regulatory elements ( FAIRE ) map genome‐wide conformations. In contrast growing cells, whose genomes rich with features open closed chromatin, profiles senescent cells significantly smoothened. This...
Transposable elements (TEs) were discovered by Barbara McClintock in maize and have since been found to be ubiquitous all living organisms. Transposition is mutagenic organisms evolved mechanisms repress the activity of their endogenous TEs. somatic cells very low, but recent evidence suggests that it may derepressed some cases, such as cancer development. We during normal aging several families retrotransposable (RTEs) start being transcribed mouse tissues. In advanced age expression...
Repetitive elements comprise at least 55% of the human genome with more recent estimates as high two-thirds. Most these are retrotransposons, DNA sequences that can insert copies themselves into new genomic locations by a "copy and paste" mechanism. These mobile genetic play important roles in shaping genomes during evolution, have been implicated etiology many diseases. Despite their abundance diversity, few studies investigated regulation endogenous retrotransposons genome-wide scale,...
Senescent cells acquire a unique chromosome architecture characterized by genome-wide shrinkage of arms.
Histone modification H4K20me3 and its methyltransferase SUV420H2 have been implicated in suppression of tumorigenesis. The underlying mechanism is unclear, although abundance increases during cellular senescence, a stable proliferation arrest tumor suppressor process, triggered by diverse molecular cues, including activated oncogenes. Here, we investigate the function senescence suppression. Using immunofluorescence ChIP-seq determine distribution proliferating senescent human cells. Altered...
PURPOSE The PAOLA-1/ENGOT-ov25 trial of maintenance olaparib plus bevacizumab for newly diagnosed advanced high-grade ovarian cancer demonstrated a significant progression-free survival (PFS) benefit over placebo bevacizumab, particularly in patients with homologous recombination deficiency (HRD)–positive tumors. We explored whether mutations non- BRCA1 or BRCA2 repair (non–BRCA HRRm) genes predicted from PAOLA-1. METHODS Eight hundred and six were randomly assigned (2:1). Tumors analyzed...
Long INterspersed Element-1 (LINE-1 or L1) is the only autonomously active, transposable element in human genome. L1 sequences comprise approximately 17 % of genome, but evolutionarily recent, human-specific subfamily retrotransposition competent. The promoter has a bidirectional orientation containing sense that drives transcription two proteins required for and an antisense promoter. can drive chimeric transcripts: 5' spliced to exons neighboring genes. impact activity on cellular...
Here we present and develop the hypothesis that derepression of endogenous retrotransposable elements (RTEs) - "genomic parasites" is an important hitherto under-unexplored molecular aging process can potentially occur in most tissues. We further envision activation continued presence retrotransposition contribute to age-associated tissue degeneration pathology. Chromatin a complex dynamic structure needs be maintained functional state throughout our lifetime. Studies diverse species have...
Abstract Purpose: Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2–selective inhibitor, had success the clinic, another member, Bcl-xL, also target and mechanism resistance. Therefore, we developed dual Bcl-2/Bcl-xL inhibitor that broadens therapeutic activity while minimizing Bcl-xL–mediated thrombocytopenia. Experimental Design: We used structure-based chemistry to design small-molecule Bcl-xL...
Abstract Background: Small-cell lung cancer (SCLC), an aggressive type, presents challenges in management due to limited treatment options. In the CASPIAN study (NCT03043872) assessing durvalumab (D) ± tremelimumab (T) and platinum-based chemotherapy extensive-stage SCLC, improved survival with D + was revealed. Ongoing research exploring SCLC subtypes, responses, epigenetic modifications like DNA methylation, association outcomes, is offering insights into tailored disease progression....
Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or T790M resistance mutations. While patients treated osimertinib show clinical benefit, disease progression and drug common. Emergence of de novo acquired from a tolerant persister (DTP) population is one mechanism proposed to explain on other targeted therapies. Here we profiled DTPs using RNA-seq...
B-cell receptor (BCR) signaling is essential for the diffuse large lymphoma (DLBCL) subtype that originates from activated B-cells (ABCs). ABC-DLBCL cells are sensitive to Bruton tyrosine kinase intervention. However, patients with relapsed or refractory had overall response rates 33% 37% inhibitors, suggesting evaluation of combination-based treatment improved efficacy. We investigated efficacy and mechanism bromodomain extraterminal motif (BET) inhibitor AZD5153 combined acalabrutinib in...
Abstract In cancer, chronic antigen stimulation drives effector T cells to exhaustion, limiting the efficacy of cell therapies. Recent studies have demonstrated that epigenetic rewiring governs transition from exhausted states and makes a subset non-responsive PD1 checkpoint blockade. Here, we describe an antigen-specific assay for exhaustion generates are phenotypically transcriptionally similar those found in human tumors. We performed screen regulators, identifying validating IKAROS as...
Abstract Background: PRMT5 is an epigenetic enzyme that catalyzes symmetric di-methylation of arginine (SDMA) multiple substrates regulate biological processes including RNA splicing and cell cycle. The role in controlling chromatin accessibility has been investigated some cancer contexts, but its non-small lung (NSCLC) global regulation not known. AstraZeneca developed MTA-cooperative inhibitor (AZD3470) selectively inhibits MTAP-null tumors currently Phase I clinical trial (NCT06130553,...
Abstract Cyclin-dependent kinase 9 (CDK9) regulates elongation of transcription through phosphorylation RNA polymerase II (pSer2-RNAPII), and its short-term inhibition downregulates genes with short-lived transcripts labile proteins. We developed a novel selective CDK9 inhibitor, AZD4573, nanomolar potency physicochemical properties suitable for IV administration short exposure. Initial transcriptomic proteomic analyses were performed on MCF7 breast cancer cells treated AZD4573 4h or 8h to...
Osimertinib is an EGFR tyrosine kinase inhibitor (TKI) with proven clinical efficacy; however, acquired resistance presents obstacle to curing EGFR-driven disease. Recent studies have shown that drug-tolerant persister cells (DTP) a distinct transcriptional profile may confer specific vulnerabilities. By definition these avoid apoptosis, yet little known about how their survival regulated. We found paradoxically, the proapoptotic gene BIM was upregulated in osimertinib DTPs, and cotreatment...
Abstract AZD5153 is a bivalent bromodomain and extraterminal (BET) inhibitor that simultaneously engages the two bromodomains of bromodomain-containing protein 4 (BRD4). Here, we initially tested in combination with acalabrutinib, Bruton tyrosine kinase (BTK) inhibitor, panel diffuse large B-cell lymphoma (DLBCL) cell lines. The ABC type DLBCL cells responded to acalabrutinib at lower drug concentrations compared other Many these were below clinical equivalent dose for each drug. Similar...