A5007116086- Synthesis and Catalytic Reactions
- Mast cells and histamine
- Immune cells in cancer
- Cancer Research and Treatments
- Cancer, Stress, Anesthesia, and Immune Response
- Immune Cell Function and Interaction
- Cancer Immunotherapy and Biomarkers
- Adenosine and Purinergic Signaling
- Protein Degradation and Inhibitors
- CAR-T cell therapy research
- Chronic Lymphocytic Leukemia Research
- Immunotherapy and Immune Responses
- Single-cell and spatial transcriptomics
- T-cell and B-cell Immunology
- RNA Interference and Gene Delivery
- Cancer, Hypoxia, and Metabolism
- Inflammatory mediators and NSAID effects
- Multiple Myeloma Research and Treatments
- Click Chemistry and Applications
- Cell Image Analysis Techniques
- Viral Infectious Diseases and Gene Expression in Insects
- Cancer-related gene regulation
- Scientific Computing and Data Management
- DNA Repair Mechanisms
- interferon and immune responses
AstraZeneca (United States)
2019-2025
Kala Pharmaceuticals (United States)
2024
Bioscience Research
2023
Accumulation of extracellular adenosine within the microenvironment is a strategy exploited by tumors to escape detection immune system. Adenosine signaling through 2A receptor (A2AR) on cells elicits range immunosuppressive effects which promote tumor growth and limit efficacy checkpoint inhibitors. Preclinical data with A2AR inhibitors have demonstrated regressions in mouse models rescuing T cell function; however, mechanism role other has not been fully elucidated.We report here...
PARP inhibitors are synthetically lethal with BRCA1/2 mutations, and in this setting, accumulation of DNA damage leads to cell death. Because increased subsequent immune activation can prime an anti-tumor response, we studied the impact olaparib ± checkpoint blockade (ICB) on activity microenvironment. Concurrent combination olaparib, at clinically relevant exposures, ICB gave durable deeper Brca1m BR5 model vs. monotherapies. Olaparib treatment modulated microenvironment, including...
Abstract Cyclin-dependent kinases (CDKs) are an attractive class of cancer targets due to their role in cell-cycle regulation. CDK2 is a Ser/Thr kinase activated via interaction with its cyclin partners CCNE and CCNA, driving G1/S progression the cell cycle. inhibition has potential address multiple resistance mechanisms CDK4/6 inhibitors breast cancer. In addition, CCNE1 frequently amplified over-expressed cancers including ovarian, pre-clinical data linking sensitivity high CCNE1....
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin with poor patient overall survival rate. While Bruton tyrosine kinase inhibitors (BTKis) have shown benefit in relapsed/refractory MCL (Wang M, et al., 2018; Song Y, al.,2020; Wang ML 2013) portion of patients eventually progress. Here, we explored which biomarkers might be associated resistance to acalabrutinib, second generation BTKi, by analyzing samples from who were on treatment or progressed acalabrutinib the...
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...
Immuno-oncology (IO) research relies heavily on murine syngeneic tumor models. However, whilst the average age for a cancer diagnosis is 60 years or older, practical purposes majority of preclinical studies are conducted in young mice, despite fact that ageing has been shown to have significant impact immune response.Using aged (60-72 weeks old) mice bearing CT26 tumors, we investigated growth as well composition and peripheral lymphoid organs.We found many differences cell both...
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 Antitumor immunity can be hampered by immunosuppressive mechanisms in the tumor microenvironment, including recruitment of arginase (ARG) expressing myeloid cells that deplete l-arginine essential for optimal T-cell and natural killer cell function. Hence, ARG inhibition reverse immunosuppression enhancing antitumor immunity. We describe AZD0011, a novel peptidic boronic acid prodrug to deliver an orally available, highly potent, inhibitor payload (AZD0011-PL). demonstrate...
Abstract Cyclin-dependent Kinase 2 (CDK2) is a Ser/Thr kinase activated via interaction with its cyclin partners CCNE and CCNA, driving G1/S progression of the cell cycle. CDK2 inhibition has potential to address multiple resistance mechanisms CDK4/6 inhibitors in breast cancer. In addition, CCNE1 frequently amplified over-expressed cancers including ovarian, uterine, breast, gastric others, pre-clinical data linking sensitivity high CCNE1. The inhibitor field historically suffered from...
Abstract The tumor microenvironment (TME) has multiple mechanisms of immune-suppression, one being recruitment arginase (ARG) expressing myeloid cells. ARG is an enzyme that catalyzes hydrolysis L-arginine into urea and L-ornithine. a semi-essential amino acid required for optimal function T cells natural killer (NK) Arginine depletion in the TME inhibits cell NK function. Therefore, inhibition can reverse immune-suppression optimize anti-tumor immunity. To determine dependence to arginine,...
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<div>Abstract<p>Anti-tumor immunity can be hampered by immunosuppressive mechanisms in the tumor microenvironment including recruitment of arginase (ARG) expressing myeloid cells which deplete L-arginine essential for optimal T cell and natural killer function. Hence, ARG inhibition reverse immunosuppression enhancing anti-tumor immunity. We describe AZD0011, a novel peptidic boronic acid prodrug to deliver an orally available, highly potent, inhibitor payload (AZD0011-PL)....
<p>Supplementary Figure 5</p>
<p>Supplementary Figure 4</p>
<p>Supplementary Figure 3</p>
<p>Supplementary Figure 1</p>