A5019761569- Cancer Immunotherapy and Biomarkers
- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- CAR-T cell therapy research
- Advanced Breast Cancer Therapies
- Radiopharmaceutical Chemistry and Applications
- Nanoparticle-Based Drug Delivery
- Synthesis and pharmacology of benzodiazepine derivatives
- Peptidase Inhibition and Analysis
- DNA Repair Mechanisms
- Calpain Protease Function and Regulation
- Cancer therapeutics and mechanisms
- Immune cells in cancer
- Wnt/β-catenin signaling in development and cancer
- Genomics and Chromatin Dynamics
- Nanoplatforms for cancer theranostics
- Immunotherapy and Immune Responses
- CRISPR and Genetic Engineering
- Cancer Cells and Metastasis
- RNA Interference and Gene Delivery
- Chemokine receptors and signaling
- 14-3-3 protein interactions
- Lung Cancer Treatments and Mutations
- Neuroblastoma Research and Treatments
- Drug Transport and Resistance Mechanisms
Incyte (United States)
2018-2023
Wilmington University
2023
Teledyne Technologies (United States)
2009-2012
Intezyne (United States)
2009-2012
Moffitt Cancer Center
2006-2009
University of Michigan
2001-2004
Harvard University
2004
University Hospital Ulm
2003
MEDI9447 is a human monoclonal antibody that specific for the ectoenzyme CD73 and currently undergoing Phase I clinical trials. Here we show potent inhibitor of ectonucleotidase activity, with wide ranging immune regulatory consequences. results in relief from adenosine monophosphate (AMP)-mediated lymphocyte suppression vitro inhibition mouse syngeneic tumor growth vivo. In contrast other cancer immunotherapy agents such as checkpoint inhibitors or T-cell agonists, drives changes both...
Blocking the activity of programmed cell death protein 1 (PD-1) inhibitory receptor with therapeutic antibodies against either ligand (PD-L1) or PD-1 itself has proven to be an effective treatment modality for multiple cancers. Contrasting antibodies, small molecules could demonstrate increased tissue penetration, distinct pharmacology, and potentially enhanced antitumor activity. Here, we describe identification characterization INCB086550, a novel, oral, small-molecule PD-L1 inhibitor. In...
Based on the previously described roles of doxorubicin in immunogenic cell death, both and liposomal (Doxil) were evaluated for their ability to boost antitumor response different cancer immunotherapies including checkpoint blockers (anti-PD-L1, PD-1, CTLA-4 mAbs) TNF receptor agonists (OX40 GITR ligand fusion proteins) syngeneic mouse models. In a preventative CT26 tumor model, Doxil synergized with anti-PD-1 mAbs. was active when tumors grown immunocompetent mice but not immunocompromised...
Immunogenic cell death (ICD) is the process by which certain cytotoxic drugs induce apoptosis of tumor cells in a manner that stimulates immune system. In this study, we investigated whether antibody-drug conjugates (ADCS) conjugated with pyrrolobenzodiazepine dimer (PBD) or tubulysin payloads ICD, modulate microenvironment, and could combine immuno-oncology to enhance antitumor activity. We show these on their own induced an response prevented growth tumors following subsequent challenge....
The E-cadherin protein mediates Ca(2+)-dependent interepithelial adhesion. Association of with the catenin family proteins is critical for maintenance a functional adhesive complex. We have identified novel truncated species 100-kDa (E-cad(100)) in prostate and mammary epithelial cells. E-cad(100) was generated by treatment cells ionomycin or TPA. Cell-permeable calpain inhibitors prevented induction ionomycin. Immunoblotting spectrin mu-calpain confirmed activation response to treatment....
Background Preclinical evaluation of drugs targeting the human immune system has posed challenges for oncology researchers. Since commercial introduction humanized mice, antitumor efficacy and pharmacodynamic studies can now be performed with cancer cells within mice bearing components a system. However, development characterization these models is necessary to understand which model may best suited different agents. Methods We characterized A375, A549, Caki-1, H1299, H1975, HCC827, HCT116,...
ADAM17 is the primary sheddase for HER pathway ligands. We report discovery of a potent and specific inhibitory antibody, MEDI3622, which induces tumor regression or stasis in many EGFR-dependent models. The activity MEDI3622 correlated with EGFR both series models across several indications as well focused set head neck patient-derived xenograft antitumor was superior to that EGFR/HER inhibitors OE21 esophageal model COLO205 colorectal suggesting additional outside pathway. Combination...
Chemotherapeutic drugs are widely used for the treatment of cancer; however, use these is often associated with patient toxicity and poor tumor delivery. Micellar drug carriers offer a promising approach formulating achieving improved delivery hydrophobic chemotherapeutic drugs; conventional micelles do not have long-term stability in complex biological environments such as plasma. To address this problem, novel triblock copolymer has been developed to encapsulate several different into...
TYRO3, AXL, and MERTK constitute the TAM family of receptor tyrosine kinases, which play important roles in tumor growth, survival, cell adhesion, as well innate immunity, phagocytosis, immune-suppressive activity. Therefore, targeting both AXL kinases may directly impact growth relieve immunosuppression. We describe here discovery INCB081776, a potent selective dual inhibitor that is currently phase 1 clinical trials. In cellular assays, INCB081776 effectively blocked autophosphorylation or...
Abstract Mutations in the NH2-terminal regulatory domain of β-catenin gene lead to aberrant stabilization and accumulation protein increased TCF/LEF-dependent transcription. Although these mutations are common some cancers, they infrequent prostate breast cancer. We have found that metastatic cancer specimens, obtained through a rapid autopsy tissue procurement program, expressed novel Mr 75,000 proteolytic fragment (β-cat75). β-Cat75 was also multiple cell lines closely associated with...
ADAM17 (a disintegrin and metalloproteinase 17)/TACE (TNFα converting enzyme) has emerged as a potential therapeutic target in colorectal cancer (CRC) other cancers, due part to its role regulating various tumor cell surface proteins growth factors cytokines the microenvironment. The emergence of MEDI3622, highly potent specific antibody-based inhibitor, allowed testing concept that targeting may be an important new approach for CRC patients. We demonstrate MEDI3622 is efficacious on...
Polymer micelles are promising drug delivery vehicles for the of anticancer agents to tumors. Often, drugs display potent cytotoxic effects towards cancer cells but too hydrophobic be administered in clinic as a free drug. To address this problem, polymer micelle was designed using triblock copolymer (ITP-101) that enables encapsulated. An SN-38 encapsulated micelle, IT-141, prepared exhibited vitro cytotoxicity against wide array cell lines. In mouse model, pharmacokinetic analysis revealed...
Recent evidence from a wide variety of biological systems has indicated important regulatory roles for post-translation histone modifications in cellular processes such as regulation gene expression, DNA damage response and recombination. Phosphorylation H2AX at serine 139 is critical event the to damage, but functional implications this modification are not yet clear. To investigate role phosphorylation we ectopically expressed epitope-tagged or mutants site. GFP-tagged wild type H2AX,...
E-cadherin, a fundamental component of the adherens junction, is known to mediate aggregation-dependent cell survival. We have previously identified novel, calpain-dependent proteolytic cleavage E-cadherin that resulted in generation stable 100-kDa fragment (E-cad(100)) prostate epithelial cells response death stimuli. postulated E-cad(100) may play role abrogating survival LNCaP following induction apoptosis.Wild-type and were engineered, tagged with GFP, stably expressed cells. These lines...
Abstract Tyro-3, Axl, and Mer constitute the TAM family of receptor tyrosine kinases (RTKs), which are amplified, translocated, or over-expressed in numerous types human cancer. These RTKs play important roles tumor growth, survival, cell adhesion migration as well drug resistance. In addition, it has been shown that both AXL MER critical regulators innate immunity, phagocytosis, immune-suppressive activity. Therefore targeting may not only impact survival malignant progression neoplastic...
Phosphorylation of histone H2AX at Serine 139 is one the earliest events after DNA damage and required for retention factors involved in repair site break. Intriguingly, phosphorylation spreads from vicinity break to both directions spanning large chromosomal regions. Phosphorylated (also known as ?-H2AX) then progressively disappears with kinetics that correlates completion repair. Despite intense investigation on kinases stimuli ?-H2AX formation, mechanism disappearance has remained...
Abstract Drugs that target cancer stem cells (CSCs) are thought to be a critical component of any successful therapy against cancer. CSCs responsible for chemoresistance, metastasis, and ultimately relapse the cancer, even after an initial therapeutic intervention. While it is well known driven by some same major self-renewal pathways drive embryonic cells, knowledge other cellular CSC activity still limited. In this work, we uncover novel role chemokine (C-C motif) ligand 20 (CCL20) in...
Abstract Transforming growth factor-β (TGFβ) signaling is common in many solid tumors and initiated by binding of the high affinity canonical ligands TGFβ1, 2, οr 3 to TGFβR2, which forms a heteromeric receptor complex with TGFβR1 (Derynck et al, Nature Review Clinical Oncology 2020). Activation pathway results potent suppression immune cell-mediated anti-tumor immunity has been reported predict poor response PD-(L)1 targeted therapy patients (Mariathasan 2018; Kieffer Cancer Discovery...
Supplementary Figure from Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor
Green fluorescent protein (GFP) has become a powerful tool for monitoring the expression of transfected genes by flow cytometry including GFP-tagged histones tracking chromatin and elucidating histone function. We describe here method simultaneous detection three nucleus-localized signals: histone, DNA content phosphorylated H3, which labels mitotic cells. also demonstrate another application this content, cleaved caspase-3.
Abstract Immunogenic cell death (ICD) is the process by which certain cytotoxic drugs induce apoptosis of tumor cells in a manner that stimulates immune system. In this study, we investigated whether ADCs conjugated with pyrrolobenzodiazepine dimer (PBD) or tubulysin payloads induced ICD, modulated microenvironment, and could combine IO to enhance antitumor activity. We show these on their own an response prevented growth tumors following subsequent challenge. had greater activity...