A5021078557- Lung Cancer Treatments and Mutations
- HER2/EGFR in Cancer Research
- Monoclonal and Polyclonal Antibodies Research
- Radiopharmaceutical Chemistry and Applications
- Prostate Cancer Treatment and Research
- Cancer Treatment and Pharmacology
- RNA modifications and cancer
- Cancer therapeutics and mechanisms
- Hemoglobinopathies and Related Disorders
- Lung Cancer Research Studies
- Genomics and Chromatin Dynamics
- Epigenetics and DNA Methylation
- Acute Myeloid Leukemia Research
- Colorectal Cancer Treatments and Studies
- Advanced Breast Cancer Therapies
- Pancreatic and Hepatic Oncology Research
- Cancer, Hypoxia, and Metabolism
- Medical Imaging Techniques and Applications
- Immune Cell Function and Interaction
- Lung Cancer Diagnosis and Treatment
- Phagocytosis and Immune Regulation
- RNA and protein synthesis mechanisms
- T-cell and B-cell Immunology
- CRISPR and Genetic Engineering
- CAR-T cell therapy research
Dana-Farber Cancer Institute
1997-2023
Daiichi Sankyo (United States)
2017-2023
Harvard University
1963-2021
Broad Institute
2016-2021
Daiichi Sankyo (Germany)
2021
Daiichi-Sankyo (South Korea)
2021
Osaka International Cancer Institute
2019
Osaka National Hospital
2019
Sapporo National Hospital
2019
National Cancer Center Hospital East
2019
Features of chronic asthma include airway hyperresponsiveness, inflammatory infiltrates, and structural changes in the airways, termed remodeling. The contribution eosinophils, cells associated with allergy, remains to be established. We show that mice a total ablation eosinophil lineage, increases hyperresponsiveness mucus secretion were similar those observed wild-type mice, but eosinophil-deficient significantly protected from peribronchiolar collagen deposition smooth muscle. These data...
Transcription factor GATA-1 reprograms immature myeloid cells to three different hematopoietic lineages-erythroid cells, megakaryocytes, and eosinophils. is essential for maturation of erythroid megakaryocytic precursors, as revealed by gene targeting in mice. Here we demonstrate that deletion a high-affinity GATA-binding site the promoter, an element presumed mediate positive autoregulation expression, leads selective loss eosinophil lineage. These findings suggest required specification...
Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR-mutated lung cancers but not a known mechanism of resistance to EGFR inhibitors. HER3-DXd an antibody-drug conjugate consisting HER3 antibody attached topoisomerase I inhibitor payload via tetrapeptide-based cleavable linker. This phase I, dose escalation/expansion study included patients with locally advanced or metastatic non-small cell cancer (NSCLC) prior tyrosine (TKI) therapy. Among 57 receiving 5.6 mg/kg...
The zinc finger transcription factor GATA-1 is essential for erythropoiesis. In its absence, committed erythroid precursors arrest at the proerythroblast stage of development and undergo apoptosis. To study function in an cell environment, we generated line from vitro-differentiated GATA-1− murine embryonic stem (ES) cells. These cells, termed G1E erythroid, proliferate as immature erythroblasts yet complete differentiation upon restoration function. We used rescue terminal maturation cells...
Most patients with KIT-mutant gastrointestinal stromal tumours (GISTs) benefit from imatinib, but treatment resistance results outgrowth of heterogeneous subclones KIT secondary mutations. Once emerges, targeting tyrosine kinase inhibitors (TKIs) sunitinib and regorafenib provides clinical benefit, albeit limited duration. We systematically explored GIST mechanisms to KIT-inhibitor TKIs that are either approved or under investigation in trials: the studies draw upon models trial correlative...
Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard-of-care treatment for EGFR-mutant non–small cell lung cancers (NSCLC). However, most patients develop acquired drug resistance to EGFR TKIs. HER3 is a unique pseudokinase member of ERBB family that functions by dimerizing with other members (EGFR and HER2) frequently overexpressed in NSCLC. Although TKI mechanisms do not lead alterations HER3, we hypothesized targeting might improve efficacy...
Abstract Aurora kinases B and C (AURKB/AURKC) are activated by binding to the C-terminal domain of INCENP. Full activation requires phosphorylation two serine residues INCENP that conserved through evolution, although mechanism this has not been explained. Here we present crystal structures fully active complex AURKC bound INCENP, consisting phosphorylated, activated, phosphorylated on its TSS motif, revealing structural biochemical synergistic AURKC:INCENP. The show motif stabilises kinase...
9007 Background: Patients (pts) with advanced EGFRm NSCLC have limited treatment options after failure of EGFR TKI and platinum-based chemotherapy (PBC). HER3-DXd is an antibody drug conjugate consisting a fully human monoclonal to HER3 attached topoisomerase I inhibitor payload via tetrapeptide-based cleavable linker. We previously presented efficacy/safety data (median follow-up, 5.4 mo) from ongoing study in therapy. now present extended follow-up pts receiving the recommended dose for...
9010 Background: Treatment options are limited for EGFRm NSCLC resistant to EGFR TKIs. HER3 is expressed in a majority of tumors. U3-1402 HER3-targeted antibody drug conjugate with fully human antibody, novel cleavable peptide-based linker, and topoisomerase I inhibitor payload. Methods: An ongoing multicenter phase 1 dose escalation expansion study assessing safety/tolerability preliminary activity metastatic or unresectable patients (pts) who T790M negative after disease progression while...
2512 Background: U3-1402 is a human epidermal growth factor receptor 3 (HER3)-targeting antibody-drug conjugate (ADC) of high drug-to-antibody-ratio (DAR: 7 to 8) with novel linker and topoisomerase I inhibitor payload. HER3 overexpressed in variety cancers, including breast, lung, colorectal, ovarian, prostate urothelial cancer. This ongoing, Phase 1/2 study (NCT02980341) HER3-expressing metastatic breast cancer (MBC) divided into three parts: dose escalation (Part 1), finding 2), expansion...
Abstract Background: Human epidermal growth factor receptor 3 (HER3) is overexpressed in a variety of solid tumors, including breast cancer. However, there are no approved HER3-targeted anti-cancer therapies. U3-1402 antibody drug conjugate with novel peptide-based cleavable linker attached to potent topoisomerase I inhibitor payload. It has high drug-to-antibody ratio (7:1 8:1), which stable plasma and selectively cleaved by lysosomal cathepsins up-regulated cancer cells, payload short...
Androgen receptor (AR) inhibition can upregulate c-MET expression, which may be a resistance mechanism driving progression of castration-resistant prostate cancer (CRPC). We conducted phase I trial investigating the safety and pharmacokinetics potent inhibitor, crizotinib, with AR antagonist, enzalutamide, in CRPC.Employing 3+3 dose-escalation design, we tested three dose levels crizotinib (250 mg daily, 200 twice day, 250 day) standard-dose enzalutamide (160 daily). The primary endpoint was...
Many transcriptional regulators function in homo- or heterodimeric combinations. The same protein can carry out distinct regulatory functions depending on the partner with which it associates. Here, we describe a mutant of Escherichia coli cAMP receptor (CRP) that has an altered dimerization specificity; is, mutant/mutant homodimers form preferentially over wild-type/mutant heterodimers. CRP involves formation parallel coiled-coil structure, and our bears amino acid substitution affecting...
TPS1116 Background: There is a need for effective late-line treatments in metastatic breast cancer. HER3 overexpression cancer associated with poor prognosis, but there as yet no approved targeted treatment against HER3. U3-1402 novel antibody-drug conjugate (ADC) comprised of fully humanized anti-HER3 antibody (patritumab) covalently conjugated via cleavable peptide linker to derivative the topoisomerase I inhibitor exatecan. After binds on tumor cell surface, it internalized and leads...