A5085430315- Cancer Mechanisms and Therapy
- PARP inhibition in cancer therapy
- Peptidase Inhibition and Analysis
- Cancer Immunotherapy and Biomarkers
- Multiple Myeloma Research and Treatments
- Cancer-related Molecular Pathways
- Hedgehog Signaling Pathway Studies
- Cancer Research and Treatments
- Ferroptosis and cancer prognosis
- Cancer Genomics and Diagnostics
- Pancreatic and Hepatic Oncology Research
- Galectins and Cancer Biology
- Mechanisms of cancer metastasis
- interferon and immune responses
- Cancer Cells and Metastasis
- Genomic variations and chromosomal abnormalities
- Advanced Breast Cancer Therapies
- Epigenetics and DNA Methylation
- Chronic Lymphocytic Leukemia Research
- Animal Genetics and Reproduction
- Cancer, Hypoxia, and Metabolism
- Cytokine Signaling Pathways and Interactions
- Histone Deacetylase Inhibitors Research
- Adenosine and Purinergic Signaling
- Advanced Biosensing Techniques and Applications
Ribon Therapeutics (United States)
2021-2023
Tesaro (United States)
2017-2021
AstraZeneca (United States)
2009-2018
AstraZeneca (United Kingdom)
2013
University of Michigan
2013
Amgen (Canada)
2013
Michigan Center for Translational Pathology
2013
Kala Pharmaceuticals (United States)
2010
Dartmouth College
2002-2003
Abstract Purpose: To determine the tumor tissue/cell distribution, functional associations, and clinical significance of PD-1, LAG-3, TIM-3 protein expression in human non–small cell lung cancer (NSCLC). Experimental Design: Using multiplexed quantitative immunofluorescence, we performed localized measurements CD3, >800 clinically annotated NSCLCs from three independent cohorts represented tissue microarrays. Associations between marker's major genomic alterations were studied The...
Proviral integration Moloney virus (PIM) kinases (PIM1, 2 and 3) are overexpressed in several tumour types contribute to oncogenesis. AZD1208 is a potent ATP-competitive PIM kinase inhibitor investigated patients with recurrent or refractory acute myeloid leukaemia (AML) advanced solid tumours. Two dose-escalation studies were performed evaluate the safety tolerability, define maximum tolerated dose (MTD), of AML Secondary objectives pharmacokinetics, pharmacodynamics (PD) preliminary...
MET, the receptor for hepatocyte growth factor (HGF), plays an important role in signaling normal and tumor cell migration invasion. Here, we describe a previously unrecognized mechanism that promotes MET expression multiple types. The levels of Pim-1 protein kinase show positive correlation with human lines patient-derived materials. Using small interfering RNA (siRNA), Pim knockout mice, small-molecule inhibitors, overexpression Pim-1, confirmed this found activity regulates HGF-induced...
New immuno-oncology therapies targeting programmed cell death receptor 1 (PD-1) have improved patient outcomes in a broad range of cancers. The objective this analysis was to evaluate the PK, pharmacodynamics (PDy), and safety dostarlimab monotherapy adult patients with previously-treated advanced solid tumors who participated parts 2A phase GARNET study.Part featured 3 + weight-based dose-escalation study, which 21 received 1, 3, or 10 mg/kg intravenously every 2 weeks. fixed-dose...
The hedgehog pathway has been implicated in the tumorigenesis, tumor progression, and metastasis of numerous human cancers. We generated first fully antibody MEDI-5304 characterized its antitumor activity preclinical toxicology. bound sonic (SHH) Indian (IHH) with low picomolar affinity neutralized SHH IHH cellular mGLI1 reporter assays. inhibited transcription target genes osteoblast differentiation C3H10T1/2 cells. evaluated vivo model systems that allowed us to evaluate two primary...
3000 Background: Targeting cytosolic nucleic acid sensing pathways and the Type I interferon (IFN) response is an emerging therapeutic strategy in oncology. PARP7 a member of monoPARP class enzymes newly identified negative regulator tumor cells. expression increased by cellular stress aromatic hydrocarbons, gene amplified multiple cancers. RBN-2397 potent, selective inhibitor PARP7. In preclinical models, restored IFN signaling tumors, caused complete regressions, induced adaptive immunity....
Abstract Introduction: TSR-042 is a humanized monoclonal antibody targeting programmed death (PD)-1, effectively blocking interaction with its ligands PD-L1 and PD-L2. being evaluated in patients (pts) advanced solid tumors the ongoing phase 1 GARNET trial (NCT02715284). Weight based dose escalation (Part 1) fixed-dose safety studies 2A) have been completed,1 study currently enrolling pts specific tumor types into expansion cohorts. Here, we present efficacy data from microsatellite...
The global changes in gene expression induced by transient increased of full length BRCA1 as well the spliced variant BRCA1(S) were evaluated cDNA array a human non-tumorigenic mammary epithelial cell line, MCF10A. Over 30 genes identified that displayed an altered pattern response to splice variants. NFkappaB inducing kinase was markedly down-regulated BRCA1(L) transfected cells. However, NFkappaB-responsive promoter construct yielded basal activity cells, following treatment with tumor...
<h3>Background</h3> PARP7 is a mono-ART that upregulated in response to cellular stress (e.g., viral infection, cigarette smoke), and suppresses the Type I interferon (IFN) following cytosolic nucleic acid sensing. RBN-2397 first-in-class inhibitor, inducing cancer cell autonomous immune stimulatory effects preclinical models through enhanced IFN signaling cells. Moreover, induces CD8 T cell-dependent tumor-specific memory an immunocompetent mouse model.<sup>1</sup> currently being tested...
Abstract The Pim serine/threonine kinase family is composed of three highly homologous members; Pim-1, Pim-2 and Pim-3, identified by the ability prototype member Pim-1 to drive lymphomagenesis in mice. Upregulation observed leukemias lymphomas, including AML, NHL CLL, highlighting potential these kinases as therapeutic targets indications. Overexpression or Pim-3 has also been prostate, pancreatic, gastric, bladder hepatocellular cancers. are downstream effectors many cytokine growth factor...
Abstract Background: PARP7 is a stress-induced monoART that suppresses the cellular type I interferon (IFN) response following cytosolic nucleic acid sensing. RBN-2397 first-in-class inhibitor induces IFN and an adaptive immune response. The tumor-intrinsic immunomodulatory mechanism of preliminary antitumor activity in patients (pts) was demonstrated during dose escalation (Falchook, ASCO 2021; Kuplast-Barr, AACR 2022). Methods: Pts with solid tumors were treated at RP2D 200 mg BID 3...
Abstract The process of mitosis is a validated point intervention in cancer therapy and variety anti-mitotic drugs are successfully being used the clinic. To date, all approved antimitotics target spindle microtubules, thus interfering with dynamics, leading to mitotic arrest apoptosis. While effective, these also associated side effects, including neurotoxicity. In recent years, kinesins have attracted significant attention search for novel, alternative drug targets. addition, kinesin...
PARP14 is an enzyme of the ADP-ribosyltransferase (ART) family which modifies its substrates by ADP-ribosylation. Published work suggests that promotes Th2/Th17 signaling in immune cells amplifying STAT6- and STAT3-driven transcription, thereby modulating inflammation. expression promoted interferons TLR agonists many cell types, including epithelial cells. Tissue analysis from patients with inflammation lung, skin, colon shows increased structural affected organs, compared to normal...
Abstract AZD1208 is a potent oral ATP-competitive, pan-PIM kinase inhibitor. Here we report the results of 2 Phase 1, open-label, multi-center dose escalation studies, recruiting patients with recurrent or refractory AML advanced solid tumors including malignant lymphoma. The studies examined safety, tolerability, pharmacokinetics and preliminary efficacy in evaluation pharmacodynamic biomarkers study. study was first-in-patient where 32 were treated range treatment duration ranged from 15...