A5053603997- Fibroblast Growth Factor Research
- Eosinophilic Disorders and Syndromes
- Kruppel-like factors research
- Microtubule and mitosis dynamics
- Epigenetics and DNA Methylation
- Axon Guidance and Neuronal Signaling
- Liver physiology and pathology
- Ubiquitin and proteasome pathways
- Gastrointestinal disorders and treatments
- Organometallic Complex Synthesis and Catalysis
- IgG4-Related and Inflammatory Diseases
- Advanced Polymer Synthesis and Characterization
- Neuroendocrine Tumor Research Advances
- Caveolin-1 and cellular processes
- Lanthanide and Transition Metal Complexes
- Cancer Genomics and Diagnostics
- Protein Kinase Regulation and GTPase Signaling
- Angiogenesis and VEGF in Cancer
- Monoclonal and Polyclonal Antibodies Research
- Retinoids in leukemia and cellular processes
- PI3K/AKT/mTOR signaling in cancer
- Computational Drug Discovery Methods
- Cellular Mechanics and Interactions
- Hippo pathway signaling and YAP/TAZ
- Plant Molecular Biology Research
Relay Therapeutics (United States)
2023-2024
Sage Therapeutics (United States)
2021
Merrimack Pharmaceuticals (United States)
2015-2019
Center for Cancer Research
2011-2012
Harvard University
2011-2012
Massachusetts General Hospital
2011-2012
Duke University
2005
Abstract Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting FGFR2 has not been achieved. Although the clinical efficacy pan-FGFR inhibitors (pan-FGFRi) validates driver status in fusion–positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- FGFR4-mediated toxicities (hyperphosphatemia diarrhea, respectively) emergence...
Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring FGFR2 alterations, but toxicity these drugs frequently leads dose reduction or interruption such that maximum efficacy cannot achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition diarrhea due FGFR4 inhibition, as current therapies not selective among FGFRs. Designing has...
Individual cell types are defined by architecturally and functionally specialized cortical domains. The Ezrin, Radixin, Moesin (ERM) proteins play a major role in organizing domains assembling membrane protein complexes linking them to the actin cytoskeleton. Many studies have focused on individual roles of ERM stabilizing membrane-cytoskeleton interface, controlling distribution function apical complexes, regulating small GTPase Rho, or establishing cell-cell junctions. We previously found...
The ability to generate asymmetry at the cell cortex underlies polarization and asymmetric division. Here we demonstrate a novel role for tumor suppressor Merlin closely related ERM proteins (Ezrin, Radixin, Moesin) in generating cortical absence of external cues. Our data reveal that functions restrict distribution actin regulator Ezrin, which turn positions interphase centrosome single epithelial cells three-dimensional organotypic cultures. In Merlin, ectopic Ezrin yields mispositioned...
Activation of the Met receptor tyrosine kinase, either by its ligand, hepatocyte growth factor (HGF), or via ligand-independent mechanisms, such as MET amplification overexpression, has been implicated in driving tumor proliferation, metastasis, and resistance to therapy. Clinical development Met-targeted antibodies challenging, however, bivalent exhibit agonistic properties, whereas monovalent lack potency capacity down-regulate Met. Through computational modeling, we found that a antibody...
Abstract FGFR2 fusions, amplifications, and mutations are oncogenic drivers that occur across multiple tumor types. Clinical efficacy observed with pan-FGFR inhibitors has validated the driver status of in fusion-positive intrahepatic cholangiocarcinoma (ICC), however, FGFR1-mediated toxicities (hyperphosphatemia, tissue mineralization) emergence on-target resistance limit inhibitors. To overcome these limitations, we designed RLY-4008, a potent highly selective, inhibitor. Despite...
Degradation of specific protein substrates by the anaphase-promoting complex/cyclosome (APC) is critical for mitotic exit. We have identified Xenopus nuclear factor 7 (Xnf7) as a novel APC inhibitor able to regulate timing exit from mitosis. Immunodepletion Xnf7 laevis egg extracts accelerated degradation cyclin B1, B2, and securin upon release cytostatic arrest, whereas excess inhibited activity. Interestingly, exhibited intrinsic ubiquitin ligase activity, this activity was required...
Abstract Purpose: MM-131 is a purely antagonistic, bispecific antibody that potently inhibits HGF/c-Met signaling by co-targeting the widely expressed tumor antigen EpCAM. The purpose of these studies to uncover mechanism which exhibits potent inhibition both HGF-dependent and HGF-independent c-Met in EpCAM positive cells. Methods: To assess role mediating avid binding c-Met, we quantified cell surface levels panel cancer lines using flow cytometry determined how each line. Using data, built...
<div>Abstract<p>Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting FGFR2 has not been achieved. Although the clinical efficacy pan-FGFR inhibitors (pan-FGFRi) validates <i>FGFR2</i> driver status in fusion–positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- FGFR4-mediated toxicities...
<p>ReFocus entry criteria</p>
<p>ReFocus entry criteria</p>
<p>three references cited in supplementary data</p>
<p>Supplementary Figure 1. RLY-4008 is an irreversible inhibitor of FGFR2.</p>
<p>Supplementary Figure 1. RLY-4008 is an irreversible inhibitor of FGFR2.</p>
<p>Supplementary Figure 2. Treatment with RLY-4008 is well-tolerated and leads to dose-dependent inhibition of FGFR2 tumor regression in multiple FGFR2-altered models.</p>
<div>Abstract<p>Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting FGFR2 has not been achieved. While the clinical efficacy pan-FGFR inhibitors (pan-FGFRi) validates driver status in fusion-positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- FGFR4-mediated toxicities (hyperphosphatemia diarrhea) emergence...
<p>Supplementary Figure 2. Treatment with RLY-4008 is well-tolerated and leads to dose-dependent inhibition of FGFR2 tumor regression in multiple FGFR2-altered models.</p>
<p>three references cited in supplementary data</p>