A5001703655- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Epigenetics and DNA Methylation
- Phagocytosis and Immune Regulation
- Cancer Mechanisms and Therapy
- Cancer Research and Treatments
- Cancer-related Molecular Pathways
- Peptidase Inhibition and Analysis
- Ubiquitin and proteasome pathways
- Microtubule and mitosis dynamics
- Neuroblastoma Research and Treatments
- Fibroblast Growth Factor Research
- Cancer Genomics and Diagnostics
- Cancer, Hypoxia, and Metabolism
- Cancer-related gene regulation
- Monoclonal and Polyclonal Antibodies Research
- Cell Adhesion Molecules Research
- Signaling Pathways in Disease
- MicroRNA in disease regulation
- 14-3-3 protein interactions
- RNA modifications and cancer
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Gastrointestinal Tumor Research and Treatment
- Sarcoma Diagnosis and Treatment
- Tuberous Sclerosis Complex Research
Basilea Pharmaceutica (Switzerland)
2019-2024
University Health Network
2023
Harvard University
2010-2014
Massachusetts General Hospital
2010-2014
Hospital for Sick Children
2014
Wellcome Sanger Institute
2012
Beth Israel Deaconess Medical Center
2010
Dana-Farber Cancer Institute
2010
Institute of Molecular Biology
2007-2008
Philipps University of Marburg
2007
Squamous cell carcinoma (SCC) is a treatment-refractory subtype of human cancer arising from stratified epithelium the skin, lung, esophagus, oropharynx, and other tissues. A unifying feature SCC high-level expression p53-related protein p63 (TP63) in 80% cases. The major isoform expressed ΔNp63α, an N-terminally truncated form which functions as key survival factor by mechanisms that are unclear. In this study, we show ΔNp63α associates with histone deacetylase 1 (HDAC1) HDAC2 to active...
African trypanosomes are the causative agent of sleeping sickness. The therapeutics used to control and treat disease very ineffective thus, development improved drugs is urgently needed. Recently, new strategies for design novel trypanocidals have been put forward. Among them techniques that rely on parasite-specific RNA aptamers. One approach involves aptamer-directed transport lytic compounds lysosome parasite. aptamer has termed 2-16 here we report optimization its applications in vivo....
The p53 tumor suppressor, a central mediator of chemosensitivity in normal cells, is functionally inactivated many human cancers. Therefore, challenge cancer therapy the identification pathways that control cell survival and absence functional p53. p53-related transcription factors p63 p73 exhibit distinct functions—p73 mediates while promotes proliferation survival—and are both overexpressed squamous carcinomas (SCCs). However, how interact govern balance between prosurvival proapoptotic...
Effective targeted therapeutics for squamous cell carcinoma (SCC) are lacking. Here, we uncover Mcl-1 as a dominant and tissue-specific survival factor in SCC, providing roadmap new therapeutic approach. Treatment with the histone deacetylase (HDAC) inhibitor vorinostat regulates Bcl-2 family member expression to disable axis thereby induce apoptosis SCC cells. Although dominance renders cells resistant BH3-mimetic ABT-737, primes them sensitivity ABT-737 by shuttling Bim from Bcl-2/Bcl-xl,...
The progression from preinvasive lesion to invasive carcinoma is a critical step contributing breast cancer lethality. We identified downregulation of milk fat globule-EGF factor 8 (MFG-E8) as contributor using microarray analysis laser capture microdissected (LCM) tissues. first MFG-E8 in lesions transgenic mammary tumor models, which were confirmed LCM-isolated human ductal carcinomas compared with patient-matched normal In situ analyses expression estrogen receptor (ER) positive cases its...
<h3>Purpose</h3> To identify the genetic cause of autosomal-dominant pattern dystrophy (PD) retinal pigment epithelium (RPE) in two families. <h3>Methods and results</h3> Two families with PD were identified. Eight members family 1 (five affected) subjected to whole-genome SNP genotyping; multipoint genome-wide linkage analysis identified 7 regions potential linkage, genotyping four additional individuals from resulted a maximum logarithm odds score 2.09 observed across chromosomal regions....
Lipoprotein(a) [Lp(a)] was measured by both a radial immunodiffusion (RID) kit from Immuno AG (Zurich, Switzerland) and Tint Elize enzyme-linked immunosorbent assay (ELISA) CytRx Biopool Ltd. (Umeå, Sweden) in serum samples that had been stored at -20 -70 degrees C for six months. Storage temperature no significant effect on the Lp(a) concentrations obtained either method. After months, mean degradation 46% (95% confidence interval, 34-58%) with RID kit; ELISA data could not be compared...
Abstract Conditional knock-in mice expressing a histone acetyltransferase-deficient version of the transcriptional coregulator p300 exclusively in B lymphocytes die prematurely with full penetrance. The develop an autoimmune disease similar to systemic lupus erythematosus its pathological manifestations, such as splenomegaly, glomerulonephritis, vasculitis, deposition immune complexes, and production autoantibodies against dsDNA. Aged show severe reduction transitional marginal zone cells...
Background Threonine tyrosine kinase (TTK) and polo-like 1 (PLK1) are common essential kinases that collaborate in activating the spindle assembly checkpoint (SAC) at kinetochore, ensuring appropriate chromosome alignment segregation prior to mitotic exit. Targeting of either TTK or PLK1 has been clinically evaluated cancer patients; however, dual inhibitors have not yet pursued. Here we present vitro vivo characterization a first class, TTK/PLK1 inhibitor (BAL0891). Methods Mechanism action...
Derazantinib (DZB) is an inhibitor of fibroblast growth factor receptors 1-3 (FGFR1-3), with additional activity against colony-stimulating-factor-1 receptor (CSF1R). We have profiled the DZB in gastric cancer (GC) as monotherapy and combined paclitaxel, explored means stratifying patients for treatment. The antiproliferative potency vitro was quantified 90 tumor cell lines shown to correlate significantly FGFR expression (<0.01) but not DNA copy-number (CN) or mutations. In four GC , little...
Abstract Background: DZB is an oral small-molecule Fibroblast Growth Factor Receptor 1/2/3 inhibitor (FGFRi) with clinically relevant activity in FGFR2-fusion cholangiocarcinoma. Extensive kinase profiling identified Colony-Stimulating 1 receptor (CSF1R) as additional anti-cancer target for DZB. CSF1R plays a role the maintenance of tumor-promoting M2-macrophages; inhibition facilitates repolarization to M1-type thus restoring tumor T cell activity. Screening urothelial cancer (UC) models...
421 Background: DZB is an oral small-molecule Fibroblast Growth Factor Receptor 1/2/3 inhibitor (FGFRi) with clinical activity in FGFR2-fusion-positive cholangiocarcinoma. was screened for gastrointestinal cancer (GIC), by using a panel of GIC cell-lines, human tumor xenografts and 30 patient-derived xenograft (PDX) models. Methods: anti-proliferative potency determined 26 cell lines to determine the GI50. The cell-line, SNU-16 grown s.c. nude mice treated daily 3-weeks at MTD 75 mg/kg, p.o....
Abstract Effective targeted therapeutics for squamous cell carcinoma (SCC) are lacking. Here we uncover Mcl-1 as a dominant and tissue-specific survival factor in SCC, providing roadmap new therapeutic approach. Treatment with the HDAC inhibitor vorinostat regulates Bcl-2 family member expression to disable axis thereby induce apoptosis SCC cells. Although dominance renders cells resistant BH3 mimetic ABT-737, primes them sensitivity ABT-737 by shuttling Bim from Bcl-2/Bcl-xl, resulting...
Abstract Background: BAL0891 is a dual inhibitor of threonine tyrosine kinase (TTK) and polo-like 1 (PLK1). These kinases collaborate in activating the mitotic spindle assembly checkpoint (SAC) at kinetochore (KT) to regulate chromosome alignment segregation prior exit. In vitro, has combined prolonged effect on TTK transient PLK1, leading rapid disruption SAC that potentiates aberrant progression tumor cells. this work, efficacy was investigated mouse models human triple negative breast...
Abstract Microtubules are major components of the cellular cytoskeleton, ubiquitously founded in all eukaryotic cells. They involved mitosis, cell motility, intracellular protein and organelle transport, maintenance cytoskeletal shape. Avanbulin (BAL27862) is a microtubule-targeted agent (MTA) that promotes tumor death by destabilization microtubules. Due to its unique binding colchicine site tubulin, differently from other MTAs, avanbulin has previously shown activity solid lines. Its...
Supplementary Figures 1-4, Table 1, Methods from Physical Association of HDAC1 and HDAC2 with p63 Mediates Transcriptional Repression Tumor Maintenance in Squamous Cell Carcinoma
Supplementary Figures 1-4, Table 1, Methods from Physical Association of HDAC1 and HDAC2 with p63 Mediates Transcriptional Repression Tumor Maintenance in Squamous Cell Carcinoma
Supplementary Figure Legends 1-2 from The Integrin α<sub>v</sub>β<sub>3-5</sub> Ligand MFG-E8 Is a p63/p73 Target Gene in Triple-Negative Breast Cancers but Exhibits Suppressive Functions ER<sup>+</sup> and erbB2<sup>+</sup>
Supplementary Methods from The Integrin α<sub>v</sub>β<sub>3-5</sub> Ligand MFG-E8 Is a p63/p73 Target Gene in Triple-Negative Breast Cancers but Exhibits Suppressive Functions ER<sup>+</sup> and erbB2<sup>+</sup>