A5034065748- Fibroblast Growth Factor Research
- Eosinophilic Disorders and Syndromes
- PI3K/AKT/mTOR signaling in cancer
- Lung Cancer Treatments and Mutations
- HER2/EGFR in Cancer Research
- Monoclonal and Polyclonal Antibodies Research
- Colorectal Cancer Treatments and Studies
- Advanced Breast Cancer Therapies
- Kruppel-like factors research
- Radiopharmaceutical Chemistry and Applications
- Gene expression and cancer classification
- Cancer Genomics and Diagnostics
- Chronic Myeloid Leukemia Treatments
- Genomics and Chromatin Dynamics
- Cancer Treatment and Pharmacology
- Chronic Lymphocytic Leukemia Research
- Acute Myeloid Leukemia Research
- Colorectal Cancer Surgical Treatments
- Cancer, Hypoxia, and Metabolism
- Cancer Research and Treatments
- RNA Research and Splicing
- Gastric Cancer Management and Outcomes
- Hepatocellular Carcinoma Treatment and Prognosis
- Cancer-related Molecular Pathways
- Myeloproliferative Neoplasms: Diagnosis and Treatment
Relay Therapeutics (United States)
2020-2024
Mersana Therapeutics (United States)
2014-2023
Sage Therapeutics (United States)
2020-2022
Sanofi (France)
2014-2015
Sanofi (United States)
2015
AVEO Oncology (United States)
2011-2013
Merck (Japan)
2012
Merck & Co., Inc., Rahway, NJ, USA (United States)
2009-2010
Purdue University West Lafayette
2008
University of Washington
1999-2007
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...
AbstractThe activation of muscle-specific gene expression requires the coordinated action muscle regulatory proteins and chromatin-remodeling enzymes. Microarray analysis performed in presence or absence a dominant-negative BRG1 ATPase demonstrated that approximately one-third MyoD-induced genes were highly dependent on SWI/SNF To understand mechanism activation, we chromatin immunoprecipitations analyzing myogenin promoter. We found H4 hyperacetylation preceded Brg1 binding MyoD-dependent...
The development and differentiation of distinct cell types is achieved through the sequential expression subsets genes; yet, molecular mechanisms that temporally pattern gene remain largely unknown. In skeletal myogenesis, initiated by MyoD includes specific Mef2 isoforms activation p38 mitogen-activated protein kinase (MAPK) pathway. Here, we show activity facilitates binding at a subset late-activated promoters, Mef2D recruits Pol II. Most importantly, genes can be shifted to early stages...
After significant effort over the last 30 years, antibody-drug conjugates (ADC) have recently gained momentum as a therapeutic modality, and nine ADCs been approved by FDA to date, with additional in late stages of development. Here, we introduce dolaflexin, novel ADC technology that overcomes key limitations most common platforms two features: higher drug-to-antibody ratio auristatin controlled bystander effect. The novel, cell permeable payload, F-hydroxypropylamide, undergoes metabolic...
PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur the and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, prominently hyperglycemia due inhibition wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations cryo-electron microscopy identify an allosteric network that provides explanation for how mutations favor...
We have identified two new genes, neuroD2 and neuroD3, on the basis of their similarity to neurogenic basic-helix-loop-helix (bHLH) gene neuroD. The predicted amino acid sequence shows a high degree homology neuroD MATH-2/NEX-1 in bHLH region, whereas neuroD3 is more distantly related family member. expressed transiently during embryonic development, with highest levels expression between days 10 12. initially at day 11, persistent adult nervous system. In situ Northern (RNA) analyses...
The myogenic basic helix-loop-helix (bHLH) proteins regulate both skeletal muscle specification and differentiation: MyoD Myf5 establish the lineage, whereas myogenin mediates differentiation. Previously, we demonstrated that was more efficient than at initiating expression of genes, in this study present molecular basis for difference. A conserved amphipathic alpha-helix carboxy terminus bHLH has distinct activities myogenin: helix facilitates initiation endogenous gene expression,...
Development of targeted therapeutics required translationally relevant preclinical models with well-characterized cancer genome alterations. Here, by studying 52 colorectal patient-derived tumor xenografts (PDX), we examined key molecular alterations the IGF2-PI3K and ERBB-RAS pathways response to cetuximab. PDX data were compared that published for patient tumors in The Cancer Genome Atlas. We demonstrated a significant pattern mutual exclusivity genomic abnormalities pathways. anomaly...
The t(1;19) chromosomal translocation of pediatric pre-B cell leukemia produces chimeric oncoprotein E2a-Pbx1, which contains the N-terminal transactivation domain basic helix-loop-helix (bHLH) transcription factor, E2a, joined to majority homeodomain protein, Pbx1. There are three Pbx family members, bind DNA as heterodimers with both broadly expressed Meis/Prep1 proteins and specifically Hox proteins. These can augment function transcriptional activators bound adjacent elements. In...
Abstract The recombinant fusion protein aflibercept (ziv-aflibercept in the United States) binds VEGF-A, VEGF-B, and placental growth factor (PlGF). monoclonal antibody bevacizumab VEGF-A. Recent studies hypothesized that dual targeting of VEGF/PlGF is more beneficial than either ligand. We compared activity versus 48 patient-derived xenograft (PDX) colorectal cancer models. Nude mice engrafted subcutaneously with PDX tumors received biweekly aflibercept, bevacizumab, or vehicle injections....
2546 Background: XMT-1522 is comprised of 10-15 molecules the payload AF-HPA, an auristatin-derivative with two-step intra-tumor metabolism intended to optimize therapeutic index, conjugated a novel anti-HER2 monoclonal antibody via Dolaflexin ADC platform. Methods: In this ongoing Phase 1 study, pts advanced HER2-expressing (IHC ≥1+) breast cancer (BC), gastric (GC) and non-small cell lung (NSCLC) progressing on standard therapy or for whom no exists are treated administered intravenously...
Abstract Target selection for antibody–drug conjugates (ADC) frequently focuses on identifying antigens with differential expression in tumor and normal tissue, to mitigate the risk of on-target toxicity. However, this strategy restricts possible target space. SLC34A2/NaPi2b is a sodium phosphate transporter expressed variety human tumors including lung ovarian carcinoma, as well tissues from which these arise. Previous clinical trials NaPi2b targeting MMAE-ADCs have shown objective durable...
Amplification of large chromosomal regions (gene amplification) is a common somatic alteration in human cancer cells and often associated with advanced disease. A critical event initiating gene amplification DNA double-strand break (DSB), which immediately followed by the formation palindrome. Large palindromes are frequent nonrandomly distributed genomes facilitate further increase copy number. Although importance as very early widely recognized, it not known how DSB resolved to form...
3009 Background: The AKs are essential for mitotic progression, spindle formation, centrosome maturation, chromosomal segregation, and cytokinesis. Elevated expression occurs frequently in tumors. MK-0457 (VX-680) is a potent AK inhibitor, with Ki values of 0.66, 18 4.6 nM A, B C, respectively. inhibits proliferation transformed cells vitro (IC 50 ’s 15–113 nM), induces colon pancreatic cancer xenograft regressions. Methods: After IRB approval, consenting patients (pts) refractory solid...
Blood-based biomarker discovery with gene expression profiling has been hampered by interference from endogenous, highly abundant alpha- and beta-globin transcripts. We describe a means to quantify the of globin transcripts on effectiveness transcript mitigation (a) defining characterizing interference, (b) reproducing synthetic transcripts, (c) using ROC curves measure sensitivity specificity for protocol removing transcripts.We collected blood at 2 sites extracted total RNA in PreAnalytiX...
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...
14657 Background: MK-2461 is a potent small molecule inhibitor of c-Met, receptor tyrosine kinase involved in tumor cell proliferation and motility. Over-expression c-Met or Met gene amplification has been associated with poorer prognosis several types. Methods: Multicenter, open-label, phase I dose escalation study patients advanced solid tumors refractory to standard therapy. Drug was administered by mouth daily twice (BID) for 28 days followed 14 day rest period during cycle 1. Patients...
Abstract Antibody-drug conjugates are effective in the treatment of HER2-amplified breast cancer and Hodgkin's lymphoma, but current ADC technologies have faced limitations expanding addressable patient population target space. Ado-trastuzumab emtansine (T-DM1) is an with 3-4 cytotoxic drugs per antibody that was recently approved for HER2 IHC 3+ or cancer. Even within this high HER2-expressing population, several studies now shown greater T-DM1 benefit patients mRNA expression above median....