A5001006001- CAR-T cell therapy research
- Acute Lymphoblastic Leukemia research
- Multiple Myeloma Research and Treatments
- Folate and B Vitamins Research
- Immunotherapy and Immune Responses
- Acute Myeloid Leukemia Research
- Occupational and environmental lung diseases
- Hematopoietic Stem Cell Transplantation
- Lung Cancer Treatments and Mutations
- RNA modifications and cancer
- Biosimilars and Bioanalytical Methods
- Pneumocystis jirovecii pneumonia detection and treatment
- Cancer, Lipids, and Metabolism
- Cancer, Hypoxia, and Metabolism
- SARS-CoV-2 and COVID-19 Research
- Chronic Myeloid Leukemia Treatments
- Renal Transplantation Outcomes and Treatments
- Biochemical and Molecular Research
- RNA Interference and Gene Delivery
- Ubiquitin and proteasome pathways
- Cytokine Signaling Pathways and Interactions
- Cancer Immunotherapy and Biomarkers
- Peptidase Inhibition and Analysis
- Mesenchymal stem cell research
- Cancer-related Molecular Pathways
TScan Therapeutics (United States)
2020-2024
Broad Institute
2011-2019
Massachusetts General Hospital
2011-2019
Merrimack Pharmaceuticals (United States)
2019
Global Cancer Institute
2016
Harvard University
2012-2014
California Institute for Regenerative Medicine
2012
Harvard Stem Cell Institute
2011
Harvard University Press
2010
Albert Einstein College of Medicine
2004-2007
Modulation of histone deacetylase (HDAC) activity has been implicated as a potential therapeutic strategy for multiple diseases. However, it difficult to dissect the role individual HDACs due lack selective small-molecule inhibitors. Here, we report synthesis series highly potent and isoform-selective class I HDAC inhibitors, rationally designed by exploiting minimal structural changes clinically experienced inhibitor CI-994. We used this toolkit isochemogenic or chemically matched...
We examined the effects of isoform-specific histone deacetylase (HDAC) inhibitors on β-catenin posttranslational modifications in neural progenitor cells (NPCs) derived from human induced pluripotent stem (iPSCs). is a multifunctional protein with important roles developing and adult central nervous system. Activation Wnt pathway results stabilization nuclear translocation β-catenin, resulting activation multiple target genes. In addition, forms complex cadherins at plasma membrane as part...
Abstract A methotrexate (MTX)-resistant HeLa subline (R5), developed in this laboratory, with impaired transport due to a genomic deletion of the reduced folate carrier (RFC) was only 2-fold resistant pemetrexed (PMX), but 200- and 400-fold raltitrexed (ZD1694) Nα-(-4-amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-1-ornithine (PT523), respectively, compared parental cells when grown 2 μm folic acid. When acid replaced more physiological 25 nm 5-formyltetrahydrofolate, R5 were collaterally sensitive...
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 Prior studies from this laboratory documented the prevalence of methotrexate (MTX) transport activity with a low pH optimum in human solid tumor cell lines. In HeLa cells, has high affinity for pemetrexed [PMX (Alimta)] and is reduced folate carrier (RFC)-independent because it not diminished RFC-null subline (R5). R5 cells also have residual activity, specificity PMX, at neutral pH. current study, subline, R1, was selected under MTX selective pressure modest reduction There...
Pemetrexed is a novel antifolate recently approved for the treatment of pleural mesothelioma and non-small cell lung cancer. In clinical regimens, pemetrexed administered in conjunction with folic acid to minimize toxicity. However, excessive folate supplementation may also diminish activity this agent. The current study demonstrates, several human solid tumor lines, that when extracellular 5-formyltetrahydrofolate levels are increased vitro, within range normal blood levels, there...
Novel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal to identify compounds that overcome resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered be an unusual ATP non-competitive kinesin-5 (Eg5) inhibitor. A novel mutation caused resistance, suggesting binding site distinct from known Eg5 inhibitors, BRD9876...
Abstract Development of effective strategies to detect, treat, or prevent COVID-19 requires a robust understanding the natural immune response SARS-CoV-2, including cellular mediated by T cells. We used an unbiased, genome-wide screening technology, termed T-Scan, identify specific epitopes in SARS-CoV-2 that are recognized memory CD8+ cells 25 convalescent patients, focusing on presented six most prevalent HLA types: A*02:01, A*01:01, A*03:01, A*11:01, A*24:02, and B*07:02. For each type,...
Abstract Pemetrexed, a new generation antifolate recently approved for the treatment of mesothelioma and non–small cell lung cancer, is an excellent substrate reduced folate carrier (RFC). To explore carrier's effect on pemetrexed activity, RFC was inactivated in HCT-15 colon cancer cells by mutagenesis PT632 selective pressure. A clone (PT1) obtained with glycine to arginine substitution at amino acid 401, resulting loss function. PT1 were resistant (178-fold), methotrexate (4-fold), ZD1694...
Abstract The p16INK4A/CDKN2A gene on chromosome 9p21 is a site of frequent allelic loss in human cancers, and subset cases, homozygous deletions at this locus encompass the telomeric methylthioadenosine phosphorylase (MTAP) gene. MTAP product principal enzyme involved purine synthesis via salvage pathway, such that MTAP-negative cancers are solely dependent de novo mechanisms. Inhibitors pathway can then be used to selectively blockade cancer cells while causing minimal collateral damage...
Abstract Pemetrexed [PMX (Alimta)] is a new generation antifolate with activity in variety of solid tumors. It an excellent substrate for most folate transporters, notably the reduced carrier (RFC) and receptor (FR)-α. The role FR-α PMX pharmacological uncertain. Whereas high-level expression may enhance this agent, it not clear what constitutive levels transporter contribute to activity. In study, were abolished by small interfering RNA-induced silencing HeLa cells RFC-null R5 as confirmed...
Abstract Pemetrexed is a novel antifolate with polyglutamate derivatives that are potent inhibitors of thymidylate synthase (TS) and to lesser extent glycinamide ribonucleotide formyltransferase (GARFT). Conditions might modulate relative suppression these sites were assessed by the pattern hypoxanthine thymidine protection. When grown 25 nmol/L racemic 5-formyltetrahydrofolate, alone fully protected wild-type HeLa cells at least 1 μmol/L pemetrexed, but protection reduced folate carrier...
Many studies suggest the presence of aberrations in cellular metabolism bipolar disorder. We studied metabolome disorder to gain insight into pathways that may be dysregulated and discover evidence novel biomarkers. measured polar nonpolar metabolites fibroblasts from subjects with I matched healthy control subjects, under normal conditions two physiologic perturbations: low-glucose media exposure stress-mediating hormone dexamethasone. Metabolites were significantly different between showed...
2542 Background: Solid tumors are notoriously heterogenous with highly variable antigen expression and an immunosuppressive microenvironment. HLA loss of heterozygosity (LOH) has also been identified in up to 40% solid tumors, allowing tumor cells evade T cell attack. To overcome these issues a lack potent endogenous antitumor cancer patients, TScan developed T-Plex, multiplexed therapy comprising two three different TCR-Ts, chosen from collection TCR-Ts called the ImmunoBank. Product study...