A5042503296- Cancer Immunotherapy and Biomarkers
- Cancer-related Molecular Pathways
- CAR-T cell therapy research
- Cancer Research and Treatments
- Phagocytosis and Immune Regulation
- Monoclonal and Polyclonal Antibodies Research
- Epigenetics and DNA Methylation
- Immunotherapy and Immune Responses
- Pancreatic and Hepatic Oncology Research
- RNA modifications and cancer
- Virus-based gene therapy research
- PI3K/AKT/mTOR signaling in cancer
- Heat shock proteins research
- Renal cell carcinoma treatment
- RNA and protein synthesis mechanisms
- Radiation Therapy and Dosimetry
- Computational Drug Discovery Methods
- Cancer Genomics and Diagnostics
- Hepatitis C virus research
- Endometrial and Cervical Cancer Treatments
- Lung Cancer Treatments and Mutations
- Effects of Radiation Exposure
- Drug Transport and Resistance Mechanisms
- Bladder and Urothelial Cancer Treatments
- Synthetic Organic Chemistry Methods
National Human Genome Research Institute
2012-2023
Harvard University
2003-2023
Massachusetts General Hospital
2004-2023
Cancer Research Center
2004-2023
Merck & Co., Inc., Rahway, NJ, USA (United States)
2015-2023
Cancer Genetics (United States)
2012-2023
Tennessee Oncology
2018
Fox Chase Cancer Center
2018
University of Chicago
2018
Gwynedd Mercy University
2014
Patients with advanced endometrial carcinoma have limited treatment options. We report final primary efficacy analysis results for a patient cohort receiving lenvatinib plus pembrolizumab in an ongoing phase Ib/II study of selected solid tumors.
Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, programmed death protein inhibitor, in patients with advanced solid tumors. Phase I results on maximum tolerated dose, safety, tolerability, preliminary antitumor activity, pharmacokinetics are reported.
Abstract PD-1 inhibitors are approved for treating advanced melanoma, but resistance has been observed. This phase Ib trial evaluated intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9), in combination with pembrolizumab patients unresectable or metastatic malignant melanoma. The most common adverse events related to SD-101 were injection-site reactions and transient, mild-to-moderate “flu-like” symptoms. Among the naïve anti–PD-1 therapy, overall...
Abstract Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human IgG2 mAb agonist T-cell costimulatory receptor 4-1BB/CD137 in combination with humanized, PD-1–blocking IgG4 pembrolizumab patients advanced solid tumors. Experimental Design: Utomilumab (0.45–5.0 mg/kg) (2 were administered intravenously every 3 weeks. dose escalation was conducted using time-to-event continual reassessment method....
The eukaryotic cell cycle is driven by a cascade of cyclins and kinase partners including the G 1 cyclin Cln3p in yeast. As first step this cascade, uniquely positioned to determine critical growth-rate threshold for division. To analyze factors regulating CLN3 expression, we identified short upstream open reading frame (uORF) 5′ leader mRNA as translational control element. This element growth-dependent regulation synthesis because it specifically represses expression during conditions...
Gastrin is transiently expressed in fetal islets during a critical period of their development from protodifferentiated islet pre- cursors pancreatic ducts.To examine the possible role gastrin as an cell growth factor, postnatal was studied transgenic mice which overexpress and TGFa pancreas.Overexpression transgene causes metaplastic ductules containing numerous insulin ex- pressing cells that resemble precursors pancreas.However, mass not increased.Pancreatic overexpression chimeric...
Regulation of the cell cycle is orchestrated by cyclins and cyclin-dependent kinases. We have demonstrated previously that overexpression eukaryotic translation initiation factor 4E (eIF-4E) in NIH 3T3 cells growing 10% fetal calf serum leads to highly elevated levels cyclin D1 protein without significant increase mRNA levels, suggesting a post-transcriptional mechanism involved. (Rosenwald, I. B., Lazaris-Karatzas, A., Sonenberg, N., Schmidt, E. V.(1993) Mol. Cell. Biol. 13, 7358-7363). In...
Hepatocyte growth factor (HGF) is a potent mitogen for primary hepatocytes. Therefore, we examined HGF as possible autocrine in hepatocellular carcinoma (HCC). We introduced an albumin-HGF expression vector into Fao HCC cells and transgenic mice. Expression of the inhibited their vitro. In vivo, FaoHGF produced tumors that averaged 10% sizes G418-resistant controls when transplanted nude contrast, hepatocytes from mice expressing grew more rapidly than did those normal siblings. Further,...
Although activation of c-myc is a critical step in the development lymphomas and other tumors, its normal function(s) cell growth remain obscure because few myc-regulated genes are known. myc expression normally increases response to mitogens peaks G1 when additional protein synthesis required for cell-cycle progression. Protein controlled by availability translation initiation factors, including mRNA cap binding (eIF-4E) alpha subunit eIF-2 complex that binds initiator Met-tRNA....
The mRNA cap-binding protein (eukaryotic initiation factor 4E [eIF4E]) binds the m7 GpppN cap on mRNA, thereby initiating translation. eIF4E is essential and rate limiting for synthesis. Overexpression of transforms cells, mutations in arrest cells G, cdc33 mutants. In this work, we identified promoter region gene encoding eIF4E, because previously as a potential myc-regulated gene. support our previous data, minimal, functional, 403-nucleotide was found to contain CACGTG E box repeats, core...
The relationship between abnormal cell proliferation and aberrant control of hormonal secretion is a fundamental poorly understood issue in endocrine neoplasia. Transgenic mice with parathyroid-targeted overexpression the cyclin D1 oncogene, modeling gene rearrangement found human tumors, were created to determine whether primary defect this cell-cycle regulator can cause an serum calcium parathyroid hormone response, as typical hyperparathyroidism. We also sought develop animal model...
The common acute lymphoblastic leukemia antigen (CALLA) is a 749-amino acid type II integral membrane protein expressed by most leukemias, certain other lymphoid malignancies with an immature phenotype, and normal progenitors. A computer search against the recent GenBank release (no. 56) indicates that human CALLA cDNA encodes nearly identical to rat rabbit neutral endopeptidase 24.11 ("enkephalinase;" EC 3.4.24.11). This zinc metalloendopeptidase, which has been shown inactivate variety of...
In an effort to identify widely active positive regulatory elements, we have examined the action of cytomegalovirus enhancer-promoter in transgenic mice. These elements activated expression 24 28 tissues tested. The greatest was observed heart, kidney, brain, and testis. Maximum further localized specific cells within heart kidney.
ABSTRACT High rates of genetic variation ensure the survival RNA viruses. Although this is thought to result from error-prone replication, viruses must also maintain highly conserved genomic segments. A balance between and variable viral elements especially important in order for avoid “error catastrophe.” Ribavirin has been shown induce error catastrophe other We therefore used a novel hepatitis C virus (HCV) replication system determine relative mutation frequencies regions HCV genome, we...
Cyclin D1 is a G1-specific cyclin that has been linked to lymphoid, parathyroid, and breast tumors. Recent studies suggested high protein levels of are not always produced when mRNA overexpressed in transfected cells, suggesting posttranscriptional events may be important regulation. The cap-binding (eukaryotic initiation factor 4E [eIF-4E]) potential regulatory several events, it can itself induce neoplastic transformation. Consequently, we examined eIF-4E as regulator D1. Overexpression...
The CIITAdel keeps viruses at bay A better understanding of cellular mechanisms involved in viral resistance is needed for the next generation antiviral therapies. Bruchez et al. used a transposon-mediated gene-activation screen to search previously unreported host restriction factors Ebola virus (see Perspective by Wells and Coyne). authors found that transcription factor, major histocompatibility complex class II transactivator (CIITA), induces human cell lines directing expression p41...
New therapies are needed to treat immune checkpoint inhibitor-resistant non-small cell lung cancer (NSCLC) and identify biomarkers personalize treatment. Epigenetic therapies, including histone deacetylase inhibitors, may synergize with programmed death-1 (PD-1) blockade overcome resistance. We report outcomes in patients anti-programmed death ligand-1 [PD-(L)1]-resistant/refractory NSCLC treated pembrolizumab plus entinostat ENCORE 601.The expansion cohort of 601 included who previously...
Background The phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab 2 (P2)) patients advanced solid tumors. Methods (0.003–10 mg/kg) ± (200 mg) was administered intravenously every 3 weeks using a continuous reassessment method for dose escalation. Primary objectives were safety and tolerability; secondary included pharmacokinetics, immunogenicity, pharmacodynamics, clinical...
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary point, may be published when key planned co-primary or secondary analyses are not yet available. Trial Updates provide an opportunity to disseminate additional results from studies, in JCO elsewhere, for which point has already been reported.The open-label phase Ib/II Study 111/KEYNOTE-146 of daily lenvatinib 20 mg plus pembrolizumab 200 once every 3 weeks...