A5088825252- Immune cells in cancer
- Cancer Immunotherapy and Biomarkers
- CAR-T cell therapy research
- Monoclonal and Polyclonal Antibodies Research
- Phagocytosis and Immune Regulation
- Glycosylation and Glycoproteins Research
- Epigenetics and DNA Methylation
- Immunotherapy and Immune Responses
- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- PI3K/AKT/mTOR signaling in cancer
- Cancer Genomics and Diagnostics
- Ferroptosis and cancer prognosis
- Cell Adhesion Molecules Research
- Cancer Mechanisms and Therapy
- Click Chemistry and Applications
- Chromatin Remodeling and Cancer
- CRISPR and Genetic Engineering
- Cancer, Hypoxia, and Metabolism
- Chemokine receptors and signaling
- Statistical Methods in Clinical Trials
- Fibroblast Growth Factor Research
- Computational Drug Discovery Methods
- Lung Cancer Treatments and Mutations
- DNA Repair Mechanisms
Moderna Therapeutics (United States)
2023-2024
Epizyme (United States)
2015-2017
Merck & Co., Inc., Rahway, NJ, USA (United States)
2010-2016
Marymount University
2016
Data Harbor (United States)
2015
United States Military Academy
2010
Columbia University
2003-2008
New York Genome Center
2003
Technion – Israel Institute of Technology
2002
Combination drug therapy is a widely used paradigm for managing numerous human malignancies. In cancer treatment, additive and/or synergistic combinations can convert weakly efficacious monotherapies into regimens that produce robust antitumor activity. This be explained in part through pathway interdependencies are critical cell proliferation and survival. However, identification of the various difficult due to complex molecular circuitry underlies tumor development progression. Here, we...
By analyzing, in parallel, large literature-derived and high-throughput experimental datasets we investigate genes harboring human inherited disease mutations the context of molecular interaction networks. Our results demonstrate that network properties influence likelihood phenotypic consequences mutations. Genes with intermediate connectivities have highest probability germ-line mutations, suggesting tend to occupy an niche terms their physiological cellular importance. analysis tissue...
Abstract mRNA-4157 (V940) is an individualized neoantigen therapy targeting up to 34 patient-specific tumor neoantigens induce T-cell responses and potentiate antitumor activity. We report mechanistic insights into the immunogenicity of via characterization from first-in-human, phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non–small cell lung cancer (Part A: 1-mg mRNA-4157, n = 4) or cutaneous melanoma D: + 200-mg pembrolizumab, 12). Safety, tolerability, were assessed....
Phosphorylation sites on proteins in the phosphatidylinositol 3-kinase pathway that are regulated by candidate drugs can serve as useful biomarkers to predict tumor sensitivity AKT inhibitors.
Abstract Inhibition of the DNA damage checkpoint kinase WEE1 potentiates genotoxic chemotherapies by abrogating cell-cycle arrest and proper repair. However, is also essential for unperturbed cell division in absence extrinsic insult. Here, we investigate anticancer potential a inhibitor, independent chemotherapy, explore possible cellular context underlying sensitivity to inhibition. We show that MK-1775, potent selective ATP-competitive inhibitor WEE1, cytotoxic across broad panel tumor...
The SWI/SNF complex is a major regulator of gene expression and increasingly thought to play an important role in human cancer, as evidenced by the high frequency subunit mutations across virtually all cancer types. We previously reported that preclinical models, malignant rhabdoid tumors, which are deficient core component INI1 (SMARCB1), selectively killed inhibitors H3K27 histone methyltransferase EZH2. Given demonstrated antagonistic activities EZH2-containing PRC2 complex, we...
Abstract Background Hyperactivation of the Ras signaling pathway is a driver many cancers, and RAS activation can predict response to targeted therapies. Therefore, optimal methods for measuring are critical. The main focus our work was develop gene expression signature that predictive dependence. Methods We used coherent pathway-related genes across multiple datasets derive generate scores in pre-clinical cancer models human tumors. then related this KRAS mutation status drug data clinical...
Inhibition of kinases involved in the DNA damage response sensitizes cells to genotoxic agents by abrogating checkpoint-induced cell cycle arrest. CHK1 and WEE1 act a pathway upstream CDK1 inhibit progression damaged DNA. Therapeutic targeting either or WEE1, combination with chemotherapy, is under clinical evaluation. These studies examine overlap potential for synergy when are inhibited cancer models.Small molecules MK-8776 MK-1775 were used selectively potently respectively.In vitro,...
Abstract The EZH2 small-molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin lymphoma (NHL). We have previously shown that inhibitors display an antiproliferative effect multiple preclinical models NHL, and bearing gain-of-function mutations were consistently more sensitive to inhibition than lymphomas with wild-type (WT) EZH2. Here, we demonstrate cell lines show a cytotoxic response, while WT-EZH2 cytostatic...
V-set immunoglobulin domain-containing 4 (VSIG4) is a B7 family protein with known roles as C3 fragment complement receptor involved in pathogen clearance and negative regulator of T cell activation by an undetermined mechanism. VSIG4 expression specific for tumor-associated select tissue-resident macrophages. Increased has been associated worse survival multiple cancer indications. Based upon computational analysis transcript data across thousands tumor normal tissue samples, we...
Common genetic disorders are believed to arise from the combined effects of multiple inherited variants acting in concert with environmental factors, such that any given DNA sequence variant may have only a marginal effect on disease outcome. As consequence, correlation between status and marker allele genomewide linkage study tends be relatively weak implicated regions typically encompass hundreds positional candidate genes. Therefore, new strategies needed parse large sets ‘positional’...
The immune suppressive microenvironment is a major culprit for difficult-to-treat solid cancers. Particularly, inhibitory tumor-associated macrophages (TAM) define the resistant nature of tumor milieu. To tumor-enabling mechanisms TAMs, we analyzed molecular clinical datasets correlating cell surface receptors with TAM infiltrate. Though P-selectin glycoprotein ligand-1 (PSGL-1) found on other cells and functions as an adhesion molecule, PSGL-1 highly expressed TAMs across multiple types....
LBA9515 Background: The combination of mRNA-4157/V940 and pembrolizumab improved recurrence free survival (RFS) compared to monotherapy in patients with resected high-risk stage III/IV cutaneous melanoma the randomized Phase 2 mRNA-4157-P201/KEYNOTE-942 trial (RFS event rate 22.4% (24/107) versus 40% (20/50); HR = 0.561; 95% CI: 0.309, 1.017). Across multiple cancer types disease settings, detection minimal residual (MRD) by circulating tumor DNA (ctDNA) assays plasma identifies at higher...
Abstract Introduction: In HPV- HNSCC, limited durable clinical responses to PD1/PD-L1 blockade may be due diminished effector cytolytic activity and clonal diversity.1-4 mRNA-4157 is a novel mRNA-based INT that encodes up 34 neoantigens inducing specific antitumor T-cell activation; with pembro have been shown in melanoma.5 We assessed + unresectable, metastatic HNSCC the Phase 1 mRNA-4157-P101/KEYNOTE-603 study (NCT03313778). Methods: Part C of this enrolled ≥18-year-old patients (pts)...
<p>Supplementary methods.</p>
Abstract A panel of more than 600 cell lines from 17 tumor types has been profiled and sensitivity to a set FDA approved compounds with different mechanisms action tested. Comparison gene expression profiles overlapping publicly available showed 100% accuracy line identity prediction using nearest neighbor classifier. Similar analysis CNV data had 80% due relatively little perturbation in some the lines. Significant signatures have detected for compounds. De-novo agnostic classification...
Abstract Background: The open-label randomized Phase 2 mRNA-4157-P201/Keynote-942 trial met its primary endpoint of prolonged recurrence free survival (RFS) in patients with resected high-risk stage III/IV melanoma. Tumor immunogenicity provides a favorable landscape for inflammatory processes associated clinical benefit to checkpoint inhibitors (ICI) and tumor mutational burden (TMB) has been shown be an independent predictor treatment outcomes treated ICI therapy. mRNA-4157 is novel...
<h3>Background</h3> The identification of cancer-specific T cell receptor (TCR) sequences is paramount to the advancement cancer immunotherapies. Recent studies and clinical trials have shown that monoclonal therapy prone immune evasion cells by loss HLA heterozygosity low antigen heterogeneity. Cocktail which comprises TCRs corresponding multiple HLAs antigens has been proposed improve efficacy adoptive transfer therapy. In addition CD8+ cytotoxic cells, neoantigen-specific CD4+ while...
<h3>Background</h3> Macrophages play an important role in cancer by modulating both the innate and adaptive parts of immune system. In non-pathological conditions, multiple subsets macrophages balance response. cancer, M2-like immune-suppressive tumor-associated (TAMs) dominate tumor microenvironment (TME). TAMs promote growth, support neo-angiogenesis enable metastasis formation. Macrophage modulators driving macrophage repolarization from to a pro-inflammatory M1-like phenotype are...
Omnipresent suppressive myeloid populations in the tumor microenvironment limit efficacy of T-cell-directed immunotherapies, become more inhibitory after administration T-cell checkpoint inhibitors, and are overall associated with worse survival cancer patients. In early clinical trials, positive outcomes have been demonstrated for therapies aimed at repolarizing microenvironment. We previously described key role P-selectin glycoprotein ligand-1 (PSGL-1) maintaining an state tumor-associated...
<p>Supplementary Figure 3. Patient responses to individual neoantigens at pre-treatment and post-treatment for patients who received mRNA-4157 monotherapy (A–C) or combination therapy (D–J) using ELISpot assay.</p>
<p>Supplementary Figure 6. mRNA-4157 in combination with pembrolizumab activates an adaptive immune response.</p>