A5065583907- Bioinformatics and Genomic Networks
- Ferroptosis and cancer prognosis
- Cancer Genomics and Diagnostics
- Fibroblast Growth Factor Research
- Peptidase Inhibition and Analysis
- Melanoma and MAPK Pathways
- CRISPR and Genetic Engineering
- Cell Image Analysis Techniques
- RNA modifications and cancer
- Protein Degradation and Inhibitors
- Advanced Proteomics Techniques and Applications
- Metastasis and carcinoma case studies
- 14-3-3 protein interactions
- Computational Drug Discovery Methods
- Renal cell carcinoma treatment
- Cancer-related gene regulation
- Click Chemistry and Applications
- Neuroendocrine Tumor Research Advances
- Innovative Microfluidic and Catalytic Techniques Innovation
- Epigenetics and DNA Methylation
- IgG4-Related and Inflammatory Diseases
Broad Institute
2021-2025
Combinatorial CRISPR technologies have emerged as a transformative approach to systematically probe genetic interactions and dependencies of redundant gene pairs. However, the performance different functional genomic tools for multiplexing sgRNAs vary widely. Here, we generate benchmark ten distinct pooled combinatorial libraries targeting paralog pairs optimize digenic knockout screens. Libraries composed dual Streptococcus pyogenes Cas9 (spCas9), orthogonal spCas9 Staphylococcus aureus...
Translocations involving FGFR2 gene fusions are common in cholangiocarcinoma and predict response to FGFR kinase inhibitors. However, rates durability limited due the emergence of resistance, typically domain mutations, sub-optimal dosing, relating drug adverse effects. Here, we develop biparatopic antibodies targeting extracellular (ECD), as candidate therapeutics. Biparatopic can overcome drawbacks bivalent monospecific antibodies, which often show poor inhibitory or even agonist activity...
Abstract Inactivation of the VHL gene stabilizes HIF2a, which drives clear cell renal carcinoma (ccRCC). The HIF2a inhibitor belzutifan is approved for ccRCC treatment, but de novo and acquired resistance are common. bound to ARNT, transcriptionally activates many genes. We performed CRISPRa screens in HIF2a-dependent lines treated with a analog identify HIF2a-responsive genes that confer cell-autonomous when not downregulated. Sustaining expression target CCND1, encoding Cyclin D1, promoted...
Abstract Translocations involving FGFR2 gene fusions are common in cholangiocarcinoma and predict response to FGFR kinase inhibitors. However, the rate durability of limited due emergence resistance, typically acquired domain mutations, sub-optimal dosing, relating drug adverse effects. Here, we report development biparatopic antibodies targeting extracellular (ECD), as candidate therapeutics. Biparatopic can overcome drawbacks standard bivalent monoparatopic antibodies, which often show...
Abstract Large-scale cancer sequencing efforts coupled with deep functional genomic interrogation of models provides us an increasingly detailed view the critical drivers required for persistent growth and survival cells. Targeting such has provided significant therapeutic benefit to patients across a wide range cancers, yet progress been, in large part, confined targeting catalytic domains kinases. To expand reach therapeutics into new classes targets, we need identify validate specific...
Abstract The paradigm of cancer dependencies and targeted therapies has been nearly exclusively focused on inhibiting critical pathways or nodes in cancer. However, conditional activation signaling as a new source selective vulnerabilities not systematically characterized. In this study, we sought to identify context-specific gene lethalities We performed lineage-specific mutual-exclusivity (ME) analysis using 69,393 patient genomes cohorts AACR-GENIE, TCGA, Foundation One, across 12...
Abstract Abstract: Most clear cell renal carcinomas (ccRCCs) are caused by loss of the pVHL tumor suppressor function. Inactivation leads to increased accumulation HIF2a, which drives ccRCC in preclinical models. HIF2a interacts with ARNT and functions as a heterodimeric transcription factor. can activate hundreds downstream target genes, including many that suspected playing role pathogenesis based on their biological functions. Peloton Therapeutics developed specific allosteric inhibitor...
Abstract PRMT5 is an essential arginine methyltransferase and a therapeutic target in MTAP-null cancers. uses adaptor proteins for substrate recruitment through previously undefined mechanism. Here, we identify evolutionarily conserved peptide sequence shared among the three known adaptors (CLNS1A, RIOK1, COPR5) show that it necessary sufficient interaction with PRMT5. We demonstrate modular containing common binding motif recruitment, comparable other enzyme classes such as kinases E3...