A5051662107- Glioma Diagnosis and Treatment
- Protein Degradation and Inhibitors
- CRISPR and Genetic Engineering
- Histone Deacetylase Inhibitors Research
- Nanoplatforms for cancer theranostics
- Peptidase Inhibition and Analysis
- Chromatin Remodeling and Cancer
- Immune cells in cancer
- Ubiquitin and proteasome pathways
- RNA Interference and Gene Delivery
- Neuroblastoma Research and Treatments
- Microtubule and mitosis dynamics
- RNA modifications and cancer
- Immunotherapy and Immune Responses
- Acute Myeloid Leukemia Research
- RNA Research and Splicing
- Nerve injury and regeneration
- Biochemical and Structural Characterization
- Pluripotent Stem Cells Research
- Multiple Myeloma Research and Treatments
- Photoacoustic and Ultrasonic Imaging
- Amino Acid Enzymes and Metabolism
- Cancer Genomics and Diagnostics
- Monoclonal and Polyclonal Antibodies Research
- Antimicrobial Peptides and Activities
Fred Hutch Cancer Center
2015-2024
Seattle Children's Hospital
2019-2024
Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa
2013-2022
University of Washington
2014-2019
Cancer Research Center
2013-2019
Sanofi (France)
2014
Amgen (United States)
2012
To identify therapeutic targets for glioblastoma (GBM), we performed genome-wide CRISPR-Cas9 knockout (KO) screens in patient-derived GBM stem-like cells (GSCs) and human neural stem/progenitors (NSCs), non-neoplastic stem cell controls, genes required their vitro growth. Surprisingly, the vast majority GSC-lethal hits were found outside of molecular networks commonly altered GSCs (e.g., oncogenic drivers). In vivo validation GSC-specific revealed several strong hits, including wee1-like...
To identify key regulators of human brain tumor maintenance and initiation, we performed multiple genome-wide RNAi screens in patient-derived glioblastoma multiforme (GBM) stem cells (GSCs). These identified the plant homeodomain (PHD)-finger domain protein PHF5A as differentially required for GSC expansion, compared with untransformed neural (NSCs) fibroblasts. Given PHF5A's known involvement facilitating interactions between U2 snRNP complex ATP-dependent helicases, examined...
Simultaneous in vivo assessment of multiple cancer drugs and drug combinations using microinjection technology predicts systemic response model tumors has shown feasibility for efficacy a pilot study patients.
Abstract Background The extent of intratumoral mutational heterogeneity remains unclear in gliomas, the most common primary brain tumors, especially with respect to point mutation. To address this, we applied single molecule molecular inversion probes targeting 33 cancer genes assay both mutations and gene amplifications within spatially distinct regions 14 glial tumors. Results We find evidence regional multiple including TP53 RB1 an anaplastic oligodendroglioma PDGFRA KIT two glioblastomas...
Highlights•BuGZ is a kinetochore protein that binds to and stabilizes Bub3•BuGZ localizes the Bub3 through conserved GLEBS domain•BuGZ depletion in transformed cells results severe chromosome alignment defects•Inhibiting Bub3's domain interactions may be therapeutic strategy for GBMSummaryDuring mitosis, spindle assembly checkpoint (SAC) monitors attachment of kinetochores (KTs) plus ends microtubules (MTs) prevents anaphase onset until chromosomes are aligned KTs under proper tension. Here,...
Abstract Background Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine (DIPGs), have a dismal prognosis, with less than 2% surviving 5 years postdiagnosis. The majority of DIPGs and all DMGs harbor mutations altering the epigenetic regulatory histone tail (H3 K27M). Investigations addressing DMG epigenetics identified few promising drugs, HDAC inhibitor (HDACi) panobinostat. Here, we use clinically relevant models to identify validate other effective HDACi their biomarkers...
BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms its action, and ultimately resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss function ORF/cDNA driven rescue screens, cell-based models spontaneous we identify bHLH/homeobox transcription factors cell-cycle regulators as key genes mediating BETi's response resistance. Cells that acquire...
A scorpion-derived peptide-steroid conjugate accumulates in cartilage and reverses inflammation a rat model of arthritis without steroid toxicity.
The impenetrability of the blood-brain barrier (BBB) to most conventional drugs impedes treatment central nervous system (CNS) disorders. Interventions for diseases like brain cancer, neurodegeneration, or age-associated inflammatory processes require varied approaches CNS drug delivery. Cystine-dense peptides (CDPs) have drawn recent interest as drug-delivery vehicles. Found throughout phylogenetic tree, often in drug-like roles, their size, stability, and protein interaction capabilities...
There is an unmet need in the treatment of pediatric brain tumors for chemotherapy that efficacious, avoids damage to developing brain, and crosses blood-brain barrier. These experiments evaluated efficacy cabazitaxel mouse models tumors. The antitumor activity docetaxel were compared flank orthotopic xenograft patient-derived atypical teratoid rhabdoid tumor (ATRT), medulloblastoma, central nervous system primitive neuroectodermal (CNS-PNET). Efficacy also assessed Smo/Smo spontaneous...
Fluorescence molecular imaging with exogenous probes improves specificity for the detection of diseased tissues by targeting unambiguous signatures. Additionally, increased diagnostic sensitivity is expected application multiple probes. We developed a real-time multispectral fluorescence-reflectance scanning fiber endoscope (SFE) wide-field fluorescent dye-labeled at nanomolar levels. Concurrent multichannel SFE also allows mitigation background autofluorescence (AF) signal, especially when...
Macrophage migration inhibitory factor (MIF) has been proposed as a link between inflammation and tumorigenesis. Despite its potentially broad influence in tumour biology prevalent expression, the value of MIF therapeutic target cancer remains unclear. We sought to validate models by achieving complete inhibition expression cells stroma.We used shRNA-transduced B16-F10 melanoma implanted wild-type MIF-/- C57Bl6 mice investigate effect loss on growth. Cytokine detection immunohistochemistry...
Zinc finger domain genes comprise ~3% of the human genome, yet many their functions remain unknown. Here we investigated roles for vertebrate-specific BTB zinc gene ZNF131 in context brain tumors. We report that is broadly required Glioblastoma stem-like cell (GSC) viability, but dispensable neural progenitor (NPC) viability. Examination expression changes after knockdown (kd) revealed activity notably promotes Joubert Syndrome ciliopathy genes, including KIF7, NPHP1, and TMEM237, as well...
Medulloblastoma (MB) is the most common malignant paediatric brain tumour and a leading cause of cancer-related mortality morbidity. Existing treatment protocols are aggressive in nature resulting significant neurological, intellectual physical disabilities for children undergoing treatment. Thus, there an urgent need improved, targeted therapies that minimize these harmful side effects. We identified candidate drugs MB using network-based systems-pharmacogenomics approach: based on results...
Cystine-dense peptides (CDPs) are a miniprotein class that can drug difficult targets with high affinity and low immunogenicity. Tools for their design, however, not as developed those small-molecule antibody drugs. CDPs have diverse taxonomic origins, but structural characterization is lacking. Here, we adapted Iterative Threading ASSEmbly Refinement (I-TASSER) Rosetta protein modeling software prediction of 4298 CDP scaffolds performed in silico prescreening binders to interest. Mammalian...
Introduction Ependymomas (EPN) are the third most common malignant brain cancer in children. Treatment strategies for pediatric EPN have remained unchanged over recent decades, with 10-year survival rates stagnating at just 67% children aged 0-14 years. Moreover, a proportion of patients who survive treatment often suffer long-term neurological side effects as result therapy. It is evident that there need safer, more effective treatments patients. There ten distinct subgroups EPN, each their...
Although a greater extent of tumor resection is important for patients' survival, complete removal, especially margins, remains challenging due to the lack sensitivity and specificity current surgical guidance techniques at margins. Intraoperative fluorescence imaging with targeted fluorophores promising margin delineation. To verify margins detected by images, it necessary register histological which provide ground truth regions. However, registration methods compare images single-layer...
Abstract To identify key regulators of human brain tumor maintenance and initiation, we performed multiple genome-wide RNAi screens in patient-derived glioblastoma multiforme (GBM) stem cells (GSCs). These identified the PHD-finger domain protein PHF5A as differentially required for GSC expansion gene, compared to untransformed neural (NSCs) fibroblasts. Given PHF5A's known involvement facilitating interactions between U2 snRNP complex ATP-dependent helicases, examined cancer-specific roles...
Diffuse intrinsic pontine glioma (DIPG) remains a universally fatal childhood cancer with median survival of less than 1 year. Focal radiation the standard care as surgical resection is impossible and conventional cytotoxic chemotherapy has very limited efficacy. Building on success other autopsy-derived DIPG cell cultures, we have created novel patient-derived culture, PBT-14FHTC, characterized by mutations in H3FA3, TP53, amplifications PDGFRα cKIT. Previous work demonstrated efficacy...
Many disease-causing proteins have multiple pathogenic mechanisms, and conventional inhibitors struggle to reliably disrupt more than one. Targeted protein degradation (TPD) can eliminate the protein, thus all its functions, by directing a cell's turnover machinery towards it. Two established strategies either engage catalytic E3 ligases or drive uptake endolysosomal pathway. Here we describe CYpHER (CatalYtic pH-dependent Endolysosomal delivery with Recycling) technology potency durability...
Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. To identify genes differentially required for viability of GBM stem-like cells (GSCs), we performed functional genomic lethality screens comparing GSCs control human neural stem cells. Among top-scoring hits a subset was F-box-containing gene FBXO42, which also predicted to be essential ∼15% cell lines derived from broad range cancers. Mechanistic studies revealed that, sensitive cells, FBXO42 activity prevents...