A5011524529- Neuroblastoma Research and Treatments
- Ubiquitin and proteasome pathways
- RNA modifications and cancer
- Immunotherapy and Immune Responses
- Protein Degradation and Inhibitors
- RNA and protein synthesis mechanisms
- Signaling Pathways in Disease
- Glioma Diagnosis and Treatment
- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- Cancer, Hypoxia, and Metabolism
- T-cell and B-cell Immunology
- Protein Kinase Regulation and GTPase Signaling
- Histone Deacetylase Inhibitors Research
- ATP Synthase and ATPases Research
- PI3K/AKT/mTOR signaling in cancer
- Immune Cell Function and Interaction
- Peptidase Inhibition and Analysis
- Genetics and Neurodevelopmental Disorders
- 14-3-3 protein interactions
- Bacterial biofilms and quorum sensing
- RNA Research and Splicing
- Hematopoietic Stem Cell Transplantation
- Phagocytosis and Immune Regulation
- Microtubule and mitosis dynamics
UCSF Helen Diller Family Comprehensive Cancer Center
2017-2024
University of California, San Francisco
2016-2024
Revolution Medicines (United States)
2022-2024
Neurological Surgery
2021-2022
Oregon State University
2011-2019
UCSF Benioff Children's Hospital
2016
Center for Cancer Research
2012-2014
Cancer Institute (WIA)
2014
National Cancer Institute
2011-2013
National Institutes of Health
2011-2013
Abstract RAS oncogenes (collectively NRAS , HRAS and especially KRAS ) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 61 1 . Small molecule inhibitors of KRAS(G12C) oncoprotein have demonstrated clinical efficacy patients multiple cancer types led to regulatory approvals for treatment non-small cell lung 2,3 Nevertheless, G12C account only around 15% -mutated cancers 4,5 there no approved majority tumours containing other...
Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy. For the childhood neuroblastoma, amplification of oncogene MYCN is associated with high-risk disease and poor prognosis. Here, we deployed genome-scale CRISPR-Cas9 screening MYCN-amplified neuroblastoma found preferential dependency on genes encoding polycomb repressive complex 2 (PRC2) components EZH2, EED, SUZ12. Genetic pharmacological suppression EZH2 inhibited growth...
Glioblastoma (GBM) is refractory to immune checkpoint inhibitor (ICI) therapy. We sought determine what extent this evasion due intrinsic properties of the tumor cells versus specialized context brain, and if it can be reversed.
Abstract Mutant RAS is common in pancreatic carcinoma (PDAC), non-small cell lung cancer (NSCLC) and colorectal (CRC) exists predominantly the GTP-bound (RAS(ON)) state, leading to excessive downstream oncogenic signaling. KRASG12C(OFF) inhibitors have provided clinical proof of concept for targeting mutant KRAS. Preclinical data suggests inhibition RAS(ON) may be a superior therapeutic strategy. In addition, KRASG12 mutations such as KRASG12D KRASG12V remain unserved.RMC-6236...
Abstract The KRASG12C mutation is found in 11% of non-small cell lung cancers, 4% colorectal and 2% pancreatic cancers the U.S., drives these by shifting cellular equilibrium KRAS towards GTP-bound, active state, KRASG12C(ON). resulting increased levels KRASG12C(ON) turn increase signaling output to initiate support oncogenic state. In recent years, a class KRASG12C(OFF) inhibitors has transformed treatment landscape for patients with bearing KRASG12C. These work via sequestration GDP-bound,...
591 Background: RAS proteins (such as KRAS, NRAS, HRAS) are small GTPases that drive cell proliferation and survival when bound to GTP. Mutant exist predominantly in the GTP-bound (RAS(ON)) state, leading excessive downstream signaling via interaction with effectors such RAF kinases. Oncogenic KRAS is required for initiation, progression, maintenance of pancreatic ductal adenocarcinoma (PDAC) (Hezel et al, 2006, Ying al 2012). Although extinction expression well pharmacological inhibition...
Abstract Major epithelial tumors harboring the cancer driver KRASG12D, most common oncogenic KRAS mutation1, remain an outstanding unmet medical need. While RAS primarily promotes tumor progression through sustained cellular proliferation, there is also increasing evidence that it adversely shapes microenvironment (TME) induction of immuno-suppressive cytokines2, downregulation MHCI, and modulation checkpoint proteins3. KRASG12D oncoproteins can be selectively targeted with covalent...
Neuroblastoma is the most common extracranial solid tumor of childhood. While MYCN and mutant anaplastic lymphoma kinase (ALKF1174L) cooperate in tumorigenesis, how ALK contributes to formation remains unclear. Here, we used a human stem cell-based model neuroblastoma. Mis-expression ALKF1174L resulted shorter latency compared alone. tumors resembled adrenergic, while ALK/MYCN mesenchymal, Transcriptomic analysis revealed enrichment focal adhesion signaling, particularly extracellular matrix...
Cyclin-dependent kinases (CDKs) that have critical roles in RNA polymerase II (Pol II)-mediated gene transcription are emerging as therapeutic targets cancer. We previously shown THZ1, a covalent inhibitor of CDKs 7/12/13, leads to cytotoxicity MYCN-amplified neuroblastoma through the downregulation super-enhancer-associated transcriptional upregulation. Here we determined effects YKL-5-124, novel with greater selectivity for CDK7 cells.We tested YKL-5-124 and nonamplified cells individually...
Abstract Deregulation of neuroblastoma-derived myc (N-myc) is a leading cause malignant brain tumors in children. To target N-myc-driven medulloblastoma, most research has focused on identifying genomic alterations or the analysis medulloblastoma transcriptome. Here, we have broadly characterized translatome and shown that N-myc unexpectedly drives selective translation transcripts promote protein homeostasis. Cancer cells are constantly exposed to proteotoxic stress associated with...
Abstract Background Neuroblastoma is the most common extra-cranial pediatric solid tumor. 131 I-metaiodobenzylguanidine (MIBG) a targeted radiopharmaceutical highly specific for neuroblastoma tumors, providing potent radiotherapy to widely metastatic disease. Aurora kinase A (AURKA) plays role in mitosis and stabilization of MYCN protein neuroblastoma. We aimed study impact AURKA inhibitors on DNA damage tumor cell death combination with I-MIBG therapy pre-clinical model high-risk Results...
// Kieuhoa T. Vo 1 , Erin E. Karski Nicole M. Nasholm Shelly Allen Fabienne Hollinger W. Clay Gustafson Janel R. Long-Boyle 2 Stephen Shiboski 3 Katherine K. Matthay and Steven G. DuBois Department of Pediatrics, UCSF Benioff Children’s Hospital, University California, San Francisco School Medicine, Francisco, CA, USA Clinical Pharmacy, Epidemiology Biostatistics, Correspondence to: Vo, email: Keywords : phase 1, mTOR, sirolimus, topotecan, cyclophosphamide Received August 23, 2016...
Extracorporeal photopheresis (ECP) is emerging as a therapy for graft-versus-host-disease (GVHD), but the full mechanism of action and impact on immunity have not been fully established. After murine minor histocompatibility antigen-mismatched bone marrow (BM) transplantation (allo-BMT), coinfusion ECP-treated splenocytes with T cell-replete BM attenuated GVHD irrespective donor strain splenocytes, was associated increased numbers regulatory cells. Coculture myeloid dendritic cells (DCs)...
Abstract The KRASG12C mutation occurs in 11 - 14% of non-small cell lung cancers, ~4% colorectal and ~2% pancreatic cancers the U.S., drives these by shifting cellular equilibrium KRAS towards GTP-bound, active state, KRASG12C(ON). resulting increased levels KRASG12C(ON) turn increase signaling output to initiate support oncogenic state. RMC-6291 is a potent, orally bioavailable inhibitor that forms tri-complex within tumor cells along with cyclophilin A (CypA), driving near-immediate...
Amplification of MYCN is a poor prognostic feature in neuroblastoma (NBL) indicating aggressive disease. We and others have shown BET bromodomain inhibitors (BETi) target indirectly by downregulating its transcription. Here we sought to identify agents that synergize with BETi biomarkers resistance. previously performed viability screen ∼1,900 oncology-focused compounds combined against MYCN-amplified NBL cell lines. Reanalysis our screening results prominently identified aurora kinase A...
Abstract Tumor-targeted vaccines represent a strategy to enhance the graft-versus-leukemia effect after allogeneic blood and marrow transplantation (BMT). We have previously shown that graft-versus-host disease (GVHD) can negatively impact quantitative responses vaccines. Using minor histocompatibility Ag–mismatched BMT (B6→B6 × C3H.SW) followed by adoptive transfer of HY-specific T cells HY-expressing dendritic cells, we assessed whether GVHD induced donor lymphocyte infusion (DLI) affects...
Biofouling is synonymous with unwanted biofilms and leads to problems ranging from efficiency resource loss health risks. While a number of bacterial properties including biomass concentration hydrophobicity are considered critical biofilm development adhesion, the variations in these under growth starvation conditions not very well known. Here, we describe trends for four Gram-negative bacteria extended conditions. A convenient frequently-used laboratory assay, microbial adhesion...
The clinical success of allogeneic T cell therapy for cancer relies on the selection antigens that can effectively elicit antitumor responses with minimal toxicity toward nonmalignant tissues. Although minor histocompatibility (MiHA) represent promising targets, broad expression these has been associated poor and dysfunction may not be prevented by targeting MiHA limited expression. In this study, we hypothesized activity MiHA-specific CD8 cells after bone marrow transplantation (BMT) is...
Abstract Hydrophobicity is a vital parameter for initial cell adhesion that ultimately leads to biofouling of surfaces and loss system performance health issues. The efficiency number biological systems could be improved by increasing the hydrophobicity concerned bacteria. Here we used ammonium sulfate (salt) enhance bacterial hydrophobicity, as measured commonly liquid–liquid partitioning based assessment assay — MATH test. We observed successive increases in with incremental increase salt...
Abstract RAS oncogenes (collectively NRAS , HRAS and especially KRAS ) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 61 1 . Small molecule inhibitors of G12C oncoprotein have demonstrated clinical efficacy patients multiple cancer types led to regulatory approvals for treatment non-small-cell lung (NSCLC) 2,3 Nevertheless, account only ~14% cancers 4 there no approved majority tumors harboring other mutations. Here, we describe...
Abstract KRAS is the most frequently mutated oncogene in pancreatic ductal adenocarcinoma (PDAC), with KRASG12D driving initiation and progression of ~40% tumors. Mutant proteins exist predominantly GTP-bound (RAS(ON)) state, leading to excessive downstream signaling via interaction effectors such as RAF kinases. RMC-9805 an orally bioavailable, mutant-selective covalent inhibitor active state KRASG12D. RM-044, used here, corresponding representative preclinical tool compound. cyclophilin A...