A5026935337- Cancer Mechanisms and Therapy
- PI3K/AKT/mTOR signaling in cancer
- Protein Degradation and Inhibitors
- Signaling Pathways in Disease
- Cytokine Signaling Pathways and Interactions
- interferon and immune responses
- PARP inhibition in cancer therapy
- Caveolin-1 and cellular processes
- Cancer Genomics and Diagnostics
- Hematological disorders and diagnostics
- Quinazolinone synthesis and applications
- Single-cell and spatial transcriptomics
- Berberine and alkaloids research
- Cell Image Analysis Techniques
- Bioactive Natural Diterpenoids Research
- Histone Deacetylase Inhibitors Research
- Inflammatory Biomarkers in Disease Prognosis
- FOXO transcription factor regulation
- Cancer Diagnosis and Treatment
- Autophagy in Disease and Therapy
University of California, San Francisco
2019-2022
UCSF Helen Diller Family Comprehensive Cancer Center
2019-2022
Central South University
2018-2019
Second Xiangya Hospital of Central South University
2018-2019
Abstract On-target–off-tissue drug engagement is an important source of adverse effects that constrains the therapeutic window candidates 1,2 . In diseases central nervous system, drugs with brain-restricted pharmacology are highly desirable. Here we report a strategy to achieve inhibition mammalian target rapamycin (mTOR) while sparing mTOR activity elsewhere through use brain-permeable inhibitor RapaLink-1 and brain-impermeable FKBP12 ligand RapaBlock. We show this combination mitigates...
Abstract The mTOR signaling is dysregulated prominently in human cancers including glioblastoma, suggesting as a robust target for therapy. Inhibitors of have had limited success clinically, however, part because their mechanism action cytostatic rather than cytotoxic. Here, we tested three distinct kinase inhibitors (TORKi) PP242, KU-0063794, and sapanisertib against glioblastoma cells. All agents similarly decreased proliferation cells, whereas PP242 uniquely induced apoptosis. Apoptosis...
The transcription factor signal transducer and activator of 3 (STAT3) drives progression in glioblastoma (GBM), suggesting STAT3 as a therapeutic target. Surprisingly however, GBM cells generally show primary resistance to blockade.Human cell lines LN229, U87, SF767, U373, patient-derived xenografts (PDXs) GBM8 GBM43 were used evaluate epidermal growth receptor (EGFR) activation during inhibition. Protein gene expression experiments, protein stability assays, cytokine arrays,...
Abstract On-target-off-tissue drug engagement is an important source of adverse effects that constrains the therapeutic window candidates. In diseases central nervous system, drugs with brain-restricted pharmacology are highly desirable. Here we report a strategy to achieve inhibition mTOR while sparing activity elsewhere through use brain-permeable inhibitor RapaLink-1 and brain-impermeable FKBP12 ligand RapaBlock. We show this combination mitigates systemic inhibitors but retains efficacy...
Abstract On-target-off-tissue drug engagement is an important source of adverse effects that constrains the therapeutic window candidates. In diseases central nervous system, drugs with brain-restricted pharmacology are highly desirable. Here we report a strategy to achieve inhibition mTOR while sparing activity elsewhere through use brain-permeable inhibitor RapaLink-1 and brain-impermeable FKBP12 ligand RapaBlock. We show this combination mitigates systemic inhibitors but retains efficacy...
<div>Abstract<p>The mTOR signaling is dysregulated prominently in human cancers including glioblastoma, suggesting as a robust target for therapy. Inhibitors of have had limited success clinically, however, part because their mechanism action cytostatic rather than cytotoxic. Here, we tested three distinct kinase inhibitors (TORKi) PP242, KU-0063794, and sapanisertib against glioblastoma cells. All agents similarly decreased proliferation cells, whereas PP242 uniquely induced...
<p>Supplementary Figure S1. PP242 induced apoptosis through a mitochondrial-dependent pathway. Supplementary S2. showed potent blockade of p-MARCKS, but not p-STAT3Y705 in GBM6 cells. S3. Effects PKC, JAK2, and mTOR inhibitors on cell proliferation apoptosis. S4. Cooperative PKCα JAK2 drives S5. Efficacy tolerability combination therapy mice.</p>
<p>Supplementary Figure S1. PP242 induced apoptosis through a mitochondrial-dependent pathway. Supplementary S2. showed potent blockade of p-MARCKS, but not p-STAT3Y705 in GBM6 cells. S3. Effects PKC, JAK2, and mTOR inhibitors on cell proliferation apoptosis. S4. Cooperative PKCα JAK2 drives S5. Efficacy tolerability combination therapy mice.</p>
<div>Abstract<p>The mTOR signaling is dysregulated prominently in human cancers including glioblastoma, suggesting as a robust target for therapy. Inhibitors of have had limited success clinically, however, part because their mechanism action cytostatic rather than cytotoxic. Here, we tested three distinct kinase inhibitors (TORKi) PP242, KU-0063794, and sapanisertib against glioblastoma cells. All agents similarly decreased proliferation cells, whereas PP242 uniquely induced...
BACKGROUND: Glioblastoma (GBM) has dysregulated signaling of the mTOR pathway. Rapalink-1, a bivalent inhibitor created by linking rapamycin and sapanisertib, can bind to both drug binding pockets, potently inhibits mTORC1 in vitro vivo. Although Rapalink-1 represents novel path towards inhibition, cellular responses glioblastoma are mostly cytostatic. B cell lymphoma 2 (Bcl-2) family members play central role programmed death, orchestrating pro- anti- apoptotic signals. Pro-survival Bcl-2...
Abstract Activation of phosphatidylinositol 3-kinase (PI3K)/PTEN pathway and oncogenic signaling via the mechanistic target rapamycin (mTOR) occur in a majority high-grade glial brain tumors. Allosteric mTOR inhibitors, such as other rapalogs, incompletely block mTORC1 by reducing phosphorylation some substrates, including S6K1, but not 4EBP1. In contrast, ATP-competitive sapanisertib, fully inhibit mTORC1. However these inhibitors are also active against mTORC2 lipid kinases, likely...