Papers by Natalie Pursell
CUDC-907, a Dual HDAC and PI3K Inhibitor, Potentially Targets Cancer Cells and The Microenvironment In Hematological Malignancies
Blood, Nov 15, 2013
Inhibition of Glycolate Oxidase with Dicer-Substrate siRNA Reduces Calcium Oxalate Deposition in a Mouse Model of Primary Hyperoxaluria Type I
Molecular Therapy, 2016
Primary hyperoxaluria type 1 (PH1) is an autosomal recessive, metabolic disorder caused by mutati... more Primary hyperoxaluria type 1 (PH1) is an autosomal recessive, metabolic disorder caused by mutations of alanine-glyoxylate aminotransferase (AGT), a key hepatic enzyme in the detoxification of glyoxylate arising from multiple normal metabolic pathways to glycine. Accumulation of glyoxylate, a precursor of oxalate, leads to the overproduction of oxalate in the liver, which accumulates to high levels in kidneys and urine. Crystalization of calcium oxalate (CaOx) in the kidney ultimately results in renal failure. Currently, the only treatment effective in reduction of oxalate production in patients who do not respond to high-dose vitamin B6 therapy is a combined liver/kidney transplant. We explored an alternative approach to prevent glyoxylate production using Dicer-substrate small interfering RNAs (DsiRNAs) targeting hydroxyacid oxidase 1 (HAO1) mRNA which encodes glycolate oxidase (GO), to reduce the hepatic conversion of glycolate to glyoxylate. This approach efficiently reduces GO mRNA and protein in the livers of mice and non-human primates. Reduction of hepatic GO leads to normalization of urine oxalate levels and reduces CaOx deposition in a preclinical mouse model of PH1. Our results support the use of DsiRNA to reduce liver GO levels as a potential therapeutic approach to treat PH1.Molecular Therapy (2016); doi:10.1038/mt.2016.4.
Abstract B20: EnCore-LNP mediated tumor delivery of MYC and CTNNB1 Dicer Substrate RNAs (DsiRNAs)
Molecular Cancer Research, 2015
Molecular Cancer Therapeutics, 2013
CUDC-101 is a novel, small-molecule, anti-cancer agent targeting histone deacetylases (HDACs), ep... more CUDC-101 is a novel, small-molecule, anti-cancer agent targeting histone deacetylases (HDACs), epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER2). It is currently in Phase I clinical development in patients with solid tumors. Previously, we reported that CUDC-101 has potent anti-proliferative and proapoptotic activity in cultured tumor cells and in vivo xenograft models. We now show that cancer cells that have acquired resistance to single-target EGFR inhibitors through upregulation of AXL or loss of E-cadherin remain sensitive to CUDC-101, which inhibits MET-and AXL-mediated signaling, restores E-cadherin expression, and reduces cell migration. CUDC-101 also efficiently inhibited the proliferation of MET-overexpressing non-small cell lung cancer and gastric cancer cell lines and inhibited the migration and invasion of invasive tumor cells. Taken together, these results suggest that coupling HDAC and HER2 inhibitory activities to an EGFR inhibitor may potentially be effective in overcoming drug resistance and preventing cancer cell migration.
Eukaryotic Cell, 2012
The Hsp90 chaperone is required for the maturation of signal transduction clients, including many... more The Hsp90 chaperone is required for the maturation of signal transduction clients, including many kinases and nuclear steroid hormone receptors. The binding and hydrolysis of ATP by Hsp90 drive conformational rearrangements in three structure domains. Two intrinsically disordered regions of Hsp90 located between these domains and at the C terminus have traditionally been considered to impart flexibility. We discovered that the charged nature of these acid-rich disordered regions imparts a solubility-promoting function to Hsp90 that is important for its cellular activity in yeast. Both the solubility-promoting function and ATPase activity must occur in the same Hsp90 molecule in order to support robust growth, suggesting that the solubility-promoting function is required during the ATP-driven client maturation process. Expression of model clients together with Hsp90 variants indicated interdependent solubilities mediated by the aggregation propensities of both the client and Hsp90. We propose a model whereby the charge-rich disordered regions of Hsp90 serve a solubility-promoting function important for complexes with aggregation-prone clients. These findings demonstrate a novel biological function of the intrinsically disordered regions in Hsp90 and provide a compelling rationale for why their charged properties are conserved throughout eukaryotic evolution.
Abstract 748: Novel selective orally bioavailable small molecule PAK4 allosteric modulators display antitumor activity and induce apoptosis in vitro and in vivo
Cancer Research, 2014
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Papers by Natalie Pursell