The translational goal in Project 4 is to identify and bring forward into clinical trials one or two lead compounds that will suppress c-Myc transcription by targeting the NM23-H2-DNA complex. This proposal builds upon progress from the last grant period and will further test hypothesis that the NM23-H2-DNA complex is critically involved in transcriptional activation of c-Myc and c-Myc is a critical factor in colon cancer.
The specific aims of the proposal are (1) structural characterization of the G-quadruplex-drug complexes in the c-Myc promoter, (2) to establish in vitro biochemical and cell-based screens to identify small molecules that inhibit binding of NM23-H2 to the G-quadruplex in the silencer element of the c-Myc promoter, (3) to discover and optimize G-quadruplex- and NM23-H2-interactive compounds using computer- aided drug design and structure-based and virtual-screening approaches, (4) In vivo evaluation and subsequent preclinical development, and (5) to file an IND for Phase I clinical trial and overall clinical development program. High-field NMR will be used to characterize the drug-G-quadruplex complex, molecular modeling will be used to identify new lead compounds, and fluorescence resonance energy transfer (FRET) and double-filter methods will be used for identification of in vitro biochemical hits. A luciferase-based high-throughput screen has already been used to identify hits, and subsequent assays will be carried out in matched cell lines genetically engineered to provide proof of principle that the mechanism of action is as proposed. Structure-based approaches will be used to aid in lead optimization. Following lead optimization, an IND will be filed and the clinical development program will be based upon discoveries from specific aims 1-4. Immunohistochemistry will be used to guide patient selection and phase I and II clinical trial plans will be designed to determine whether the new agents will help patients with advanced colorectal cancer. The long-term goal of this research is to develop novel target-directed drugs for treatment of colorectal cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA095060-08
Application #
7799145
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
8
Fiscal Year
2009
Total Cost
$342,587
Indirect Cost
Name
University of Arizona
Department
Type
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Goldenberg, Joshua M; Pagel, Mark D; Cárdenas-Rodríguez, Julio (2018) Characterization of D-maltose as a T2 -exchange contrast agent for dynamic contrast-enhanced MRI. Magn Reson Med 80:1158-1164
Jones, Kyle M; Pollard, Alyssa C; Pagel, Mark D (2018) Clinical applications of chemical exchange saturation transfer (CEST) MRI. J Magn Reson Imaging 47:11-27
Goldenberg, Joshua M; Cárdenas-Rodríguez, Julio; Pagel, Mark D (2018) Preliminary Results that Assess Metformin Treatment in a Preclinical Model of Pancreatic Cancer Using Simultaneous [18F]FDG PET and acidoCEST MRI. Mol Imaging Biol 20:575-583
Daryaei, Iman; Randtke, Edward A; Pagel, Mark D (2017) A biomarker-responsive T2exMRI contrast agent. Magn Reson Med 77:1665-1670
Daryaei, Iman; Jones, Kyle M; Pagel, Mark D (2017) Detection of DT-diaphorase Enzyme with a ParaCEST MRI Contrast Agent. Chemistry 23:6514-6517
Shkreta, Lulzim; Blanchette, Marco; Toutant, Johanne et al. (2017) Modulation of the splicing regulatory function of SRSF10 by a novel compound that impairs HIV-1 replication. Nucleic Acids Res 45:4051-4067
Kurzius-Spencer, Margaret; Harris, Robin B; Hartz, Vern et al. (2016) Relation of dietary inorganic arsenic to serum matrix metalloproteinase-9 (MMP-9) at different threshold concentrations of tap water arsenic. J Expo Sci Environ Epidemiol 26:445-51
Tsikitis, Vassiliki L; Potter, Amiee; Mori, Motomi et al. (2016) MicroRNA Signatures of Colonic Polyps on Screening and Histology. Cancer Prev Res (Phila) 9:942-949
Hingorani, Dina V; Montano, Luis A; Randtke, Edward A et al. (2016) A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals. Contrast Media Mol Imaging 11:130-8
Fernández-Cuervo, Gabriela; Sinharay, Sanhita; Pagel, Mark D (2016) A CatalyCEST MRI Contrast Agent that Can Simultaneously Detect Two Enzyme Activities. Chembiochem 17:383-7

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