Molecules that disrupt cell division are employed broadly in the treatment of cancer. The mechanism is effective because cancer cells replicate more frequently than normal. However, systemic poisoning of this kind has limits and side effects accompanying the use of conventional anti-mitotics are well discussed. For the past three years, we have studied a new type of small molecule anti-mitotic - a natural product called diazonamide A. It is highly effective at blocking spindle assembly in cell culture, and does so through a unique mechanism. The compound targets a previously unknown proteolyzed form of the metabolic enzyme ornthine 5-amino transferase (OAT). This truncated protein functions in the spindle assembly process, acting in concert with mitotic machinery downstream of the small GTPase Ran. Diazonamide inhibits this unexpected second function of OAT. A particularly exciting aspect of this discovery is that OAT-mediated spindle assembly is not required for normal development, as evidenced by the viability of OAT-null mice. Redundancies must exist, although OAT clearly supports rapid cell division. When a synthetic diazonamide is dosed intravenously in nude mice, one can fully regress implanted human tumors without noticeable neutropenia or weight loss. This is unprecedented for a small molecule anti-mitotic. Our proposal aims to explore the origins of this selectivity and chart what appears to be a new regulatory pathway controlling onset of spindle assemble in higher eukaryotes. We propose a rigorous biochemical analysis of OAT functions in mitosis as well as studies of animals lacking the OAT gene product on genetic backgrounds predisposed to cancer. This research is relevant to public health because it could help understand how a new cancer drug works and guide its use in the clinic.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA095471-09
Application #
8117615
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
9
Fiscal Year
2010
Total Cost
$317,946
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Qi, Chen; Wang, Xin; Shen, Zhirong et al. (2018) Anti-mitotic chemotherapeutics promote apoptosis through TL1A-activated death receptor 3 in cancer cells. Cell Res 28:544-555
Zhang, Lu; Theodoropoulos, Panayotis C; Eskiocak, Ugur et al. (2016) Selective targeting of mutant adenomatous polyposis coli (APC) in colorectal cancer. Sci Transl Med 8:361ra140
Guo, Yirui; Scheuermann, Thomas H; Partch, Carrie L et al. (2015) Coiled-coil coactivators play a structural role mediating interactions in hypoxia-inducible factor heterodimerization. J Biol Chem 290:7707-21
Scheuermann, Thomas H; Stroud, Daniel; Sleet, Christopher E et al. (2015) Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2. J Med Chem 58:5930-41
Rose, Tristan E; Lawson, Kenneth V; Harran, Patrick G (2015) Large ring-forming alkylations provide facile access to composite macrocycles. Chem Sci 6:2219-2223
Zhang, Yongyou; Desai, Amar; Yang, Sung Yeun et al. (2015) TISSUE REGENERATION. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration. Science 348:aaa2340
Iscla, Irene; Wray, Robin; Wei, Shuguang et al. (2014) Streptomycin potency is dependent on MscL channel expression. Nat Commun 5:4891
Rogers, Jamie L; Bayeh, Liela; Scheuermann, Thomas H et al. (2013) Development of inhibitors of the PAS-B domain of the HIF-2ýý transcription factor. J Med Chem 56:1739-47
Wang, Changguang; Williams, Noelle S (2013) A mass balance approach for calculation of recovery and binding enables the use of ultrafiltration as a rapid method for measurement of plasma protein binding for even highly lipophilic compounds. J Pharm Biomed Anal 75:112-7
Kilgore, Jessica A; Du, Xinlin; Melito, Lisa et al. (2013) Identification of DNMT1 selective antagonists using a novel scintillation proximity assay. J Biol Chem 288:19673-84

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