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WE ARE PLEASED TO ANNOUNCE A SEMINAR PRESENTED BY
Doris Benbrook, Ph.D.
Professor, Director of Research and Chair in Gynecologic Oncology
Department of Obstetrics and Gynecology
University of Oklahoma Health Science Center
“A Journey from Vitamin A to Mortalin in a Quest to Prevent Cancer”
Thursday, April 16, 2015 at 3:00 PM
Astellas Conference Room, SLSRC 3410/3430
Refreshments will be served at 2:45 PM
Our goal is to develop a dietary supplement that can prevent cancer without causing side effects. Our starting point
was retinoic acid, the active metabolite of vitamin A which is limited in its use for cancer treatment by toxicity.
Incorporation of the flexible side chain of retinoic acid into an aromatic ring produced arotinoid compounds that
retained the biological activity of retinoic acid, but which exhibited 1000 fold greater toxicity. We reduced the
toxicity of arotinoids 1000 fold by incorporating a heteroatom into the bicyclic ring. Our structure activity
relationship studies found that increasing the specificity of heteroarotinoid compounds for individual nuclear
retinoic acid receptors could not separate the efficacy from the toxicity. Incorporation of a flexible linker in
between the two aromatic groups of heteroarotinoids produced flexible heteroarotinoids (Flex-Hets) that induce
apoptosis in cancer cells without harming normal cells, but without activating the nuclear retinoic acid receptors.
Our lead Flex-Het, called OK-1 (previously SHetA2) possesses cancer prevention activity in rodents and was
awarded NCI RAID and RAPID grants, which completed pre-clinical tests needed to initiate clinical trials, however
identification of the molecular target was critically needed. We identified mortalin as the drug target using
magnetic microspheres conjugated with OK-1, and Mass spec analysis. Our co-IP experiments demonstrated that
OK-1 prevents mortalin from binding and inhibiting client proteins, p53 and p66shc, which can induce apoptosis.
Differential effects of OK-1 on mortalin processing observed in healthy and cancer cells is consistent with the OK-1
induction of apoptosis and autophagy in cancer cells, but not in healthy cells. Initiation of funding and FDA
approval for OK-1 clinical trials is anticipated to start within a year.
Biography: Doris Mangiaracina Benbrook, PhD earned her Bachelor’s degrees in Biology and Chemistry at North
Central College in Naperville, IL. Her PhD thesis work in Biochemistry at Loyola University Medical Center in
Maywood, IL revealed why the antibiotic Norfloxacin was cytotoxic at lower concentrations, but only cytostatic at
higher concentrations. In her postdoctoral work at the La Jolla Cancer Research Foundation, she cloned a nuclear
retinoic acid receptor, a thyroid hormone receptor and a cholesterol receptor. As a research fellow at the Imperial
Cancer Research Fund in London, England she demonstrated cross-talk between the AP-1 and CREB transcription
factors, which had previously been considered separate pathways. Since joining the faculty at the University of
Oklahoma Health Sciences Center, the primary focus of her research has been developing biomarkers and drugs for
prevention and treatment of cancer. Her expertise is recognized at the international level by extensive service as
chair and member of multiple grant review committees, Editor-in-Chief of Biologics: Targets & Therapy and expert
witness in pharmaceutical patent litigation, and by invitations to speak at international conferences.
Stephenson Life Sciences Research Center, 101 Stephenson Parkway, Norman, Oklahoma 73019
PHONE: (405) 325-2219 • FAX: (405) 325-6111 • EMAIL: [email protected] • WEBSITE: inpart.ou.edu