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OU Researcher’s Drug Targets Ovarian Cancer Prevention

Thursday, August 6, 2015 - Campus News -
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The world is always searching for a “magic bullet” or for that  “magic pill” when it comes to preventing or treating disease.  

Preventing ovarian cancer with a capsule might sound impossible to many, but not to Doris M. Benbrook, Ph.D. at the University of Oklahoma Health Sciences Center. However, she is quick to point out that it is research, not magic, that has led her team to the development of a potential cancer prevention drug in capsule form.

Benbrook is a researcher and professor of obstetrics and gynecology with the OU College of Medicine and member of the Stephenson Cancer Center. With the help of a new $3 million grant from the National Cancer Institute, her team plans to move their research from bench to bedside.

The grant funds a first-in-human clinical trial at the Stephenson Cancer Center focusing on OK-1, an anti-cancer compound shown in laboratory studies by OU researchers to prevent the formation of cancerous tumors without causing side effects.

However, Benbrook knew ovarian cancer prevention trials would be difficult without first developing better biomarkers to identify which women will get ovarian cancer and which are at higher risk for getting it soon.

“I think one reason the National Cancer Institute found our work really worth the investment is that we proposed a way to not only prevent cancer but to understand how cancer starts and identify which patients may need prevention,” Benbrook said.

The new clinical trial is the result of Benbrook’s decades-long research into chemoprevention and also of her long-standing collaboration with Oklahoma State University chemist, K.Darrell Berlin, Ph.D. Together, they developed a promising class of anti-cancer compounds called Flexible Heteroarotinoids or Flex-Hets. The lead Flex-Het is the study drug OK-1.  

In collaboration with fellow Stephenson Cancer Center member C.V. Rao, Ph.D., of the OU College of Medicine, the team proved the cancer prevention activity of OK-1 in a laboratory model.

But before clinical trials could begin, Benbrook said she needed to work through FDA regulations and also develop a formulation capable of getting the compound through the digestive process and into the tissues where it was needed.  

Multimillion dollar preclinical development grants from the National Cancer Institute as well as collaborations with Sukyung (Sue) Woo, Ph.D. and Lucila Garcia-Contreras, Ph.D., of the OU College of Pharmacy proved crucial to this process.

Now with their new NCI grant, the team plans to determine whether their formulation, when given to patients, can achieve levels necessary for cancer prevention in both the blood and also in fallopian tube tissue where ovarian cancer often starts.  

Researchers plan to enroll about 12 women in the clinical trial to first identify the number of capsules of OK-1 needed to achieve adequate blood levels. 

Then, in a second stage of the study, they will enroll women scheduled for routine hysterectomy. Those women will receive capsules of OK-1 for a period of seven days prior to surgery. Benbrook and her colleagues will study the fallopian tubes removed during surgery. The goal is to determine how many capsules are needed  to achieve adequate levels of the compound in fallopian tube tissue. 

They will also use the fallopian tubes to study how ovarian cancer develops. Benbrook said their best clue is a molecule called mortalin and its many interacting proteins. 

“At the earliest stages of cancer development, something about mortalin changes causing cells to lose normal growth control.  Because our compound affects mortalin in non-cancer cells differently than in cancer cells, we believe we can use OK-1 as a tool to understand how mortalin starts the cancer process,” she explained.

Benbrook said if OK-1 performs as hoped, it could virtually kill the cancer the moment it becomes cancerous. 

“The goal is to kill those cells at the instant they lose normal growth control, which is how cancer starts. Knowing the molecule through which this drug works provides a clue as to how to find them, in other words it helps us find the needle within the haystack of normal cells,” she said.
She expects the new clinical trial may be completed within two years. Then with the knowledge gained, Benbrook said large, nationwide clinical trials of OK-1 could be planned. 

Benbrook’s research is funded by (1R01CA196200-01A1) of the National Cancer Institute at the National Institutes of Health. The preclinical testing needed for Food and Drug Administration approval to begin the clinical trial was funded through the NCI Rapid Access to Intervention Development and Rapid Access to Prevention Interventive Development programs.  

Benbrook said researchers at Oklahoma State University working with her to develop improved versions of OK-1 include: K. Darrell Berlin, Ph.D., Richard  Bunce, Ph.D.,  Donghua Zhou, Ph.D  and Gopan Krishnan, Ph.D., and their students.  

Other collaborators William Kelly, Ph.D. at Southwestern Oklahoma State University and Dana Rundle, at the University of Central Oklahoma have mentored undergraduate student research projects that contributed to this drug development program through funding by Oklahoma IDeA Network of Biomedical Research Excellence, a grant awarded by the National Institutes of Health Institutional  Award Program.   

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