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Hitting the perfect bullseye to stop prostate cancer from spreading

May 04, 2016

Prostate cancer is not a difficult cancer to treat if it’s found before it spreads, but – like many cancers - once it metastasizes throughout the body, the chances of survival greatly lessen.

Benyi Li, M.D./Ph.D., member of the Drug Discovery, Delivery and Experimental Therapeutics Research Program at The University of Kansas Cancer Center.Benyi Li, M.D., Ph.D., member of the Drug Discovery, Delivery and Experimental Therapeutics Research Program at The University of Kansas Cancer Center, is looking to find a target for treating metastatic prostate cancer. 

Dr. Li is looking at small activating RNA (saRNA), which enhances gene transcription by acting on gene promoters. His lab will use the saRNA to target a recently identified metastatic suppressor in prostate cancers: collapsing response mediator protein-4 (CRMP4), also called DPYSL3 gene. 

“It’s hard to push gene production in the body,” said Dr. Li. “If we’re able to use these short chains of RNA to help boost the process, that will make it easier.”

Making this happen, however, is slightly more complicated. The saRNA molecules will be attached to a prostate cancer-specific Aptamer, which is a single-stranded RNA molecule that can bind to pre-selected, specific targets. In this case, the target is PSMA, a prostate cancer cell-specific membrane surface protein.

CRMP4 was determined to be the best target because it is not expressed highly in metastatic lymph node tumors compared to primary tumors. When CRMP4 is over expressed, it stopped the cells’ ability to move and also strongly inhibited metastasis in animal models.

“This is a very specific process-we only want to activate the one gene,” said Dr. Li. “We activate the driver (promoter) with the saRNA, which will hone in on the CRMP4 and stop the cells from leaving the primary tumor and metastasizing.”

Dr. Li notes that they cannot artificially make the CRMP4 protein as it will not have the same effect as if naturally occurring in the body. 

Promoting or creating gene production in the body is difficult to do, according to Dr. Li. Genes don’t do the actual work; they instead serve as an “instruction manual” of sorts for making RNA and proteins, which do the actual work. 

On the other hand, creating the saRNA is an easy process as it’s only 20 nucleotides strung together. Once the saRNA is attached to the prostate cancer-specific Aptamer, it will carry out the work itself and start promoting the transcription of the CRMP4 gene.

“We’re kind of creating the trigger to set everything in motion,” said Dr. Li. “Because it has such a specific target and is only able to enhance the production of this one particular protein, we just need to get that process in motion so the cancer cells don’t spread.”

His team has finished testing in petri dishes and has now moved on to animal model testing. Dr. Li is hopeful that eventually a therapy can be developed to prevent prostate cancer from spreading further or from spreading at all. 

“Cancer is very difficult to control once it’s moved away from its primary tumor location,” said Dr. Li. “Finding a therapy or drug that can stop or interrupt that process would likely save a lot of lives.”

Relevant publications

  • Li, B., Thrasher, J. B., & Terranova, P. (2015, November). Glycogen synthase kinase-3: A potential preventive target for prostate cancer management. In Urologic Oncology: Seminars and Original Investigations(Vol. 33, No. 11, pp. 456-463). Elsevier.

  • Parker, W., Hu, Q., Wencong, J., Thrasher, J. B., & Li, B. (2015). MP61-09 Promoter-targeted double-strand RNA duplex enhances DPYSL3 gene expression in prostate cancer cells. The Journal of Urology, 193(4), e749-e750.

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