Despite the continually rising incidence and mortality rates for prostate cancer, options for targeted imaging of the disease remain relatively limited.
To that end, in 2009 one researcher parlayed a $30,000 Bracco Diagnostics/RSNA Research Resident Grant into a project to develop a novel imaging tool that seeks to overcome those limitations and ultimately improve image-guided radiation therapy. That project led to additional American Cancer Society (ACS)-funded research on the subject.
“Improved imaging can help with management decisions and disease targeting with image-guided radiation therapy,” said William Rockey, M.D., Ph.D., an assistant professor of radiation oncology at the University of Iowa (UI) Hospitals and Clinics in Iowa City. “Many groups are doing exciting work using different approaches to address this need, but current U.S. Food and Drug Administration (FDA)-approved options for targeted imaging of prostate cancer are limited.”
In 2013, the National Cancer Institute estimates 238,590 new cases of prostate cancer in the U.S. and approximately 29,720 deaths from the disease.
Currently the only FDA-approved targeted imaging agent for prostate cancer is capromab penetide (trade name ProstaScint®), an antibody tethered to a single-photon emitting radionuclide. The imaging agent has been successful in imaging localized prostate cancer and larger lymphatic metastases but is less effective in detecting non-necrotic prostate tumors and smaller metastases. Because capromab is directed against a receptor expressed on prostate-specific membrane antigen (PSMA), ProstaScint can only bind to necrotic cells present in large tumors, which reduces its sensitivity. In addition, the imaging agent can remain in the body up to one week, potentially leading to liver and bone marrow toxicity and lower-quality images.
Dr. Rockey sought to overcome these limitations through his research project, “High-Resolution Ribonucleic Acid (RNA)-Based Targeted PET Imaging Agents for Prostate Cancer,” launched after seeing the success of his mentor, Paloma Giangrande, Ph.D., an assistant professor of internal medicine at UI, who used aptamers that bind to PSMA to deliver therapeutic small interfering RNA (siRNA). Dr. Rockey teamed with Dr. Giangrande and co-mentor and radiochemistry expert at UI, assistant professor of radiology Michael Schulz, M.D., to investigate further.
“We wanted to investigate whether these targeted aptamers could be used for imaging,” Dr. Rockey said.
Researchers demonstrated the binding of the aptamer to purified protein, human prostate cancer cells in culture and eventually targeted in vivo delivery to a mouse xenograft model of prostate cancer. They also conducted initial work in a mouse metastatic prostate cancer model.
“The goal was to conjugate a chelator that housed a radionuclide for PET or single-photon emission CT (SPECT) imaging to the aptamer,” Dr. Rockey said. “Along with Dr. Schulz’s research team, we investigated different chemistries and radiolabeling conditions that would be compatible with RNA and produce the highest labeling yields.”
One particularly exciting outcome was the development of a new aptamer sequence with improved affinity over a previously described RNA aptamer to PSMA. “We showed that this aptamer sequence inhibits PSMA’s enzymatic activity, which has been linked to carcinogenesis,” Dr. Rockey said. “These findings could potentially have therapeutic benefit.”
In addition, researchers were able to conjugate a near-infrared (NIR) fluorophore to the aptamer. “Targeted NIR imaging may in the future have potential clinical use for intraoperative evaluation of tumor margin status, extent and lymph node involvement,” Dr. Rockey said.
“Given the therapeutic potential of this PSMA RNA aptamer for applications including targeted imaging and therapy of prostate cancer, optimization to facilitate large-scale chemical synthesis of this RNA is compelling,” Dr. Giangrande added. This image-guided therapeutic option for prostate cancer represents a crucial step toward the development of treatment strategies that are safer and more effective than current FDA-approved options, she said.
Furthermore, Dr. Rockey’s work “highlighted the utility of computational RNA secondary and tertiary structure models for guiding the truncation of RNA aptamers in order to enable and expedite large-scale chemical synthesis of these RNAs for clinical applications,” Dr. Giangrande said. “Given the emerging therapeutic potential of RNA oligonucleotide aptamers, advancements that facilitate their translation into the clinic are desirable.”
The project opened the door to exciting new directions in his research, Dr. Rockey said. “The research project gave me hands-on experience in many fields, including molecular biology and radiochemistry,” said Dr. Rockey, who learned techniques for RNA transcription and purification and was mentored in radiochemistry by Dr. Schulz.
Dr. Rockey has since received an institutional ACS seed grant to continue developing an RNA aptamer for NIR and PET imaging of prostate cancer. He credits the RSNA grant with giving him a greater appreciation of the science behind diagnostic tests commonly ordered in the clinic, as well as their strengths and weaknesses.
“I think molecular imaging will have an integral role in the future for providing individualized care for cancer patients,” he said. “I’m excited about the benefits that improved imaging technologies can offer in developing better therapeutic outcomes while minimizing side-effects and toxicity.” q
Name: William Rockey, M.D., Ph.D.
Grant Received: Bracco Diagnostics/RSNA Resident Research grant
Study: “High-Resolution Ribonucleic Acid (RNA)-based Targeted PET Imaging Agents for Prostate Cancer”
Career Impact: Dr. Rockey plans to continue this project in an academic setting and says the support obtained from the RSNA grant was invaluable in jump-starting the project for ultimately carrying it to the clinic.
Clinical Implication: The project could potentially lead to a highly specific PET-based imaging agent that may substantially improve the management of prostate cancer. “The project will also contribute to the advancement of methodologies that can be applied to engineer targeted imaging agents for other human diseases,” Dr. Rockey said.
For more information on all R&E Foundation grant programs, go to RSNA.org/Foundation or contact Scott Walter, M.S., Assistant Director, Grant Administration at 1-630-571-7816 or firstname.lastname@example.org.
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