A new biomarker with potential for improving early detection of pancreatic ductal adenocarcinoma (PDAC), which is one of the deadliest of cancers, has led one researcher down a promising path to earlier detection and perhaps better treatment.
Part of the reason PDAC is so lethal is that patients often have no symptoms until the disease has reached an advanced stage and treatments like surgery and chemotherapy are rarely curative. As a result, the 5-year survival rate for PDAC is only 4 percent, according to the American Cancer Society.
Researcher Joshua Dowell, M.D., Ph.D., knew that a certain protein, Plectin-1 (Plec-1), is buried in a cell’s cytoplasm, but in PDAC it migrates to the cellular membrane, making it a conspicuous marker for disease. Through a $30,000 Bracco Diagnostics/RSNA Research Resident Grant, Dr. Dowell developed a novel diagnostic and treatment approach to PDAC as a radiology resident at the University of Virginia in Charlottesville in 2010.
“Plec-1 is overexpressed in PDAC and clearly distinguishes PDAC from inflammatory and premalignant pancreatic changes,” said Dr. Dowell, now an assistant professor of interventional radiology at The Ohio State University Wexner Medical Center in Columbus.
Dr. Dowell worked with two professors in the University of Virginia’s Biomedical Engineering Department, Kimberly Kelly, Ph.D., and Alexander L. Klibanov, Ph.D., to develop a synthetic agent that targets Plec-1 in PDAC. The agent is a peptide paired with a liposome that can be engineered to carry drugs, dyes and imaging agents. Dr. Dowell and colleagues proposed linking liposomes carrying fluorescent DiR dye to a Plec-1 targeting peptide to study its uptake in pancreatic cancer cells.
Using the RSNA grant funding, Dr. Dowell and colleagues tested the new targeted agent on mice with human pancreatic cancer implanted under their skin. Using fluorescence molecular tomography (FMT) the researchers compared the efficacy of the targeted liposomes with control liposomes that did not have the Plec-1 targeting peptides.
Preliminary results presented at RSNA 2011 showed that the targeted agent delivered high payloads of DiR dye with a high degree of specificity to the pancreatic tumors. “There was an eight-fold increase in accumulation of dye over controls at 20 hours post-injection,” said Dr. Dowell, who received a Trainee Research Prize for his RSNA 2011 presentation. “This increased accumulation of dye within the subcutaneous pancreatic tumors persisted one week post-injection.”
The targeted agent is a potential tool in the burgeoning field of theranostics, in which one drug can have both therapeutic and diagnostic applications. Besides providing earlier detection of pancreatic lesions, the novel PDAC-targeted imaging agent may allow for higher doses of radionuclides and chemotherapy drugs, Dr. Dowell said.
“These results, although preliminary, are of great interest as a platform to deliver high payloads of chemotherapy,” he said. “We hope that by targeting the cancer we can lower the side effects associated with the drugs.” Indeed, early results using gemcitabine-loaded, targeted liposomes are promising. “We were able to deliver more small molecules to the tumor when targeting with Plec-1 than when not targeting with it and we saw some tumor-specific killing,” Dr. Kelly added.
Dr. Dowell noted that while chemotherapy is typically given to patients with PDAC to relieve pain and improve quality of life, higher levels of the drugs might increase the possibility of a cure. Targeted agents such as these may also offer the possibility of early detection, he said. “Agents which allow for earlier detection would be useful in screening patients at high risk, such as those with a family history,” Dr. Dowell said. “Currently, there are no great ways to screen such patients.”
Currently, researchers are working to optimize the technique to allow loading higher doses of drugs and contrast agents onto the liposomes.
No matter what direction his studies take, Dr. Dowell credits the RSNA R&E grant for establishing his career as a researcher and paving the way for further grants. “I’m grateful and honored to be an RSNA grant recipient,” Dr. Dowell said. “It has given me great opportunities to extend my research beyond the fellowship stage and continue to develop as a physician-scientist.”
“These grants are incredibly important,” Dr. Kelly added. “Without them, we wouldn’t get funds to do this more risky science. Dr. Dowell could one day prescribe a drug that he created with the help of this grant.”
Name: Joshua Dowell, M.D., Ph.D.
Grant Received: $30,000 Bracco Diagnostics/RSNA Research Resident Grant, 2010
Study: Plectin-1 Targeted Liposomes for Possible Early Detection and Treatment of Pancreatic Adenocarcinoma
Career Impact: Dr. Dowell continues to be interested in the early detection and treatment of targeted cancers. Addionally, his educational project, “A Pharmacopeia iPhone/iPad Mobile Communication Application for the Interventional Radiologist” was funded by a 2011-2012 RSNA/AUR/APDR/SCARD Education Research Development Grant. “These RSNA grants have, and will continue to have, an impact on my career and future as I develop as a physician-scientist,” Dr. Dowell said.
Clinical Implications: Dr. Dowell’s development of the PDAC-targeted imaging agent may allow earlier detection of pancreatic lesions based on molecular signature and serve as a platform for targeted therapies for pancreatic cancer.
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