A new strategy for targeting a protein called GRP78 — overexpressed in many breast cancers — could be used to simultaneously provide diagnostic imaging and deliver treatment for inflammatory breast cancer, according to a recent paper published in the Proceedings of the National Academy of Sciences (PNAS).
Massimo Cristofanilli, MD, professor of Medicine in the Division of Hematology/Oncology, was a co-author of the study.
Inflammatory breast cancer (IBC) is a rare and aggressive form of the disease; although it accounts for less than five percent of breast cancer cases in the United States, it makes up more than 10 percent of related deaths. Additionally, IBC is often misdiagnosed due to its atypical disease presentation and does not respond to many targeted drugs.
Given these challenges, the scientists decided to investigate a “theranostic” approach to treating IBC. Theranostics, a blend of “therapeutic” and “diagnostic,” is an emerging field within the precision medicine movement that combines tools of detection and treatment within a single agent.
To do so, the scientists first needed to pinpoint an appropriate target within IBC cells. After extensive screening, they identified a few candidate proteins. They chose to investigate GRP78, since the protein is known to relocate to the surface of cells during stress conditions, making it easily accessible. High levels of GRP78 in patients with cancer have also been linked to lower survival rates.
In the current study, scientists analyzed specimens taken from a group of patients with IBC and confirmed that GRP78 was more strongly expressed, further indicating that the protein was a good candidate for a molecular target.
Next, the team employed particles that were engineered hybrids of phage — viruses that infect and replicate within bacteria — and herpes simplex virus genes, vectors that could deliver both imaging agents and therapeutic genes directly at the tumor sites.
Using mouse models and human tumor samples, the scientists showed that releasing such a platform on GRP78 allowed for in vivo diagnosis through PET imaging, while also delivering treatment with targeted suicide transgene therapy, which triggers cancer cells to self-destruct.
“This discovery confirms the unique biological features of IBC and demonstrates the importance of multidisciplinary and translational research collaborations to advance the understanding of this aggressive form of breast cancer,” Cristofanilli said.
The strategy has potential for future clinical applications, according to the authors, because it can combine non-invasive imaging for disease monitoring with treatment in a single IV administration. If successfully translated into the clinical setting, the approach might also prove useful in treating other aggressive types of cancer, including aggressive variant prostate cancer.
Cristofanilli also serves as the associate director for Translational Research and Precision Medicine at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
The study was funded by National Cancer Institute Cancer Center Support Grants P30 CA016672 and P30 CA118100, as well as Department of Defense IMPACT Grant W81XWH-09-1-0224, AngelWorks and the Gillson-Longenbaugh Foundation.
