Targeted MRI Could Pinpoint Aggressive Prostate Cancers Before They Spread

The group identified a cancer-causing oncoprotein, known as extradomain B fibronectin (EDB-FN), and found that it is expressed at high levels by aggressive prostate tumor cells. This finding was consistent with the previously described role of EDB-FN in promoting aggressive cancers that are resistant to chemotherapy and also metastasize—move through the outer layers of affected organs, including the prostate, and into surrounding tissues.

The researchers synthesized a small peptide (called ZD2) that binds to EDB-FN. Tested in cell culture and tumor tissues, ZD2 exhibited strong specific binding to high-grade human prostate tumors, low binding to low-grade tumors, and did not bind to normal tissues.

Having shown that the ZD2 peptide specifically binds EDB-FN, the group engineered ZD2 so it could be used to non-invasively detect high-grade prostate cancers in a mouse prostate cancer model.

The researchers chemically attached a clinically used MRI contrast agent--a gadolinium (Gd) compound--to ZD2. Gadolinium is an element with magnetic properties that cause it to produce a strong signal detectable by MRI. The resulting test molecule was ZD2-Gd—the peptide that binds to the cancer cells linked to the gadolinium compound, and which is easily detected using MRI.

To determine whether MRI could be used to detect ZD2-Gd bound to prostate cancer, the group created mouse models of prostate cancer by grafting human prostate cancer cells beneath the skin in the mice. For a high-risk model, they used aggressive cancer cells with high levels of the oncoprotein EDB-FN and high metastatic potential. For the low-risk model, they employed the prostate cancer cells with little to no EDB-FN.

The tests in the mouse models revealed that a significant amount of ZD2-Gd rapidly bound to the grafted aggressive prostate tumors to produce a strong MRI signal within 10 minutes following injection of ZD2-Gd into the bloodstream of the mice. Conversely, little to no MRI signal was detected in the mouse models carrying the low-grade prostate tumor cells.

Although gadolinium is currently used routinely in humans, there has been some concern recently about residual amounts of it remaining in the system when used as an MRI contrast agent—and potentially having toxic side-effects. Therefore, the researchers looked at the clearance of ZD2-Gd from the mouse after injection and found it to be similar to a standard Gd contrast agent (Gd not bound to a targeting peptide). This was significant because it was important to know if ZD2 would also happen to bind to other mouse tissues and thus cause a slower clearance.

The researchers also examined all of the mouse tissues one week after the experiment and did not find residual gadolinium, indicating that ZD2-Gd did not “stick” to any other healthy tissues and remain in the mouse.

The authors concluded that the combination of a strong, specific signal in high-risk tumors combined with minimal residual body accumulation were excellent early results. They are hopeful that their system has real potential as a solution for non-invasively determining which men have aggressive cancers in need of treatment, and which have slow-growing tumors and can avoid unnecessary invasive treatments. In addition, the system could also be used to routinely and non-invasively monitor the slow-growing group for any changes in the aggressiveness of their tumors over time.

Adds senior author, Zheng-Rong Lu, “Not only does ZD2-Gd bind specifically to the high-grade prostate cancer cells, but it binds so well that it can detect even early stage tumors of small numbers of these cells. This means we can potentially use MRI to non-invasively find those individuals with the high-grade tumors and find them early when treatment has a much higher chance of being effective.”

The work was supported by grant # EB00489 from the National Institute of Biomedical Imaging and Bioengineering and grant # CA199826 from the National Cancer Institute.