Researchers at the University of Wisconsin-Madison have made an important advancement toward improved imaging and treatment of cancer. Over years of research, they have developed a class of molecules that accumulate in cancer cells—and not in other cells of the body—making it possible to specifically target cancerous growths.
These alkylphosphocholine (APC) molecules can be tailored to carry either tags that allow doctors to image tumors or radioactive materials that can be used to destroy tumors. Importantly, these APC analogs target cancer stem cells as well—a notoriously difficult class of cells to eliminate that is likely the cause of recurrence in many cancer cases. These agents have so far tested successfully in a range of animal and human trials.
Jamey Weichert, an associate professor of radiology at UW-Madison, spearheaded the chemical development of the APC analogs. His research capitalized upon the discovery that a related class of molecules, phospholipid ethers (PLEs), are poorly broken down by solid tumor cells and therefore accumulate within them. Weichert’s team modified PLEs to optimize retention in cancer cells while allowing the molecule to carry therapeutic agents or imaging agents.
In 2009, Weichert met John Kuo, UW-Madison associate professor of Neurologic Surgery and director of the Comprehensive Brain Tumor Program at the UW Hospital and Clinics. As a brain surgeon, Kuo is focused on improving selectivity in tumor surgery.
“With cancers of the breast, lung or skin, surgeons can aggressively remove tumors with surrounding normal tissues,” Kuo said. “But with brain tumors, surgeons try to avoid removing adjacent functional brain.” To achieve this, you need either a highly accurate imaging method before surgery or excellent follow-up treatment.
Chemotherapy and radiation are used post-surgery to destroy lingering cancer cells by disrupting cell growth and differentiation since these processes occur more rapidly in cancer cells. Unfortunately, cancer stem cells (cells capable of differentiating into a variety of cell types) divide slowly and have excellent DNA repair which allows them to survive to cause tumor recurrence later.
One strategy for eliminating all types of cancer cells is to target and bind to them microscopically, but current implementations rely upon recognition of cancer-specific genetic markers. Kuo emphasized that this level of specificity is often too great, as it can be unique to an individual strain of cancer.
In brain tumors especially, it has been observed that multiple strains of cancer can exist even within one tumor correlating to differential survival for the same treatment. In other words, you may successfully destroy or image only one part of a tumor.
On the other hand, APC retention is a general characteristic of cancer cells. It has been proven effective at in vitro imaging of renal, colorectal, glioma (brain), ovarian, pancreatic, melanoma and prostrate cancer cells. Discrimination was successfully demonstrated even between brain cancer stem cells and healthy brain cells. This is because “APC doesn’t rely upon gene signatures or mutations,” Kuo said.
Imaging studies performed on mice further showed the ability of APC analogs to localize in 55 of 57 tumor types, whether primary or metastatic, and regardless of anatomic location. The exceptions were two human liver cancers, which did not have as high of an uptake of the APCs so those cancers don’t light up relative to normal cells in an image.
APC analogs outperformed existing methods in another key manner. Positron Emission Tomography (PET) is a dominant cancer imaging technique that visualizes a radioactive tracer. 18F-labeled glucose is the standard tracer because it will preferentially accumulate in areas with high metabolism, illuminating cancer. The downside is that glucose PET will often give false positive signals due to inflammation. However by using a 124I-labeled APC tracer, Kuo said “these false positives were not observed.”
Further, because the brain normally consumes glucose at such a high rate, PET is a poor option for brain tumors. This leaves doctors relying upon methods like MRI, which yields more false positives from scarring, infections, abnormal vasculature and other treatment effects. But by using an APC tracer instead of glucose, PET becomes a viable option for patients with brain cancer.
The first clinical trials using APC for imaging have been performed on lung cancer patients. Not only did APC detect known tumors, PET imaging also discovered previously unknown and asymptomatic metastases in the brain in one patient, hastening the patient’s treatment.
These imaging studies have now entered Phase II to optimize dosing and timing strategies and evaluate toxicity in a larger population. Trials will be performed through further collaboration of Weichert’s company, Cellectar Biosciences, with Kuo and a number of cancer clinics across the country. Additionally, Phase I clinical trials will begin to look at the use of APC tagged with 131I as a post-surgical treatment method, following up on preliminary results in rodents showing statistically significant tumor growth suppression and survival benefits.
