Findings from preclinical cell-line, animal xenograft, and preliminary administration to human patients suggests that broadly tumor-targeting alkylphosphocholine (APC) analogs can deliver imaging, radiotherapy, and fluorescent payloads into cancer cells and cancer stem cells.
“I was quite skeptical that this would work,” admitted co-lead author John S. Kuo, MD, PhD, of the Carbone Cancer Center and Department of Neurological Surgery at the University of Wisconsin School of Medicine and Public Health in Madison, WI.
“It’s quite an alternative approach, unlike traditional systemic chemotherapy or targeted therapies that disrupt specific proteins or mutations or pathways,” he said. “It doesn’t seem to be the case that there is selectivity for particular cancer types; we’re looking at a property that cancer cells can’t get rid of. We’re looking at cancer cell versus normal cell.”
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Capabilities of APC Analogs
The rationale for an APC analog platform goes back to an observation first reported in 1969 and 1970, that “a lot of different cancers have too many phospholipid ethers in their cell membranes compared to normal cells; normal cells can get rid of them but cancer cells in general, could not,” Dr. Kuo told ChemotherapyAdvisor.com.
Dr. Kuo, Jamey P. Weichert, PhD, and their colleagues at the University of Wisconsin found that equipping the APC analog platform with a 124I radiolabel payload allows PET/CT imaging that illuminates primary and metastatic tumors throughout the body. And a 131I payload allows cancer-targeted radiotherapy, their preclinical work shows, suppressing xenograft tumor growth and prolonging animal survival.
“We can put on a lot of payloads,” Dr. Kuo said. 124I and 131I payloads have undergone the most study so far, and a fluorescent payload is now ready for clinical trials, he noted. “But in the lab, we’re looking at second- and third-generation payloads.”
In one patient with end-stage metastatic lung cancer, three asymptomatic and unsuspected brain metastatic tumors were revealed using 124I-bearing APC, leading to modification of the patient’s clinical management, Dr. Kuo noted.
Once cancer cells take up the APC analogs, they retain them for “days to weeks,” the authors found.
Cell lines, rodent tumor, and human xenograft tumors in rodents were tested, and APC analogs were administered to patients with breast, lung, colorectal, and brain cancers. With the important exception of liver tumors, all of the 55 other cancers studied exhibited APC analog uptake and 124I illumination, the authors reported in Science Translational Medicine.
“We have to say it hasn’t been a roaring success with liver cancer,” Dr. Kuo said. “We have intermediate uptake (of APC analog) rather than full uptake.”
He suspected that is because liver and liver cancer cells are better able than other cells to get rid of phospholipid ethers.
Because the APC analog can cross the blood-brain barrier and labels brain cancer stem cells as cancerous, it is promising for brain tumor imaging and radiotherapy, as well. That could allow more precise and prognostic imaging for brain tumors.
“Current imaging with MRI and CT with contrast can give us false-positives—pseudoprogression,” Dr. Kuo explained. “A patient has had surgery, they get radiation and CT, and then a scan 2 or 5 or 10 months later shows enhancement. It could be posttreatment scarring, or infection, or true tumor progression…So we have to go back to clinical symptoms, wait a month to see if it grows. Scars shouldn’t grow. We have to decide whether to go back and biopsy, or change treatment.”
The Future of APC Analog Imaging
APC analog imaging could change all that, he hopes. In side-by-side preclinical animal testing, APC analog imaging proved superior to traditional [18F]-fluorodeoxyglucose PET imaging in identifying malignancies.
“Because [APC analogs] are a homing agent, we could be treating cancer on a cellular level regardless of whether we can see it or not,” Dr. Kuo said.
“Even more exciting to me as a surgeon is that fluorescent-payload analogs might be very practical for getting the best surgical margins possible,” he added.
A phase 2 clinical trial is currently recruiting patients with newly diagnosed or recurrent glioblastoma. Co-lead author Dr. Weichert cofounded and serves as chief scientific officer of Cellectar Biosciences, Inc., which is developing the APC analog platform for cancer applications.
Reference
- Weichert JP, Clark PA, Kandela IK, et al. Alkylphosphocholine analogs for broad-spectrum cancer imaging and therapy. Sci Transl Med. 2014;6(24):240ra75. DOI: 10.1126/scitranslmed.3007646. http://stm.sciencemag.org/content/6/240/240ra75.short.
