Following the surgical removal of a tumour, cancer recurrence from residual tumour cells is a significant risk. "At the time of surgery, a pathologist can examine the tissue for cancer cells at the edge of the tumour using a microscope, but because of the size of cancer, it's impossible to review the entire surface during surgery," explains paper author David Kirsch, an oncologist from Duke University in North Carolina. As a consequence, not all surgeries are successful in removing the entirety of the target tumour. In patients with breast cancer and soft-tissue sarcoma of the extremity, for example, cancer ends up reoccurring in around a third of patients. "The goal," Kirsch adds, "…is to give surgeons a practical and quick technology that allows them to scan the tumour bed during surgery."

In their study, the researchers describe tests on an injectable, fluorescent probe called LUM015, which has been developed in tandem with Lumicell, a company launched by researchers at the Massachusetts Institute of Technology. LUM015 is both selectively distributed to cancerous tissues and selectively activated by cathepsin proteases, enzymes that ordinarily play a role in cellular turnover but are excessively secreted by tumour cells to promote cancer growth.

As a result, the probe produces fluorescence that is an average of four times brighter in tumours than in equivalent normal tissue. Being in the far-red, this fluorescence is not visible to the human eye, but would be detected using a handheld imaging device that Lumicell is developing.

Following surgery, this imager could be used on the cut surface to scan for fluorescing cancer cells – allowing the surgeons to better check that the whole tumour has been removed. Paper author Brian Brigman – an orthopaedic cancer surgeon at Duke University – says that, if successful in subsequent trials, the new probe will significantly change the way sarcoma is treated. He adds: "Knowing where there is residual disease can also guide radiation therapy or even reduce how much radiation a patient will receive."

Successful tests

In a phase 1 trial at Duke University Medical Center, LUM015 was injected into fifteen human breast cancer and sarcoma patients prior to surgery. The probe had no ill effects, and studies of the excised tumours revealed that fluorescence of the tumour cells was indeed significantly higher than in matched normal tissue samples.

In mice surgically treated for soft-tissue sarcoma, operations guided by LUM015 were seen to produce promising outcomes. All mice seen to have residual fluorescence after surgery later experienced a recurrence of their cancer; in contrast, only a third of mice without residual fluorescence had a recurrence.

"This is great work," says Ralph Weissleder – a radiologist and systems biologist from Harvard Medical School who was not involved in this study. "Technologies such as these are urgently needed to improve surgical resection of cancers. It will reduce the number of re-operations and help surgeons and our patients."

With this initial research complete, the researchers are now assessing the effectiveness and safety of both the LUM015 agent and their imaging device in a study of 50 women with breast cancer. At the same time, the team is exploring the potential of the probe for use in the treatment of other cancers, such as those of the gastrointestinal tract.

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