A recent Yale study sought to target and prevent one of the leading causes of ovarian cancer recurrence: micrometastasis.

In a paper published in Scientific Reports on Jan. 25, a team of researchers fluorescently labeled these micrometastases, which are groups of cancer cells — too small to be seen by the naked eye — that migrate from their original tumor site. The researchers were able to visualize them down to 100µm in mice.

“Ovarian cancer is characterized by early intraperitoneal micrometastasis,” first author Ayesha Alvero said. “These are obviously not taken out during surgery since the surgeons cannot see them. As such, they become the source of recurrence.”

Indeed, previous research has shown that most ovarian cancer patients relapse and that over 80 percent of patients have some form of micromestastasis.

Corresponding author Gil Mor said a standard treatment option for late-stage ovarian cancer is debulking, when a surgeon tries to remove as much of the tumor as they can see, meaning that recurrence would have to be caused by some remaining tumor cells in microscopic clusters. He added that chemotherapy, a further accepted method, cannot reliably target all micrometastases, as some have become chemoresistant.

“In other words, these are tumor implants that we cannot see with the naked eye, and they are there, and if we want to save the patient, we need to remove them,” Mor said.

In order to visualize the micrometastases with fluorescence, the team developed nanoparticles that bound to a peptide sequence found exclusively within blood vessels in the tumors. This meant the researchers could stain large tumors and even micrometastases dark blue without staining noncancerous tissue.

According to Alvero, nanoparticles were used so that the dye would not be cleared in circulation, as naturally occurs. Additionally, the nanoparticles served as a kind of “scaffold for targeting,” she said.

“The RGD-coating [the special protein sequence only found in tumor cells] serves as magnets that find and bind tumor-associated vessels, allowing the concentration in the tumor microenvironment,” Alvero said.

The study has implications both within the realm of cancer research and in general practice, according to Mor.

From a research perspective, the study is significant because it provides a potential platform for drug delivery if the dye attached to the nanoparticles is instead replaced with a cancer-killing drug, Alvero said.

Mor, who is the principal investigator of the lab that released the paper, said the study garnered interest from other professionals because ovarian cancer researchers have tried and failed for years to find a genetic marker specific to cancer cells.

The study is also capable of improving the rate of survival for cancer patients, Alvero said.

Mor said that the findings could make possible easier, more efficient surgeries for most abdominal cancers in addition to ovarian cancer. He gave the example of colon cancer, for which surgeons have traditionally had to remove substantial amounts of unaffected tissue since they could not be sure whether micrometastasis had occurred.

“Now, with this technology, we can say exactly whether a piece of the colon is free of disease or if there have been implants,” Mor said.

According to Alvero, an obvious limitation of the study is its use of an animal model to study human disease. She added that all the team’s findings would have to be validated in patients.

Mor also said that a major limitation could be the sensitivity of the imaging system the researchers used, since a low-resolution microscope may not be able to detect all micrometastases present.

The team is in talks with companies to secure funding for a clinical trial phase. Alvero said the majority of this funding will go toward creating clinical-grade reagents.

“I hope, if things go okay, in maybe six or eight months, we may have a product of clinical quality that then could then be used for the patients,” Mor said.

Ovarian cancer has a five-year survival rate of 45 percent, according to the American Cancer Society.