How Treating Metastases Could Prevent Cancer Recurrence

Dinaciclib may be able to eliminate metastases without shrinking the primary tumor.

It happens quickly when one cancer cell breaks off from a tumor and lodges elsewhere in the body.

This process, called metastasis, is responsible for the spread of cancer, but scientists have also discovered that these metastases can hide within the body for decades after the primary tumor is removed.

In a recent study from UC San Francisco, scientists tested on mouse models to see if they could study metastases and find out ways to stop them from developing into tumors after the primary tumor is removed.

Metastases are a major cause of cancer deaths due to the fact that their tiny seeds are difficult to track down and few researchers have been able to truly study them. However, scientists from UC San Francisco have managed to isolate some metastatic cells from human breast cancer tumors implanted into mice and study them as they escape into the bloodstream and begin to form tumors.

The researchers found that the expressed genetic programs in these cells was different from that of the primary tumor and had some of the same qualities as mammary stem cells. The findings could suggest new ways to look at metastatic cells and could lead to the development of drugs to treat them and disable their deadly capabilities.

But study senior author Zena Werb, PhD, professor and vice-chair of anatomy at UCSF, said that most modern cancer drugs ignore the differences between metastatic and primary tumors.

“We test drugs for their ability to make primary tumors shrink, but most just don’t work on metastases, and this leaves patients open to recurrence,” Werb said. “Patients have their original tumor treated or removed, but then the cancer comes back 20, 30, 40 years later because there were just a few metastatic cells sitting around.”

Little is known about how metastatic cells manage to survive for so long within the body, according to Devon Lawson, PhD, and assistant professor of physiology and biophysics at UC Irvine.

“It’s a big black box in the cancer field — mostly because it’s very difficult to study,” she said.

Because of this, just 7% of all breast cancer funding goes towards studying metastatic cancer, despite being the cause of virtually all breast cancer deaths.

In the current study, researchers were able to isolate the metastases through a process called patient derived xenograft (PDX), which involves transplanting human tumor cells into mice. The dichotomy between the healthy mouse cells and metastatic cells made isolating them a fairly easy feat.

The researchers developed a new method using flow cytometry that let them capture individual human metastatic cancer cells traveling through the mouse’s blood or lodged elsewhere in its body, then used newly-developed microfluidic technology to characterize the active genes in these rare cells.

“We were able to look at gene expression at a whole new level of resolution,” Lawson said. “We could pull 12 metastatic cells out of the brain and tell you what is special about those 12 cells. Or the two cells we found in the blood. And we discovered there’s something really unique about metastatic cells as they arrive in distant tissues.”

The team found distinct differences between early-stage and more advanced metastatic colonies when observing the gene expression in the human cancer cells lodged in different organs of the PDX mice.

In metastases that had already developed and spread throughout the organ, the gene expression of the cancerous cells mimicked that of the primary tumor transplanted into the mice with only subtle differences to account for the difference in tumor location.

By contrast, early-stage metastases and cancer cells traveling throughout the bloodstream expressed genes similar to those found in mammary stem cells, which were distinct from primary tumor cells.

Additionally, the gene expression observed in these cells led scientists to believe they should be dormant and undifferentiated, in addition to being relatively immune to cell death. This may be the reason metastatic colonies survive in new and hostile environments.

Beyond these findings, researchers observed that the signature pattern of gene activity was found in metastatic cells in mice whose tumors came from genetically and clinically diverse human patients.

In other words, the genetics of the tumor of origin played to part in the genetic program that makes a cell metastatic, leading scientists to believe that newer techniques could allow researchers to find and target these cells in a variety of patient populations.

Following these findings, the team performed a proof of principle experiment wherein they treated 24 PDX mice with dinaciclib, a CDK inhibiting drug known to kill off cells with high MYC levels.

Since the secondary tumors in these mice showed high levels of cMYC, researchers thought this method would prove effective for the elimination of metastatic cells. The results showed that the control group of mice developed secondary tumors within 4 weeks, while in the PDX mice researchers could only find 1 mouse with metastatic cell development.

Werb emphasized that this was only a proof of principal test and that it does not prove that dinaciclib is the ideal drug to target metastases. The key takeaway from the study is that the drug managed to nearly eliminate metastases without shrinking the primary tumor.

“If this drug had only been tested on primary tumors, we would have said it doesn’t work,” she said. “This tells us you actually have to look at metastases if you want drugs that treat them.”

Andrei Goga, MD, PhD, professor of cell and tissue biology, and of medicine at UCSF, said that preventing metastatic cells from invading other parts of the body has been a priority for cancer researchers for many years.

“But practically speaking, by the time you’ve detected the tumor, that horse is either already out of the barn or it isn’t. This new study is exciting because if you know the genetics of these early metastatic cells you can go after them specifically, wherever they are in the body. And that’s the name of the game,” Goga said.