During his residency, Mass General neurosurgeon Brian Nahed, MD, MSC, became intrigued by the emerging promise of a blood-based test for cancer. To pursue it, he completed a post-doctoral fellowship in the lab of Daniel Haber, Director of the Mass General Cancer Center, and Shyamala Maheswaran, PhD, who had developed the first microfluidic device to detect circulating tumor cells (CTCs) shed from a tumor into the blood stream.
The idea was of particular interest to Nahed because distinguishing brain tumor recurrence from changes that occur from radiation therapy can be difficult using modern imaging tools. Some patients must undergo a brain biopsy for a clear diagnosis. The ability to provide clinicians with a more definitive test to identify the recurrence of a tumor using a blood test rather than brain surgery had strong appeal.
Yet the promise of this new technology was uncertain. Brain cancer rarely metastasizes outside of the brain and previous attempts by others had failed to find CTCs in brain tumor patients. The blood-brain barrier has been known to limit what comes in and out of the brain, so the idea of developing a blood-based diagnostic tool for brain cancer was seen by many as a non-starter. “It was a pretty high risk, high reward project,” says Nahed.
The scales have recently begun to tip towards high reward, however. Nahed, along with co-principle investigator Shannon Stott, PhD, a bioengineer at the Center for Cancer Research at Mass General, have developed the first device that detects both glioblastoma CTCs and smaller tumor products called exosomes that contain information about the tumor and its genetic makeup in patients. “My hope is that our test will diagnose brain tumors, detect mutations, monitor for recurrence and differentiate it from normal reaction to treatment — all through a routine blood test,” says Nahed. “That’s the reward.”
Nahed’s first task in realizing this vision was to show, unequivocally, that CTCs could be detected in glioblastoma patients. In an effort to capture as many CTCs as possible, Nahed devised a cocktail of five antibodies to select glioblastoma cells from other cells in the blood stream. “It was difficult because this is a really heterogeneous tumor and it’s in the blood at low levels,” he says.
Using the test, Nahed, Dr. James Sullivan, and his team successfully identified the first evidence of circulating tumor cells in the blood of patients with glioblastoma. They also performed molecular analysis of these cells, something that could previously be done only on brain tumor tissue samples.
Nahed wanted the test to gather as much information from the blood as possible to make it even more clinically valuable. To help improve the test, Stott, a mechanical engineer by training, expanded the test to detect not only CTCs but also exosomes. Every cell in the body, including tumor cells, releases tiny packets of cellular material, presumably as some form of cell-to-cell communication. These packets contain proteins, DNA and other identifying information. Also, since their membranes are formed from a pinched off portion of the membrane of the cell that produced them, they can be picked out of the blood stream using the same external markers.
Exosomes are a promising target for Nahed’s and Stott’s microfluidic device because they are tiny and may be more likely than tumor cells to flow across the blood-brain-barrier and into the blood stream. “The big thing we’re trying to do with our technology is improve the cancer signal overall,” says Stott.
They aim to use their test to monitor glioblastoma patients during treatment. At the time of diagnosis, an MRI clearly shows the glioblastoma. But after it has been removed surgically, the image becomes less definitive. The effects of treatment can cause the image to falsely suggest that the tumor has returned. To answer this definitively, Nahed may need to perform a surgical biopsy. “If patients can avoid a second operation and instead use blood to detect the things we need to detect, this will have all been worth it,” says Nahed.
Nahed and Stott have begun enrolling patients to detect CTCs and exosomes using their blood test for glioblastoma. Patients who are being evaluated and treated for a brain tumor at Mass General can enroll in their research study and have their blood tested using the microfluidic device. They have been enrolling glioblastoma patients before surgery and intend to follow them as they progress through their care.
They are also extending this study, with the support of a private donor, to begin testing children with gliomas. “We’re over the moon because these patients have such small tumors that we can’t get biopsies,” says Stott. “We’re really excited to be doing something new for these children who are in desperate need for new diagnostic and treatment options.”