As powerful as modern cancer medicines are, they don’t work for everyone. What if there were a quick test doctors could perform on an individual person’s cancer to help determine which approved treatment would work best for them?
This testing tool is in development now and could, with further research, become a valuable part of decision making in oncology. The technology and its application to cancer is based on the work of Dana-Farber pathologist Keith Ligon, MD, PhD, director of Dana-Farber’s Center for Patient Derived Models, and longtime collaborator Scott Manalis, PhD, of the Massachusetts Institute of Technology. The team has created a functional precision medicine device that rapidly determines the density of live cells and provides a readout of their response to a medicine.
The work was published in Nature Biomedical Engineering.
“When a patient has an infection, pathologists do antibiotic sensitivity testing to recommend the right antibiotic. This is hugely helpful and standard of care,” says Ligon. “The goal of this work is to create devices and approaches that allow us to move into that arena for cancer.”
A novel microfluidic device rapidly determines the density of live cancer cells and could help guide the selection of a patient’s next treatment.
Cell density
There are many methods pathologists like Ligon use to guide the selection of cancer medicines for an individual patient. For example, pathologists examine biopsied tumor samples under a microscope to determine the type of cancer, how advanced it is, and more. This information helps pathologists make a diagnosis and identify biomarkers that can guide treatment.
In contrast, this new device rapidly assesses live tumor cells one at a time, at a rate of up to 30,000 an hour. The cells are removed using a biopsy or blood draw. Then they are injected into a microfluidic device through tiny, liquid-filled channels.
As each cell flows through the channel, the device simultaneously measures its mass and volume. A technique called fluorescence exclusion microscopy measures the volume, and a method invented in the Manalis lab called suspended microchannel resonator measures mass. Together, these numbers are used to calculate the cell’s density.
“These fundamental physical measurements are really important to the cell and give us a reliable way to check the health of the cell,” says Ligon.
A cell’s density determines its ability to function. All the molecules and organelles in a cell must interact physically to carry out the cell’s work. If they end up too far apart (not dense enough) or too close together (too dense), the cell stops functioning properly.
However, the mass and volume of a cell do fluctuate under normal conditions. For instance, mass doubles just before a cell divides, and volume increases to accommodate that change. Previous research has shown that when a cell’s mass increases but its volume doesn’t, the cell is likely close to death.
“The coupling between density and fundamental processes like cell death suggest it could be a valuable biomarker for drug response,” says Ligon.
A treatment readout
To determine if the device can predict a cancer cell’s response to a given drug, Ligon’s team in the Center for Patient Derived Models devised an experiment using an animal model of pancreatic ductal carcinoma. The researchers knew from previous studies that this tumor model would be sensitive to a drug called trametinib, but resistant to another called gemcitabine.
They placed cells from untreated tumors into petri dishes and applied the two medicines separately. At a series of timepoints after treatment, they flowed treated cells through the device, measured mass and volume, and calculated density.
The cells treated with trametinib showed more dramatic changes in density than cells treated with gemcitabine. This indicated a stronger reaction to trametinib.
“The technologies are sensitive enough that you can see that the cell is changing and responding to the drug,” says Ligon.
This signal is visible within two days of treatment, suggesting that it could provide a readout for a given patient within 48 hours of a biopsy. Other methods that test drug sensitivity, such as patient-derived organoids, typically require tumors to grow to get a readout. These methods can take weeks, potentially delaying treatment.
In a separate experiment, this study found that immune cells called lymphocytes experience detectable density changes when they move from a paused, quiescent state to an active, proliferative state. Based on this evidence, this device could also be used in settings where checking on the status of the immune system is valuable, such as after a cancer immunotherapy is administered.
Next steps
For the device to be used more widely, it needs more validation in clinical trials. To move the technology forward, Ligon and Manalis launched a company called Travera that is currently commercializing an earlier version of this technology that measures only cell mass. Based on this study, the company has created a commercial-grade device that measures both mass and volume to determine density.
“This device and the idea of functional precision medicine are really exciting to patients,” says Ligon, who is a scientific advisor for the company. “They want to know if a drug is going to work. We’d like to find the best way to answer that question for them as quickly and precisely as possible.”
Written by: Beth Dougherty