Putting tumors in context
Cambridge biotechs target so-called microenvironment rather than just cancer cells in bid to advance therapies
In cancer treatment, the tumor is the obvious enemy: an insidious, proliferating mass that grows out of control. But just as police might deploy patrols in a crime-ridden area, a growing number of researchers and companies are focusing not just on cancer cells, but on the entire neighborhood.
The interest in the tumor’s ecosystem - its “microenvironment’’ of blood vessels, cells, proteins, and molecules - is spurred partly by failure.
Time after time, researchers have seen drugs that kill cancer cells in a dish or in animal studies fail to do the same when tested in patients. They now realize that bystanders - the supporting cast of normal cells - may play a variety of roles, including fueling a cancer’s growth and even at times helping to keep it in check.
“It has become now very clear, they are not just passive sorts of standby materials,’’ said Dr. Raghu Kalluri, a professor of medicine at Harvard Medical School.
“They are actually probably doing something. Either doing something good, which is protecting us against cancer progression . . . or cancer cells are recruiting all this to help them grow bigger and spread more, to travel to other locations,’’
The tumor microenvironment is increasingly driving research and new therapies.
Infinity Pharmaceuticals in Cambridge, for example, has developed an experimental pancreatic cancer drug to deplete fibrous tissue that blocks drugs from reaching the cancer.
Pervasis Therapeutics, also of Cambridge, has found that endothelial cells lining blood vessels secrete signals that play an important regulatory role, including inhibiting tumor growth in mice.
And Axios Biosciences, a Cambridge start-up, is building a tool to screen drugs, one that more accurately reflects a cancer’s context in the body.
One of the most prominent efforts to target the tumor microenvironment - the idea of stopping a tumor by cutting off its blood supply - emerged from the work of the late Dr. Judah Folkman. But the approach has had uneven success. Dr. Elazer Edelman, a professor of health sciences and technology at the Massachusetts Institute of Technology and cofounder of Pervasis Therapeutics, said new research may help explain why.
Edelman has found that endothelial cells are more than just wallpaper: They orchestrate processes in the body, including keeping cancer in check, which means that thinking of blood vessels as tubes that nourish tumors is too simplistic.
Imagine, he said, a seesaw with slow-growing endothelial cells on one side and fast-proliferating cancer cells on the other.
The endothelial cells are able to help keep the cancer in check. That means drugs or therapies that disrupt this balance might work for a time.
But the cancer could return later and thrive because one side of the seesaw - with the slower-growing blood vessel cells that were keeping the cancer under control - would take longer to bounce back.
Pervasis has developed and tested a polymer gel with such healthy endothelial cells embedded in them for other applications. But in a study published in January in the journal Science Translational Medicine, Edelman reported that implanting those healthy cells into mice could restore order, by inhibiting tumor growth and controlling cancer.
“We put a policeman in a very rough community - a policeman or sheriff in a Wild West town - and he tames it,’’ Edelman said.
Other approaches focus on breaking down barriers in the tumor’s environment.
At Infinity Pharmaceuticals, researchers have developed a pancreatic cancer drug that inhibits signaling between the cancer cell and its microenvironment, thinning a fibrous network of tissue that helps shield cancer cells from drugs.
Data from a small safety trial presented at the American Society of Clinical Oncology this year showed preliminary signs that the drug, in combination with the chemotherapy currently used to treat the cancer, called gemcitabine, could shrink tumors.
Axios Biosciences is focused on building better drug-screening tools, based on the idea that the context for cancer cells will affect how they respond to a drug.
“The dogma in the whole tumor microenvironment field for many, many years is it acts to protect the tumor,’’ said Douglas McMillin, the founder and president of Axios. “There are some tumors that become sensitized [to a drug] as a result of interaction in the microenvironment.’’ That means the cancer cells may be more vulnerable to low doses of a drug than it appears when they are treated in isolation.
Kalluri, however, thinks the tumor microenvironment may help solve a problem that has become increasingly important: understanding why some tumors are truly life-threatening and other are slow-growing.
For example, while autopsies show that nearly half of men between the ages of 60 and 70 have small prostate tumors, only 1 percent are diagnosed with cancer.
With collaborators, Kalluri is looking at a large number of autopsies to examine those small, prevalent tumors, with the goal of understanding what is different about lesions that stay dormant.
He is interested in differences in the cancer cells themselves, and in the possibility their neighborhoods may play a role, with some subtle difference in the microenvironment helping to keep the cancer dormant in some people while letting it grow out of control in others.
“These dormant lesions - if we can isolate them, we can understand the ones that will progress and the ones that won’t,’’ Kalluri said. “And we think cancer cells alone won’t explain that.’’