Yale: New approaches to study cancer

NEW HAVEN, Conn. — Researchers at Yale University’s West Campus are teaming up to go deep within cells that make up a malignant tumor, looking for ways to fight cancer on the molecular level.
At that scale, it’s important to look at systems that molecules make up, rather than looking at them individually, say researchers at the Systems Biology Institute and the Cancer Biology Institute.
Those are two of the organizations sharing a five-year $9.5 million grant from the National Cancer Institute, part of the National Institutes of Health. They will focus first on two aggressive cancers: glioblastoma multiforme, a devastating brain cancer, and melanoma, a serious form of skin cancer.
In all, faculty from seven departments in the schools of Medicine, Engineering and Arts and Sciences are involved — “a mini-U.N. of Yale,” according to Andre Levchenko, professor of biomedical engineering and director of the Yale Systems Biology Institute. “People from genetics will talk to people from biomedical engineering,” he said. “We were quite excited to find something we could all come together and work on.”
Since all cancers share the characteristics of uncontrolled cell growth, research has for some time been focused on destroying the cells and stopping their proliferation, said Mark Lemmon, a professor of pharmacology at the Yale School of Medicine and co-director of the Cancer Biology Institute.
Once the human genome was sequenced, however, “it became clear that tumors, cancer, can be driven by a defect in one molecule,” Lemmon said.
“One example is the so-called Philadelphia chromosome,” in which “two bits of DNA got broken and then stuck back together in the wrong place.” The result of that is chronic myelogenous leukemia. That discovery “was the poster child in a sense for the molecular era of cancer,” Lemmon said, resulting in a new therapy. “There’s one screw-up in the genome that has flipped one switch on for cell growth,” Lemmon said, and the drug imatinib (Gleevec) “will shut it off again.”
However, it turned out that targeting one molecule in a cancerous cell wasn’t enough, he said. “The golden hope in a sense was, in principle, you should be able to sequence every tumor, identifying the molecular lesion, and shoot it down with one of these drugs. But it doesn’t work.”
That’s because molecules don’t operate in isolation but cooperate with each other. From that discovery was born the systems approach — the new frontier of cancer research.
“Despite these impressive successes in a few cancers, it’s now realized that it’s combinations of targets that we need to go after,” Lemmon said. “In terms of this progression of thought, we’re now going up in complexity to the system” of molecules in a tumor.
The molecules in a cell, Lemmon said, “all influence one another, and it’s like an organism. Like any organism they then collectively decide to promote cell growth,” Lemmon said.
That fact offers new, more challenging avenues for finding treatments.
“It’s a bigger challenge when you’ve got a dozen or 20 or 50 molecules all playing with one another,” Lemmon said. “It’s like understanding the internet.”
The result of this interplay is called “emergent properties,” Levchenko said, when different parts work together to form something new, like the parts in a car.
In order to tackle the complexity of molecular systems, a number of cancer researchers from Yale, as well as Emory University, have been brought on board. “The Cancer Biology Institute and the Yale Cancer Center kind of bring the cancer elements of it, and we understand the molecules,” Lemmon said. “The Systems Biology Institute really is the group that understands the social connections between the molecules.”
The effort is huge. Between them, the two centers expect to have a total of 250 scientists working on the project within seven years.
Cancer cells can be divided essentially into two groups: those that divide, causing the tumor to grow, and those that move within the body in the process known as metastasis. “Once we separate the cells out we use biochemical methods or molecular methods to ask how their molecular circuitries are wired,” Lemmon said.
In turn, “that can give us an idea of what combinations of drugs might bring the system back to normal,” he said. “In the old days, meaning 2015, we would have been looking for a single drug. . The vanguard of cancer research at the moment is: We need combinations.”
So far, the effort to find drug combinations has been somewhat ad hoc, Lemmon said. So the National Cancer Institute has supported a consortium of centers to work on new treatments.
There have been some interesting findings. For example, a scientist in one lab was working on a molecule that is key to kidney functioning, by transporting sodium, potassium and chloride ions between cells. Researchers in a different lab discovered that the same molecule is present in glioblastoma. “What is interesting is that in the normal brain cells you don’t find it, but as soon as they develop cancer you find it there,” Levchenko said. The discovery “has resulted in something that may become a drug in brain cancer,” he said.
Now, he said, glioblastoma is “not curable and has a dismal prognosis.” Surgery is the primary option, and the two-year survival rate for adults is 30 percent, according to the American Brain Tumor Association.
Another avenue of research involves the placenta, which Levchenko said is considered a highly invasive body in human anatomy but is not so in mammals such as cows and horses. Cancers also are not as invasive in those animals as they are in humans, so if the mechanism that limits cell growth in cows and horses can be better understood, perhaps the function could be mimicked in anti-cancer drugs.
“I think it’s a very novel approach because, again, we’re hoping to learn something from normal processes that will help us to understand the abnormal process of cancer,” Levchenko said.
He said having the research conducted on Yale’s West Campus is “kind of like the Manhattan Project,” that developed the atomic bomb during World War II.
In addition to Yale’s grant, the National Cancer Institute is establishing research centers at Stanford and Columbia universities and Memorial Sloan-Kettering Cancer Center.