Vander Heiden eventually found a home in the Harvard lab of
Lewis Cantley, who now directs the Meyer Cancer Center at Weil
Cornell. His research in Cantley’s lab would help solve one of the
central riddles of cancer metabolism: why cancer cells are so ravenous for glucose. Researchers had once assumed that cancer cells
were turning to fermentation because they’d lost the ability to use
oxygen properly and needed some other way to produce energy.
But Vander Heiden’s research on a mutated form of the enzyme
pyruvate kinase showed something else. Rather than being used
for energy, much of the glucose was being shunted into pathways
used to build new molecules. What a growing cancer needs most
of all from its food, the research suggested, is more spare parts—
raw materials for making new DNA, membranes, and proteins.
Vander Heiden’s research with Cantley would also lead to his
involvement with Agios Pharmaceuticals, the company behind
one of the most promising new drugs to emerge from the metabolism revival. (Cantley says he played a major role in building
the company’s science in its early days.) The drug, AG-221, treats
acute myelogenous leukemia, a cancer of the blood and bone
marrow. It works by blocking the product of a mutated form of
the mitochondrial enzyme IDH- 2. Approved by the US Food and
Drug Administration in August, it has been hailed as the first real
advance for the disease in 30 years.
The approval of AG-221 isn’t the only thing generating excitement in the cancer world. Unlike almost all other cancer drugs,
AG-221 doesn’t kill the cancer cells but, rather, allows them to
develop out of their deranged state into noncancerous, mature,
functioning cells. That a single metabolic enzyme could have
such profound effects on which genes are expressed in a cell is
now one of the many signs that changes in metabolism are not
just a response to the needs of a growing cancer. Often, they may
actually be causing the cancer itself. It represents a major shift in
thought: many cancer-causing genes long known for their ability to signal cells to keep dividing have now been shown to have
additional roles in signaling cells to keep eating. Some researchers now believe the overeating typically comes first, driving the
transformations that follow.
Since his arrival at MIT and the opening of his lab at the
Koch Institute in 2009, Vander Heiden has treated cancer
patients and continued to search for better therapies. In recent
years he has focused on improving understanding of chemotherapy. Though typically thought of as general poisons, most
chemotherapy drugs work because they disrupt metabolic functions. That much has long been known, but less clear is why a
particular drug works for some cancers and not for others, even
when two cancers carry the same mutations.
It was while explaining to his undergrad cancer biology students how targeted drugs work that Vander Heiden first thought
of an answer. As a cancer doctor, he knew that chemotherapies
are often chosen on the basis of where in the body a tumor first
arose, but what was it about this location that made the difference?
Vander Heiden’s research in mice now suggests that the answer
may lie in which foods are available to the cancer as it forms.
Melanoma and colon cancer, for example, often have the same
mutations, and yet, as he explains, because the two cancers “grow
in very different places in the body,” they likely “have access to dif-
ferent nutrients.” He adds, “It has nothing to do with the genetics.”
If he turns out to be right, it could lead to a fundamental change
in how oncologists think about which drugs to give their patients.
As Vander Heiden turns his attention to old chemotherapy
drugs, rethinking why and how they work, he is once again look-
ing to the past for new insights on cancer. It might be more than a
coincidence. As Bevis, his wife, says, the outdated Honda Civic isn’t
the only item he has struggled to let go of. “The list goes on and
on,” she says. “He hates waste and will use items long after some-
one else would have replaced them with a newer, shinier model.” n
Daniel Schmidt, a postdoc in
Vander Heiden’s lab, prepares
cells to study how metabolism
affects cancer cell proliferation.