Cancer chemotherapy: An unfolding story

To launch his lecture on cancer chemotherapy, Luke Whitesell ’79, RI ’06
displayed an image of an origami crab: a double visual metaphor. The
crab is the traditional symbol of cancer. And Whitesell, a senior
research scientist at the Whitehead Institute, has focused on how the
artful folding of proteins in cells may offer clues to more effective,
less toxic treatments. His November 17 talk — part
of the Radcliffe Institute’s Lectures in the Sciences series — richly
conveyed what he called “the most interesting subject in the world: the
drug treatment of cancer.”

Cancer is not a single disease, scientists now agree, but many diseases
with certain features in common. Over the past half-century, a
succession of therapies — beginning with chemicals from the World War II
biowarfare arsenal, continuing with drugs that kill rapidly growing
cells, and today the deployment of combination regimens after surgery
and radiation — have had only partial success. “There’s not going to be a
cure for cancer,” Whitesell said. “There are going to be cures for some
cancers.”

Three obstacles block the chances for a universal cure. First is the
redundancy in biological networks that drive the disease, meaning there
are many ways for the body to thwart cancer drugs. Second, cancer cells
have an astounding ability to change over time, especially when exposed
to agents designed to get rid of them. And third, tumors are
genetically heterogeneous — resistant cells within a malignancy have a
good chance of proliferating through natural selection.

These intrinsic challenges of tumor biology persuaded Whitesell, the
2005–2006 Grass Fellow at the Radcliffe Institute, to try a new tack.
Rather than targeting the genetic changes that trigger cancer and cause
it to progress, he is attempting to alter the cellular landscape in
which those changes take place. “Instead of going after the actors,” he
said, “you go after the stage.”

Specifically, Whitesell has focused on heat shock proteins, a class of
molecules that guide other proteins to fold correctly and function
properly. One heat shock protein in particular, Hsp90, appears to play
a role in the progression of cancer. Whitesell discovered that applying
a drug that inhibits Hsp90 deters some cells from unchecked growth. He
is further exploring ways to alter the cellular landscape by searching
for the biological mechanisms that dampen or rev up all heat shock
proteins — a path that may lead to fundamental treatments not just for
cancer but also for neurodegenerative disorders and other conditions.

Despite these promising leads, Whitesell cautioned that real progress
against cancer will take money and time. “The idea that you’re going to
do something in the lab and it’s going to be a cure tomorrow is
shortsighted,” he said. “And this single-minded idea that we just want
to fund clinical trials — because that’s what’s going to cure patients — is
extraordinarily counterproductive. You’ve got to invest in basic
insights if you’re going to move things forward. And you have to be
patient.”

Madeline Drexler is a Boston-based journalist specializing in
science, medicine, and public health. She is a visiting scientist at
the Harvard School of Public Health. This article was first published in the Radcliffe Quarterly.