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.