Cancer treatment is sometimes almost as toxic to the human body as the disease itself. But Columbia chemical biologist Brent Stockwell is on the trail of a new approach that could transform the field, and save millions of patients from devastation wrought by chemotherapy.
Many cancer drugs work by indiscriminately attacking cells that are exhibiting one of the disease’s signature characteristics: rapid division and proliferation. The process is effective for taking out tumors, but it also destroys active healthy cells in bone marrow, hair follicles and the digestive tract, causing a variety of powerful side effects.
Stockwell is developing a new class of groundbreaking anti-cancer agents able to target the cancer cells by using a much more specific marker: Their genomes.
“We’ve taken an approach that relies on personalized medicine,” Stockwell says. “The idea is to match the medicine to the mutations in the patient.”
Stockwell has been laying the groundwork for his advance since graduate school. As a Chemistry PhD candidate at Harvard and later as an independent Whitehead Fellow at the Whitehead Institute for Biomedical Research, which is associated with MIT, Stockwell used high throughput assays to search for molecules that would affect cell death mechanisms in tumor cells, and allow him to better understand how tumor cells function. At Whitehead, he began focusing on mutations in a gene called RAS, which is associated with unchecked cell proliferation. A mutated form of the RAS gene is believed to be present in 20 to 30 percent of all tumors, and 90 percent of some specific tumors. It’s especially prevalent in pancreatic and lung cancer.
Stockwell’s goal was ambitious: to identify drug-like molecules that could cause the death of cells containing the mutant form of RAS, while leaving cells without the mutation unharmed. If he could find a way to do it, it could prove transformative.
“Each tumor has a specific set of mutations,” says Stockwell, who arrived at Columbia in 2004. “But there is a lot of overlap. Disease cells may contain several key mutations. If we can find ways to target some of those specific mutations—such as RAS--we can attack the cancer in a specific way.”
In his lab at Columbia, Stockwell has developed new screening technologies, including the development of complementary isogenic cell lines, identical except for the presence of a single desired cancer-causing mutation. Using high-throughput assays, Stockwell can then test hundreds of thousands of small molecules and look for the ones that kill the cancer-causing cell lines and leave the other intact. His efforts have already paid off – he has so far identified two molecules out of more than a million tested that work in this RAS-selective way, and has been working to develop therapeutic molecules that function in mice.
“They are promising discoveries,” he says.
Meanwhile, Stockwell has begun exploring the biological mechanisms by which these small molecules cause selective cell death. His discoveries there are equally promising. Most anti-tumor drugs cause cell death by necrosis or apoptosis, the traditional ways that cells die. Instead, the cells treated with these new molecules seem to be dying through a previously unreported mechanism that involves the production of an oxidative species and mobilization of cellular iron stores.
Cells harboring the mutant RAS gene contain excess iron, which make them especially vulnerable to this new form of oxidative cell death.
For Stockwell, who attended Cornell University, the discoveries are the culmination of a journey that began during his undergraduate days when, after staying up late into the night tracing the conversion of one molecule into a completely new one, he realized he’d found his passion.
“I realized that all of these diseases were essentially complicated puzzles involving molecules, and that if I could help to solve these molecular puzzles, it could make a big impact in people's lives,” he says
To view technologies from Dr. Stockwell's lab, please click here.
