Biological engineer Forest M. White brandishes a sheet of paper covered with row after row of figures. With these numbers, he hopes to unearth targets for new cancer-fighting drugs.
The numbers are a readout of information about protein molecules, but to White, they provide a high-resolution map of a cancerous tumor’s intercellular signaling network. White, associate professor of biological engineering, hopes this information will lead to new pharmaceuticals that could provide an effective new treatment for the most common type of adult brain tumor, glioblastoma — the kind that killed Sen. Edward M. Kennedy.
“One of the big problems is that tumors — especially glioblastoma — are resistant to therapy,” White says. “By looking at tumors from many different patients, we can see which signaling networks are most commonly activated in the most aggressive tumors and identify points in the proteins’ signaling network that we would want to inhibit.”
Disrupting the network could make tumors less aggressive or wipe them out altogether, while elucidating signaling cascades also could result in early cancer diagnosis and a means of tracking how the disease is progressing over time.
Growth factors, contact with other cells, chemotherapeutic agents, ultraviolet light, even changes in temperature: these and other stimuli activate signals that govern cells’ activities. “Because biological systems are in constant flux reacting to their environments, we can present the systems with different cues, analyze how the signaling networks change in response to these cues and determine how these changes drive a corresponding biological response,” he says. In addition to glioblastoma, White applies the techniques to lung and breast cancer and hopes to identify defective signaling processes responsible for autoimmune disorders such as Type 1 diabetes.
MAKING CONNECTIONS
Mass spectrometers are commonly used in laboratories to study substances’ physical, chemical, or biological properties by calculating the mass of individual components within a sample.
A chemist by training, White went from designing and building mass spectrometers to exploiting their capability to explore signaling networks in diverse biological systems. “We’ve taken the basic technique and modified it to apply to protein signaling networks,” he says. Proteins are commonly regulated through a process called phosphorylation, which turns enzymes on and off. White seeks to identify exactly how phosphorylation launches and regulates the signaling pathways associated with cancer and other biological processes.
White has arranged with doctors in five North American hospitals to flash-freeze bits of tumors in the operating room and FedEx them to him at MIT. He takes a sample one-sixth the size of a fingernail’s half-moon cuticle and breaks it down into segments of the proteins’ basic building blocks. He then sends the sample through the mass spectrometer, which produces list of numbers representing the masses of signaling network components active at the moment the tumor was excised. White then correlates the spectrometer’s output with individual patients’ tumors.
“We look at hundreds of proteins simultaneously over time. Identifying protein phosphorylation on a global scale allows us to map complex signal transduction cascades in a variety of biological samples,” White says. “We can apply the results to a cancer cell and try to understand what drives its proliferation and migration within the body.”
PRIME TARGET
Much of White’s research is centered on a ubiquitous, widely studied protein called epidermal growth factor receptor (EGFR). In addition to skin cells, EGFR regulates a variety of other cells. Because EGFR is overexpressed or mutated in so many cancers, it’s a popular target for cancer-fighting drugs.
While investigating the role of the EGFR signaling network in glioblastoma, White recently identified a protein in the network not previously known to be active — this protein could prove to be a prime target for a new drug or chemotherapeutic agent. While excited about the finding, White is realistic about the hurdles in identifying, developing, and testing new therapeutics in animals and humans.
“My goal at the end of the day is to have an impact on human health,” he says. “I’d like to find new ways to treat people with glioblastoma that would significantly extend their lives.”