Marking progress
Clinical research coordinator Christine Frauenhoffer checks a frozen neuroendocrine cancer sample."When you work with a disease that is less well-known," she says, "you have the potential to make great strides in the diagnosis and treatment."
On a mission to gather preliminary results, Dana-Farber investigators have probed the genetics of neuroendocrine cancers, launched several clinical trials, and established two tissue banks. Located at Dana-Farber across from Shivdasani's lab and at Brigham and Women's Hospital, these banks store blood, urine, tumor, and other samples gathered from some 400 men and women with this disease, representing a range of ages and backgrounds.
The researchers are using the samples to decode the genetic patterns of neuroendocrine tumors, and they're exploring the diets, lifestyles, hormone levels, and other aspects of these patients to compare them with cancer-free individuals.
It's not uncommon to find Shivdasani and Kulke conferring about neuroendocrine cancers on the 11th floor of the Dana building, where they both see patients on Tuesdays, or in Shivdasani's lab, where they meet formally on Thursday mornings. Three research assistants working on gastrointestinal cancer projects ferry blood samples from the clinic to the lab almost daily for analysis. And on a recent afternoon, Kulke and Shivdasani continued hunting for carcinoid's genetic underpinnings by examining a pink-and-purple-stained slide with tumor DNA that had been purified in Shivdasani's lab and sent to the Institute's Molecular Diagnostics Laboratory for "whole genome analysis."
"In the past few years, there's been a shift in approach to clinical research," Kulke observes. "In addition to taking a disease and implanting it in a mouse, we're taking actual tumors from an individual, analyzing them, and trying to find out what makes the tumors tick. We're looking at patients' DNA to figure out, 'Is there something about their genetic makeup that makes them more prone to neuroendocrine cancer?' If we figured that out, it would presumably point us to the genes that are making these tumors work and show us how to attack them."
How Kulke wound up pursuing this specialty is — as with many professional interests — a story of chance encounters and an inspiring mentor. During his medical training, Kulke saw a patient with carcinoid cancer and realized the disease was both fascinating and frustrating: "It's very different from other cancers because you can develop these hormonal symptoms, like flushing and diarrhea," he says. "And even though it tends to grow slowly, there didn't seem to be much known about it."
After he and Institute physician Robert Mayer, MD, published a paper about carcinoid cancer in the New England Journal of Medicine in 1999, Kulke recalls, patients with this illness began seeking out Dana-Farber for treatment. The first few clinical trials (using traditional chemotherapy drugs) were not terribly successful, he says. But two advances provided more options. One was the development of therapies, such as Gleevec and Iressa, targeting specific genetic mutations and biological signaling pathways associated with cancer. A second was the advent of antiangiogenesis agents, which prevent tumors from developing new blood vessels to nourish them. Carcinoid appears to be more "blood-thirsty" than other forms of cancer.
In recent years, Kulke and his colleagues have tested the effectiveness of several angiogenic therapies, including Sutent, originally developed for gastrointestinal stromal tumors. Other clinical trials have combined traditional chemotherapy (such as temozolomide) with drugs that thwart blood-vessel formation (such as thalidomide or Avastin). The temozolomide-thalidomide pair shrank neuroendocrine tumors in onequarter of study participants and was biochemically active against malignancies in 40 percent of them — with fewer-than-usual noxious side effects. "We're very excited about extending these findings further," Kulke says.
"We're looking at patients' DNA to figure out, 'Is there something about their genetic makeup that makes them more prone to neuroendocrine cancer?'"
—Matthew Kulke, MD
The young clinician's inroads and enthusiasm helped draw in Shivdasani, a basic researcher who has long been fascinated by the digestive tract. He knew the neuroendocrine tumor bank and database would complement his desire to connect laboratory findings with cancer treatments.
Shivdasani and O'Hagan met at a gathering of Dana-Farber's Gastrointestinal Cancer Center Visiting Committee two years ago, after Shivdasani gave a brief talk on his work. Nancy O'Hagan serves on the committee and approached him during a break. "Nancy told me she'd been impressed by what she heard," he recalls. "That support was an important catalyst for me."
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