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In 2005, Chinnaiyan was busy hunting for such defective genes in prostate cancer when his graduate students showed him a surprising DNA sequence. His team had sifted through 20,000 candidate human genes and focused on two that were overexpressed in prostate tumors. Mutated versions of each were known to alter cell growth in other cancers. The DNA sequence revealed that the front end of each gene was replaced by part of a third gene, called TMPRSS2, which is activated by the male hormone testosterone.
Chinnaiyan’s team had discovered what myriad cancer researchers had missed: the first recurrent gene fusions in a common solid tumor. The two mutated genes, called ERG and ETV1, were overexpressed in 50 percent and 10 percent, respectively, of prostate tumors examined. Their ubiquity suggested that they might drive prostate cancer, the researchers reported in Science in 2005.
The work kicked off a whirlwind of new research on prostate cancer, raising hopes of better prognostics and targeted therapies. In a 2007 Nature paper, Chinnaiyan’s team reported four previously unknown types of gene fusions in prostate tumors. This diversity suggested for the first time that gene fusions played a major role in driving common solid tumors.
Chinnaiyan has since found recurring gene fusions in breast and stomach cancer and in melanoma. And because the driving genetic lesions of many cancers are unknown, the hunt is now on for gene fusions in other solid tumors. Chinnaiyan’s results “energized and reinvigorated a whole new field of study,” Pollack says.
Lung Cancer Pill
Exciting news came in August 2007, just a few months after Bill Schuette received his diagnosis. Hiroyuki Mano’s team at the Japan Science and Technology Agency in Saitama, Japan, reported in Nature that they’d discovered a gene fusion that drives tumor formation in about 5 percent of patients with non-small-cell lung cancer.
“He could barely breathe and was wheelchair bound. Within a week or two he completely turned around.”
The fused lung cancer gene, known as EML4-ALK, encodes a cellular signaling enzyme called a tyrosine kinase. Both Gleevec and crizotinib block tyrosine kinases. Pfizer had produced crizotinib to treat cancers that had genetic alterations in ALK or another tyrosine kinase gene, including lymphoma, brain, and rare stomach and esophageal cancers. In 2006, oncologists at Massachusetts General Hospital in Boston and elsewhere had begun testing crizotinib’s safety as part of a clinical trial. The Nature paper was big news, says thoracic oncologist Alice Shaw, who treats lung cancer patients and develops new therapies at Massachusetts General. “We got very excited because it suggested a new therapeutic target,” Shaw recalls.
Within months, molecular pathologists at the hospital had developed a way to identify the EML4-ALK gene fusion in tissue biopsies from lung cancer patients. The Massachusetts General team treated its first EML4-ALK-positive lung cancer patient with crizotinib in December 2007. “He could barely breathe and was wheelchair bound,” Shaw recalls. “Within a week or two he completely turned around.”
Inspired, Shaw and her colleagues began screening more lung cancer patients for the EML4-ALK gene fusion and treating those patients having the fusion with crizotinib as part of the phase I clinical trial. At the June 2009 American Society of Clinical Oncology (ASCO) meeting in Florida, Eunice Kwak of the Massachusetts General team reported that crizotinib stabilized the disease in 15 of 19 of these patients and significantly reduced the total mass of tumor tissue in 10 of them. ABC World News picked up on that report, and on Shaw’s experience treating her first patients, and beamed it into Bill Schuette’s living room in Ohio.
Schuette, at that point, was very sick. “I was totally out of energy. I had lost weight and was in tremendous pain. Anytime I would cough it would bring me to my knees.”
The news sent him to the computer. Schuette e-mailed Shaw, who returned the call quickly. She asked a few medical questions and requested a sample of biopsied lung tissue, which revealed that his tumors had the EML4-ALK fusion. Two weeks later, on August 12, 2009, Schuette sat in a hospital room at Massachusetts General, where he took his first dose of crizotinib.