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By studying gene fusions—in blood cancers and solid tumors—Brian Druker, Charles Sawyers, and Arul Chinnaiyan have revealed vulnerabilities in tumors that can be targeted and successfully treated.
Then, on June 2, 2009, he saw a television news report. A woman in her 50s, a nonsmoker with adenocarcinoma like Schuette, said chemotherapy hadn’t worked for her, so she’d taken an experimental drug called crizotinib that targeted a rare mutation in her tumor. “My cancer is melting away,” she told the reporter.
“You’ve got to be kidding me,” Schuette said, looking at his wife. Within weeks he was in a phase I clinical trial taking the drug himself, seeking a new lease on life.
The hope is that crizotinib is the first of a new class of drugs that will do for solid tumors what Gleevec did for the blood cancer, chronic myeloid leukemia (CML).
Crizotinib opens the door for a class of diagnostics, prognostics, and therapies that target cancer-driving mutated genes in common solid tumors. They specifically block a fusion protein—produced by an abnormal fusing of two genes in cancer cells. The new diagnostic and prognostic tests would assess a patient’s cancer by looking for these fusion genes. And new drugs, like crizotinib, would target the resulting fusion proteins.
The first fusion gene-targeted drug, called imatinib or Gleevec, was developed in the 1990s to arrest CML. “It changed a disease that was a death sentence within three to five years to a disease that’s now a manageable condition” with a five-year survival rate of 90 percent, says medical oncologist and HHMI investigator Brian Druker of Oregon Health & Science University, who helped develop the drug.
Researchers have since found several fusion genes in other blood cancers but for years had less luck in common solid tumors of the breast, prostate, colon, lung, and pancreas, which account for 80 percent of U.S. cancer deaths.
Their luck is beginning to change. Arul Chinnaiyan , an HHMI investigator at the University of Michigan Medical School, and other scientists have uncovered a variety of gene fusions in prostate, breast, thyroid, kidney, brain, and salivary gland cancers.
These discoveries, along with Gleevec’s success and promising results with crizotinib, have fueled “a gold rush” among cancer researchers to find new gene fusions in solid tumors, says oncologist and HHMI investigator Charles Sawyers of Memorial Sloan-Kettering Cancer Center. “How many exist? And, let’s find out as fast as possible because the implications are just enormous.”
A Real Puzzle
The groundwork for the current gold rush was laid more than a decade ago when Druker and Sawyers helped develop Gleevec.
Through a series of discoveries in the 1960s and 1970s, scientists learned that in patients with CML, chromosomes 9 and 22 invariably swapped segments—what has come to be called a genetic “translocation.” By the 1980s, researchers had sequenced DNA at the break point in the CML translocation and discovered a hybrid between two genes. The gene fusion produced a protein called BCR-ABL that drove white blood cells to divide incessantly.
Druker worked with colleagues at the pharmaceutical company Ciba-Geigy (now Novartis) to find a compound—imatinib—that specifically blocked BCR-ABL in leukemia cells. Druker then joined forces with Sawyers to direct the clinical trials that demonstrated the compound’s remarkable ability to stop leukemia. Marketed under the name Gleevec, the cancer therapeutic was approved by the Food and Drug Administration in 2001.
Since then researchers have learned that Gleevec and drugs like it are no panacea, as the aberrant target gene in many patients’ cancer eventually mutates again to confer resistance. Sawyers and colleagues at Bristol-Myers Squibb have developed a drug called dasatinib that targets Gleevec-resistant BCR-ABL, and researchers are developing similar backup therapeutics for other Gleevec-like drugs.
The success of Gleevec and related drugs has inspired researchers to step up their hunt for the molecular defects underlying other cancers. By the mid-2000s, fusion genes akin to BCR-ABL had been found in various types of leukemia and lymphoma as well as in rare bone and soft-tissue cancers. But none had turned up in common solid tumors.
“It was a real puzzle why people weren’t finding these things,” says cancer biologist Jonathan Pollack of Stanford University School of Medicine. Some researchers argued that cancer-driving fusion genes were difficult to detect among the many abnormal chromosomes in solid tumors. Others argued that they simply didn’t exist. Researchers hunted instead for cancer-causing genes that were mutated, copied excessively (amplified), or deleted.
Photos: Druker: John Valls, Sawyers: Liz Baylen/PR Newswire, ©HHMI, Chinnaiyan: Liz Walker/University of Michigan