Outlier. metastatic tumors of the bladder cancer patient ( red arrows ) disappeared when she took an experimental drug (CT images taken before the drugs and at 3 months, 6 months and 15 months) .
G. Iyer et al., Science
Most experimental cancer drugs never make it to market because they do not contribute enough people in early clinical trials. But even in the "failure" of drug trials, researchers may find that some patients saw their tumors shrink dramatically. As it is not known why some react, but most do not, researchers generally shake head and move on. But researchers now report that by sequencing the entire genome of the tumor of a patient outliers, they learned why her cancer disappeared when she took an experimental drug that did not help others. This drug has a new lease on life with this cancer, and these tests can help revive other drugs against cancer that have shown promise in laboratory studies, but first failed in clinical trials.
Researchers at Memorial Sloan Kettering Cancer Center (MSKCC) in New York have been intrigued by the case of a woman with metastatic bladder cancer whose tumors disappeared after she received a drug, called everolimus, which targets a protein involved in cell growth known as the mTORC1. Most patients in the trial are not helped by drugs and it was abandoned as a single agent for bladder cancer. But this patient has been cancer-free for 2.5 years, a "result quite unprecedented" for this cancer that is resistant to chemotherapy, says doctor-researcher David Solit of MSKCC and Weill Cornell Medical College in New York.
The group Solit tested the women's tumors for mutations in a few genes in the mTORC1 pathway that could explain the sensitivity of the tumor, but found nothing. So, in collaboration with bioinformatics Barry Taylor's lab at the University of California, San Francisco, the group Solit sent a sample of the woman's tumor to a commercial laboratory for whole genome sequencing.
By comparing the genome of the tumor to normal DNA of women, the researchers found mutations in two genes, NF2 and TSC1 , the laboratory studies have also suggested are in the path of mTORC1. Mutations in TSC1 but not NF2 , also turned in several other samples of bladder cancer. Although TSC1 ( tuberous sclerosis 1 ) has not been on the radar of scientists, it was logical that this gene could be involved: People born with TSC1 mutation later develop benign tumors. The researchers then looked TSC1 mutations in 13 other patients in the same drug trials failed. Four whose tumors had shrunk mutations in TSC1 , but only one of the nine who did not respond had the change, the researchers report online today in Science .
Solit and others plan to screen patients with bladder cancer who have TSC1 mutation in their tumors so they can continue the trial everolimus and other mTORC1 drugs targeted in these patients. "Now we have a clear path forward," said Solit. And he thinks that the same approach can be used in other clinical trials. "This will change the way we view these outliers" said Solit . While researchers already knew that some drugs against cancer work only on patients with specific mutations in their tumors, whole genome sequencing could help identify more such genetic changes, he said.
"This is a great story," says cancer researcher José Baselga from the Massachusetts General Hospital in Boston. Baselga, who conducted a clinical trial of everolimus in breast cancer, now expected to test for patients TSC1 mutations to see if they explain why some responded better than others. the study also shows that the search for gene sensitivity to drugs will require more than testing for a tumor only a few candidates, Baselga said. "We probably go further" and sequence whole genomes, he said.
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