The big push in the nowadays cancer treatment is to sample the tumor of a person, the test for mutations, and give the patient a medicine for genetic weak point in the tumor. A new study suggests one reason why this strategy of targeted drugs do not always work. A solid tumor, it turns out, is not a mass of identical cancer cells, but a mosaic of genetically different cells that are not captured with a single biopsy. Some of these different cells may be resistant to targeted drugs, which allows a tumor persist or grow.
The conventional view of how cancer develops is a single, normal cell accumulates mutations that allow or possibly force it to divide uncontrollably. This "clone" then grows into a tumor of identical cells, which can also sow seeds of cells in the blood that can take root somewhere else in the body, or metastasize. The hypothesis that tumors develop from a single clone has sparked a rush to find drugs that block one of the weak points genetic clone. But although the strategy has led to some very effective drugs, Iressa for lung cancer and a new melanoma drug called Zelboraf, for example, these drugs often stop working in a year or two. One reason might be that already house some solid tumors cells, or clones with "resistance" mutations that take over when the cells targeted by the drug are destroyed.
Now, British researchers confirmed this idea by using the new generation of DNA sequencing to explore the genetic landscape in unprecedented detail tumors. Charles Swanton of the UK London Cancer Research Institute Research and University College London, James Larkin of The Royal Marsden Hospital in London and colleagues took samples from nine locations within 10 centimeters wide primary tumor of the kidney of a patient and certain tumor metastases patient. The researchers then put these biopsies through a battery of genomic tests, including sequencing all genes encoding proteins in each sample.
The researchers found a huge amount of variation within tumors than patients. Only 34% of the 118 mutations detected they showed in all samples. Several genes of key cancer were mutated in the primary tumor, but in different ways in different areas. When the researchers examined which genes in the tumor were active-these so-called gene expression signatures are designed to predict whether the prognosis for a kidney patient is poor or good results differ depending on the part of the tumor, they tested.
The team then created a family tree of how these clones evolved from a single clone. The good news, Swanton said, is that this analysis revealed that certain mutations in the "trunk" of the tree persisted that cancer has evolved, which means that all the patient's tumor cells had these weaknesses. Therefore, drugs targeting these mutations should work even on tumors that heterogeneous could explain the initial success of Iressa and Zelboraf. However, other resistance mutations to existing drugs in the branches of the tree could possibly block the drugs work, Swanton said. His team reports its results today The New England Journal of Medicine .
Carlo Maley University of California, San Francisco, who studies the evolution of cancer, warns that the study was small in total, the UK team tested only four tumors and two patients in detail . Yet it is "highly suggestive that intratumoral heterogeneity should be expected," he said. "It adds a great level of noise and uncertainty that everybody does," says Maley. Swanton said bottom line of the study is that the researchers develop new therapies against cancer, they should be aware that the single biopsies can be deceiving. "We must think about the sequencing of tumors means more thoroughly"
0 Komentar