Two Boston-area teams have assembled massive encyclopedias that predict the vulnerability of hundreds of different subtypes of cancer to dozens of drugs.
The massive catalogs, being made freely available Wednesday, are an important step toward the routine personalizing of cancer care, in which patients will receive treatments tailored to the specific genetic changes that influence a tumor’s response to drug regimens.
Already, the data, which correlate cancer cells’ genetic profiles with their sensitivity to medications, are being used to design more sophisticated early-stage clinical trials of drugs. The research has also suggested at least one unexpected treatment that can be rapidly tested – that a drug used for breast and ovarian cancers may be effective against Ewing’s sarcoma, a childhood bone cancer.
Previous attempts to identify drugs most effective against specific cancers used far fewer tumor types, or “cell lines”, and the new catalogs more accurately represent the enormous genetic diversity of the disease.
“This is an invaluable resource, and in fact the term ‘encyclopedia’ is appropriate. It’s a monumental amount of work, which will be useful and used in the years to come,” said Dr. Pier Paolo Pandolfi, scientific director of the Beth Israel Deaconess Medical Center’s Cancer Center, who was not involved in the research. “An encyclopedia will be enabling for many, many labs in many countries.”
The databases, published Wednesday in the journal Nature, are the product of years of effort by two groups working in parallel and represent a significant step beyond a set of 60 cancer cell lines that have been used to screen tens of thousands of potential drugs since 1990. Researchers from the Massachusetts General Hospital Cancer Center, together with the Wellcome Trust Sanger Institute in England, analyzed more than 600 types of cancer cells and looked at their response to 130 possible therapeutics. A second team of researchers from the Cambridge genetics research powerhouse, the Broad Institute, Dana-Farber Cancer Institute in Boston, and Novartis Institutes for BioMedical Research in Cambridge created detailed genetic portraits of nearly 1,000 types of cancer cells and then looked at how about half of those cells responded to two dozen cancer drugs.
The scale of both efforts gives scientists powerful tools to answer some of the most important questions facing cancer doctors today.
“How do you know what’s intrinsically important in biology? How do you know which patients to give those drugs to?” said Dr. Levi Garraway, a senior associate member of the Broad Institute and one of the leaders of the work.
Novartis has begun using the resource to test potential therapeutics in development, altering the traditional way of structuring early-stage trials. Early-stage cancer clinical trials are generally open to “all comers” — anyone with cancer — as the researchers try to determine a safe dose of the drug.
Novartis, however, began testing the potential drugs it is developing against the encyclopedia of cell lines in 2009, said Dr. Bill Sellers, vice president and global head of oncology research. As a result, the company has begun to shift how it structures a handful of early-stage drug trials because of strong evidence that a subset of patients with a particular genetic aberration would be most likely to respond.
Both studies revealed novel insights about how drugs interacted with cancer cells that suggest ways to follow up — including not only finding new drugs that appear to work well for patients, but also finding ways to predict which patients will likely not respond to a drug, which could give doctors more informed ways to design treatments.
“It’s important to know what mutations are leading to or linked to response to what drugs,” said Cyril Benes, director of the center for molecular therapeutics at the MGH Cancer Center. “And it can also be a way of discovering a new repurposing, a new application of a given drug.”
Dr. John Weinstein, chairman of the department of bioinformatics and computational biology at the University of Texas MD Anderson Cancer Center, who was not involved in the research, said the papers would be a powerful new resource, but added it is important to keep in mind the limitations of cancer cells in a dish. Isolated cancer cells are not always predictive of how cancer behaves in the body, he said, and researchers need to be aware there will be false leads as well as real ones. Still, given the ethical, financial, and logistical difficulties of testing drugs in people and the proliferating number of potential cancer therapies, encyclopedia-like tools are badly needed to help winnow down the drugs and combinations that are most likely to work.
“Reducing the universe of possibilities from the 600 or so drugs that are potentially in or ready for clinical trials to a handful that at least have some rationale behind them,” Weinstein said. “That’s an advantage.”