3 studies offer insights into skin and blood cancers

Results could lead to trials of new treatments

Dr. Leonard Zon led a study of 100 human melanomas and found many genes that might play a role in the disease. Dr. Leonard Zon led a study of 100 human melanomas and found many genes that might play a role in the disease. (Lane Turner/ Globe Staff)
By Carolyn Y. Johnson
Globe Staff / March 24, 2011

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After research ranging from brute-force sequencing to the painstaking study of thousands of zebrafish tumors, local scientists announced yesterday new insights into blood and skin cancers that could lead to clinical trials with existing drugs.

In three papers published in the journal Nature, separate teams of researchers used different genetic approaches that highlight the strategies scientists are using to reveal the biological underpinnings of cancer.

One team, led by researchers at the Broad Institute in Cambridge and Dana-Farber Cancer Institute in Boston, reported they had sequenced the full genomes of tumors removed from 38 patients with multiple myeloma, a rare and incurable form of cancer. The research provides the deepest and most comprehensive look at a cancer yet, according to Dr. Bert Vogelstein, a professor of oncology and pathology at Johns Hopkins University School of Medicine, who was not involved in the research.

The study highlighted several new genes involved in the disease, for example, genes that are involved in blood clotting or the way genetic material is translated into proteins. Researchers also found that a small subset — an estimated 4 percent of patients — carry a mutation in a gene called BRAF. Already, treatments that target the BRAF gene have been clinically tested in melanoma patients, so the finding suggests an immediate trial that could be done in a subset of multiple myeloma patients using a drug already in late-stage development.

“There had been some speculation that maybe we’ve discovered all the cancer-causing genes and there’s nothing left,’’ said Dr. Todd Golub, a core member at the Broad and senior author of the new research. “The ability to look broadly in this way is showing us that we haven’t discovered everything.’’

Louise Perkins, chief scientific officer of the Multiple Myeloma Research Foundation, which funded the research and provided tissue samples for the work, said that already early-stage discussions have started with Roche regarding the possibility of a clinical trial of a drug, developed with another company, Plexxikon, that inhibits BRAF in melanoma patients.

Dr. Michael Kuehl, a senior investigator at the National Cancer Institute, said the work is important because it not only confirms some familiar biological insights into multiple myeloma but also adds new questions that can be investigated.

“In the end, a paper like this is basically hypothesis-generating, but not taking anything to completion,’’ Kuehl said. “I think it opens up many avenues for other people to work on.’’

In two separate studies led by scientists from Children’s Hospital Boston, researchers took a different genetic approach — using thousands of zebrafish embryos as a model for melanoma.

Dr. Leonard Zon and colleagues genetically manipulated zebrafish that develop melanoma.

Building off work that looked at 100 human melanomas and found a large number of genes that might play a role in the disease, researchers systematically looked at those genes to see which ones were drivers in the cancer. They analyzed 2,100 tumors in more than 3,000 fish to find one gene that made the cancer more aggressive and faster growing, called SETDB1. In the human tumors, that gene was also overly active, suggesting a new drug target.

In a second study, Zon and colleagues found that zebrafish that were prone to developing cancer had more gene activity associated with a certain type of stem cell.

They screened 2,000 chemicals to find one that suppressed that particular type of stem cell. That led them to a drug with a similar mode of action, called leflunomide, which is currently used to treat rheumatoid arthritis.

In mice that were engrafted with a human melanoma tumor, and then treated with the arthritis drug and another targeted compound that is already in late stage clinical trials for melanoma, the combination seemed to block tumor growth.

There is increasing emphasis on the need for combination drugs, since targeted drugs can have effects on cancer, but often the effects are only temporary.

Zon said he is now working toward a clinical trial of the drug combination in humans.

The papers use approaches that leverage the information from the human genome project in different ways — something Zon said was a good thing.

“You have to use what’s good about each technique and each model to advance science and medicine the quickest and furthest,’’ he said.

Carolyn Y. Johnson can be reached at