JOIN USGene sequencing therapy offers new hope for cancer
Beth McDaniel’s oncologist, a bear of a man, hugged her and twirled her around. “Holy cow, Beth!” Dr John J. Gohmann exclaimed.
For the first time since a rare cancer appeared eight years before, her lymph nodes had shrunk to a normal size, her skin was no longer bright red and inflamed, and the itchiness that plagued her had subsided.
McDaniel, the 69-year-old wife of a retired corporate executive, had gambled on the ultimate in personalised medicine, an approach known as whole genome sequencing, and it seemed to be paying off. Scientists had compared the entire genetic sequences of the tumor cells invading her body with those in her healthy cells, searching for mutated tumor genes that could be thwarted by drugs approved for other cancers or even other diseases. That had led them to give her an expensive drug approved just a month earlier for melanoma patients. It had never been given to anyone with a blood cell cancer like hers. In theory, the drug should have killed her. Instead, it seemed to have halted or even reversed her cancer.
But would it last? And what would it mean if it did not? In the end, McDaniel’s journey to the edge of genetics research turned out to be a decidedly mixed experience. It was hard — much harder than anyone in her family had imagined — to get the sequencing and analysis done. It was breathtaking to see the results, which indicated that her cancer was driven by a strange gene aberration that could be attacked with a new drug.
But it was heartbreaking to see how quickly her cancer recovered from the assault, roaring back in a matter of weeks. McDaniel’s story offers a sobering look at the challenges for this kind of quest for a treatment, even for someone like her, who had both the means and the connections to get the intricate geography of her cancer charted. Her husband, Roger McDaniel, was a former chief executive of two companies involved in semiconductor manufacturing, and the family could afford the approximately $49,000 that the search would cost.
Beth McDaniel’s cancer began with itching all over her body. Then her skin turned scarlet and started becoming infected. In 2005, after she had spent more than a year going from specialist to specialist, a dermatologist figured it out. McDaniel, then 62, had Sezary syndrome, a rare T cell lymphoma, in which white blood cells become cancerous and migrate to the skin. All her doctors could tell her was that the disease was incurable, that there was no standard treatment, and that on average patients at her stage die within a few years.
Before cancer, she had had a vibrant life, hiking in the mountains, travelling the world, entertaining her wide network of friends. Her disease destroyed all of that. She could not even enjoy her luxuriant garden because sun on her inflamed skin was agony.
Although there is no standard treatment, for five years chemotherapy held her disease at bay. But in the summer of 2010, she got worse, much worse, with hundreds of tumors popping up under her skin. Some grew as large as kiwi fruits and split open.
Her son, Dr McDaniel, decided he would orchestrate the use of the most advanced techniques of gene sequencing and analysis to take on her cancer. Because of his job — he works for Illumina, a company that does DNA sequencing — Dr McDaniel had read scientific reports and gone to medical conferences where he heard talks on whole genome sequencing. He noticed that the patients all seemed to have rare cancers.
In theory, it seemed straightforward for Dr McDaniel to help his mother. The technology for getting and analysing DNA sequences has advanced greatly, and the cost has plummeted. In fact, Dr McDaniel said, the price of sequencing has dropped so fast that if the work were done today, it would cost just $26,200 instead of the $46,280 it cost last year.
First obstacle
The first obstacle was just getting a sample of McDaniel’s cancer cells. One doctor told her the odds of success were so slim that she would be better off spending her money on a vacation. Another seemed interested but did not follow through. A third did two biopsies but was unable to get usable DNA.
“She believed, we all believed, she would die before we got the sequencing done,” Dr McDaniel said. Then, in January 2011, Dr. de Castro got a tissue sample from a tumor and, for comparison with normal cells, her saliva. He had removed a plug of tissue the size of a pencil eraser from one of the hundreds of tumors on McDaniel’s skin, frozen it in liquid nitrogen and shipped it overnight to the Mayo Clinic in Scottsdale, Ariz. By April, scientists at Illumina and TGen, a nonprofit research institute, had completed the genetic sequencing of the samples.
John Carpten, an oncologist at TGen, and David Craig are accustomed to working with gene sequence data, but it is hard even for them to get used to the scale of such a project. The hard drive containing McDaniel’s genetic data arrived in the mail — it had too much data to send electronically. It took a full day just to pull this terabyte of information off the drive. Dr. Carpten explained that there were three billion symbols, made from four letters — A, T, G and C — in just one cell’s DNA. If those letters were printed on paper, they would fill a medium-sized elementary school’s library.
“It is like putting together a jigsaw puzzle that has a billion pieces,” Dr Carpten said. Finally, they compared the sequences of normal cells and cancer cells. They found about 18,000 differences, most with no known significance for the disease.
At last, the work was done, and on May 18, Dr McDaniel flew to TGen. The researchers noticed an intriguing aberration in McDaniel’s cancer genes. But they were uncertain what it meant. It looked as if two genes had fused to each other in McDaniel’s cancer cells. The result was that the cell growth signals in the cancer cells were reversed, like crossed wires. The research team theorised that every time those cancer cells, T cells of her immune system, got a signal to stop growing, they reacted as though they had gotten a signal to grow. And every time they got a signal to grow, they responded by stopping their growth.
If they were right, the way to stop her cancer’s growth could be to signal it to grow. And that was what a new melanoma drug — ipilimumab, its trade name Yervoy — was designed to do. It spurred the growth of normal T cells. But if the researchers were wrong, the drug could kill her. They spent two hours at a whiteboard on Wednesday, May 18, trying to understand what the fusion really meant. Then Dr McDaniel took the data home and asked a colleague at Illumina to try to fish out a handful of crucial genetic sequences that were buried among 50 million others. On Sunday night, May 22, Dr McDaniel had them and began trying to decipher them. By 10 pm, he had it figured out.
The TGen scientists’ findings were real. “The brake pedal had been wired to the accelerator,” Dr McDaniel said.
He worked all night, found a paper by scientists who had deliberately fused those very genes and discovered that, yes, the genetically altered T cells had their growth signals reversed.