Cancer Sleuths Uncovering DNA Mysteries for Novartis, Glaxo
Most existing cancer treatments either kill tumors outright with toxic chemotherapy or block mutated genes that fuel tumor growth. Now drugmakers including GlaxoSmithKline Plc (GSK), Eli Lilly & Co. (LLY), and Novartis AG (NOVN) are chasing a third approach: reprogramming aberrant DNA that can turn cells cancerous in the first place.
These new drugs exploit an emerging understanding of the epigenome, the molecular machinery that cells use to turn genes on and off, directing them when to produce proteins that carry out most functions of life. Celgene Corp. (CELG) last year generated $534 million in revenue from its epigenetic compound Vidaza, which adds months of life for patients with myelodysplastic syndrome, a leukemia-type disorder. Bloomberg Businessweek reports in its May 16 issue that the approach also underlies blood-cancer drugs from Eisai Co. and Merck & Co.
The bigger payday will come from drugs that treat the millions who suffer from more common forms of cancer, like those affecting the lungs, breasts, or prostate. In January, Epizyme Inc., a closely held company co-founded by H. Robert Horvitz, the Massachusetts Institute of Technology Nobel laureate, agreed to a deal worth as much as $650 million with London-based Glaxo to search for epigenetics drugs for cancer. Novartis, Glaxo, Indianapolis-based Lilly, and at least four venture-backed startups are also racing to devise cell-reprogramming drugs for more prevalent tumors.
“Every major company I know of has a program” in epigenetics, says Jean-Pierre Issa, an oncologist at the University of Texas MD Anderson Cancer Center in Houston.
One reason: Cancer medicines are the world’s top-selling drug category, with $22.3 billion in U.S. sales last year, an increase from $15.8 billion in 2006, according to IMS Health Inc., a market research company in Norwalk, Connecticut.
A successful new compound based on innovative science can generate sales quickly. The last new approach to cancer targeting mutated or overactive genes led to drugs like Gleevec, a leukemia breakthrough sold by Basel, Switzerland-based Novartis, and New York-based Pfizer Inc. (PFE)’s Sutent for kidney cancer. Both drugs exceeded $1 billion in annual sales within 5 years of their debuts.
Scientists since the 1980s have focused on understanding how cancer is spurred by damage to DNA inside cells, such as the harm caused by smoking. Research over the last decade has found that defects in so-called epigenetic control molecules may be as important a cause of cancer as direct DNA damage, said Stephen Baylin, a cancer biologist at Johns Hopkins University in Baltimore. Baylin likens it to a computer malfunction caused by bad software instructions, rather than a hardware fault.
In the last few years, researchers have discovered that there are hundreds of molecules that control genetic bar-code labels on DNA. Normally, these codes help stem cells develop a specialized identity to form tissue for muscle, skin or other organs, said C. David Allis, a biochemist at Rockefeller University in New York, and co-founder of Constellation Pharmaceuticals Inc., based in Cambridge, Massachusetts. In diseases such as cancer, some of the code appears to be damaged or altered.
Epigenetic molecules are faulty in 60 percent of patients with pancreatic neuroendocrine tumors, the type of cancer that Steve Jobs, Apple Inc. (AAPL)’s chief executive officer, has been treated for, Johns Hopkins researchers reported in the journal Science in March.
While scientists aren’t certain just how epigenetic medicines work, one effect they appear to have is to reactivate so-called tumor suppressor genes that keep cells from growing out of control.
With epigenetic drugs, “the therapeutic concept is to revert those bar codes back to normal,” said Jonathan Yingling, vice-president for cancer research at Lilly. “It would be hard for you to find a drug company that is not investigating this.”
“If it lives up to its promise, it will make a significant impact on cancer,” said Dash Dhanak, who leads the GlaxoSmithKline cancer epigenetics effort.
The cancer epigenetics field started in the 1970s after an unexpected discovery by a young researcher testing an unproven drug from Czechoslovakia. Peter Jones, now director of USC Norris Comprehensive Cancer Center made a discovery that seemed outlandish at the time soon after arriving in Los Angeles in 1973 for a postgraduate fellowship having grown up in South Africa and Rhodesia.
While studying the effects of various experimental chemotherapy drugs, he stumbled onto one -- called 5-azacytidine -- with a surprising ability to turn precancerous mouse embryo cells into muscle cells. They literally would start twitching a couple weeks after treatment.
“I was elated because we seemed to have the first drug capable of completely reprogramming cells,” he wrote in a 2011 essay. He first published the results in the journal Nature in 1977 and spent the next few years teasing out how the drug worked.
It turned out that it blocked the ability of cells to add chemical tags to strands of DNA. These tags, in effect tiny molecular bar codes, were found to block cells from activating genes.
In the mid-1980s, Baylin of Johns Hopkins started finding abnormally high levels of the gene-silencing bar codes in the DNA of tumors, including those in leukemia and lung cancer. Baylin and Jones proposed the abnormal bar codes could be an important cause of cancer.
“There was a huge amount of skepticism,” said Issa, who worked with Baylin at Johns Hopkins in the 1990s before moving to MD Anderson. Biologists “said we know what causes cancer, it is genetic changes and epigenetics is irrelevant.”
In 1994, Baylin bolstered the theory by showing that a key gene involved in kidney cancer was turned off through the DNA reading process in 20 percent of human tumor samples tested, even though the gene was fully functional. This indicated to Baylin and others in the field that the bar code defects were an alternative mechanism for tumor cells.
By that time, Lewis Silverman, a hematologist at New York’s Mount Sinai School of Medicine started testing 5-azacytidine, the drug that would become Vidaza, in patients with myelodysplastic syndrome. The drug had been rejected by U.S. regulators for treating acute leukemia. Silverman used lower doses to reprogram the cells without killing them.
In 2001, the biotechnology company Pharmion Corp. obtained rights to the drug. Pharmion spent two years tracking down old patient records from Silverman’s studies, and used them to get Vidaza approved for myelodysplastic syndrome in 2004. Celgene bought Pharmion for $2.9 billion in March 2008 after the drug was shown to extend life of patients by nine months. Dacogen, a similar drug developed by SuperGen Inc. (SUPG) and marketed by Tokyo- based Eisai in the U.S. was approved in 2006.
The question now is whether epigenetic cancer drugs can move beyond their current niche in treating blood cancer to treat common solid tumors. “There is no reason why it shouldn’t work on solid tumors,” said Robert Weinberg, a researcher at MIT’s Whitehead Institute.
Faulty bar codes could prove “as important” as gene mutations as a cause of cancer, he said, adding that the next two or three years will give researchers a better sense of how broad a role the bar codes play. “There is a lot of excitement building because it is a new way in to target cancers,” said Jeff Porter, a research executive at Novartis.
One target for drugmakers is an enzyme called EZH2 that is overactive in breast cancer, prostate cancer, and other tumors. Constellation Pharmaceuticals and Epizyme are independently pursuing drugs in preclinical studies against the enzyme, while Glaxo plans human trials of its EZH2 blocker this year.
In a 2010 study, Charles Roberts, a pediatric oncologist at Boston’s Dana-Farber Cancer Institute, created a strain of mice with a cancer-causing gene defect that is lethal within four months. Then he took mice with the same defect and inactivated EZH2. They all survived.
“It completely stops the cancer when we turn off EZH2,” said Roberts. “The drug companies were swarming all over me” when he presented the results at the American Association for Cancer Research conference in April.
Epigenetic drugs also may make tumors more sensitive to existing treatments, said Joanna Horobin, chief executive of venture-backed Syndax Pharmaceuticals in Waltham, Mass. In lab experiments, Syndax’s entinostat makes breast tumors more sensitive to hormone therapy by reprogramming estrogen receptors inside cells. Syndax “successfully completed” a 130-woman trial aiming to show that entinostat in combination with Aromasin slowed the progression of advanced breast cancer, Horobin said. It plans to begin a final-stage trial in breast cancer next year.
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