In a windowless conference room on the eastern edge of Cambridge, Mass., Nicolas Stransky scrolls down a database filled with genomic sequences from thousands of tumors.
The senior scientist at Blueprint Medicines zooms in to chromosome 7, where each gene is separated into columns and color-coded by mutation. Blue means deletions, or missing pairs of DNA; red signals duplication, extra copies.
When he filters results down to glioblastoma multiforme tumors, a brain cancer that typically kills patients within months, a problem announces itself on the middle of the screen: There on position 12, known as the EGFR gene, is a line of dark red squares. For some reason, in around half of these cases, patients produce additional copies of the gene, overexpressing an enzyme that in excessive amounts appears to turn on unchecked cell growth.
This isn’t a novel discovery by Blueprint (they don’t generally show those off to reporters before publishing in scientific journals), but it represents the precise type of target the startup is after, and how they’re hunting them down.
The company has already developed a library of small molecules, known as kinases, that inhibit the family of enzymes that EGFR belongs to, and which are often implicated in cancer. Now their scientists are working backward, using growing genomic databases and sophisticated data-analysis software to spot the precise drivers of cancers that their compounds, or at least refined versions of them, may stop.
“The drug is tailored to the genomic alteration, so when you see that alteration, the chances are the tumor is going to respond,” Stransky said. “Respond meaning shrink.”
The grand hope is that Blueprint can turn a growing number of cancer types into manageable chronic diseases.
The company’s approach is emblematic of the shift that has overtaken the world of cancer in recent years: The increasingly powerful, affordable and accurate tools of genomics have redefined how science is researching, diagnosing and treating various forms of the second-leading cause of death in America.
And the life sciences sector of Greater Boston has emerged as a hotspot of this work, particularly among the pharmaceutical giants, academic labs and research institutions packed into Cambridge’s Kendall Square, the leading cluster of life sciences research in the nation.
A short walk from Blueprint, in the Athenaeum Press Building, gets you to the Institute for Integrative Medicine, Amgen’s research center, Foundation Medicine’s headquarters, the Novartis Institutes for BioMedical Research and various offices of the Broad Institute, a genomics research collaboration between MIT and Harvard. A wider circle around Boston captures Harvard Medical School’s hospitals and labs within the Longwood Medical Area, the Dana-Farber Cancer Institute, the headquarters of Berg-Pharma and much more.
“It’s just a fertile ecosystem with a lot of talent, a lot of research and a lot of venture capitalists actually funding the translation of that research into commercial products,” said John Hallinan, chief business officer at the Massachusetts Biotechnology Council. “I think we’re at the cusp of another great breakthrough in oncology.”
Next-generation sequencing allows researchers to sort through the three billion DNA base pairs that produce the muscle, hair, bones, enzymes and antibodies that produce us, and sometimes pinpoint the spots where things have gone awry.
The massive amounts of data are offering a clearer understanding of the processes driving mutations, the myriad varieties of cancers once lumped together by location, and how genetic errors distort normal cell activity.
It has enabled the creation of a number of so-called targeted therapies, customized for specific mutations rather than catch-all chemotherapies, an approach that has led to improving survival rates for certain types of melanomas and lung cancers.
“This information has led to the development of drugs for cancer that extend lives and improve quality of life, as well,” said Tyler Jacks, director of the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology. “And there will be many, many more to come.”
That all said, genomics has in many ways been a letdown for medicine to date. The seemingly simple biological roadmap has turned out to be much more complex than hoped.
The links between genes and diseases are less deterministic than once believed, swayed by overlapping and little-understood factors in the environment around us and the microbes within us. Seemingly promising compounds often don’t hit their targets, for reasons that scientists don’t quite understand.
The market has seen far fewer blockbusters than promised by the founding missions and research programs of numerous biotech firms — and the vast majority of drug candidates still fail.
So until any treatment, from Blueprint or others, proves to be more effective than existing ones in controlled clinical trials, it is nothing more than another promising possibility.
The inflection point
Foundation Medicine is housed in an L-shaped glass building three blocks north of Blueprint. But where that company is focused on using genomics to develop novel treatments, Foundation is leveraging it to improve diagnostics.
The four-year-old company raised nearly $100 million from Bill Gates, Yuri Milner, Google Ventures, Kleiner Perkins and Third Rock before going public last year.
In a long room behind glass walls on the second floor, a series of Illumina machines continuously analyze tumor biopsy samples, sent in by oncologists from around the world. The company’s data-analysis tools zero in on more than 300 genes most frequently associated with cancer, untangling the specific alterations at work.
In turn, they run those reports across internal databases of known therapies, experimental treatments and clinical trials, looking for the most promising drug for that individual at that moment.
In a paper published in Nature Biotechnology in November 2013, Foundation reported that they found “clinically actionable alterations,” generally meaning mutations for which there was some known treatment, in 76 percent of cases — three times greater than standard diagnostics tests, according to the company.
And that can mean real differences in patient outcomes.
In an interview, Chief Executive Michael Pellini highlighted the case of a 71-year-old woman diagnosed several years ago with gall bladder cancer. It had metastasized, and chemotherapy had little effect.
But the Foundation One test spotted what are known as FGFR fusions, rare abnormalities on the gene of the same name that are known to respond to Pazopanib, a kinase inhibitor. After taking the drug, her disease stabilized for months, and a recent Foundation test couldn’t detect the fusions.
It did, however, turn up a new mutation, an amplification known to respond to Herceptin. So she will soon begin a course of that treatment.
Pellini thinks this is what cancer treatment will increasingly come to look like: A chronic disease where oncologists and patients stay one step ahead by continually monitoring conditions and shifting treatments.
It’s not as good as a cure — a word Pellini deliberately avoids — but it’s better than a death sentence.
“We’re hitting the inflection point,” he said. “Every month, if not every week, we learn more than we had learned in the past five years combined. It’s really difficult to be anything other than optimistic about where we are.”
Turning on the lights
Blueprint gained attention from the start because of its founding team, three scientists — Nick Lydon, Brian Druker and Charles Sawyers — behind the breakthrough drug Gleevec, a targeted therapy that doubled the five-year survival rate for patients with a rare cancer of the white blood cells.
But where that kinase inhibitor took decades to develop — a story well told in “The Philadelphia Chromosome” — Blueprint’s leaders believe that the company can virtually crank out candidates by coming at drug discovery from a new direction.
The three-year-old company, which has raised $115 million to date, is exclusively focused on kinases because they’re so often implicated in cancer. The enzymes act as switches that regulate cell growth, so when mutations arise, things can quickly spin out of control.
The team spent the first year developing generic inhibitors with no specific disease in mind, assembling a database that ranked the compounds based on how effectively and selectively they blocked any of the 500 or so kinases.
It was only after they developed this library that they went looking for targets, setting their data tools to work exploring the scientific literature, public genome databases and their own growing pool of tumor sequences.
When they identify what looks like a genetic error driving cancer — not merely a mutant passenger along for the ride — they check their database for promising compounds. If they see one, they’ll set their chemists to work on it in the wet lab, reengineering it into something better targeted, more potent and easily deliverable in a pill.
The company has already identified encouraging targets, including various fusions, which occur when two normally separate genes are joined, that are likely implicated in cancer; and genetic alterations associated with an aggressive cancer of the female reproductive system.
But the real test, of course, is whether or not Blueprint delivers new drugs that improve patient outcomes.
The company has two candidates set to begin Food and Drug Administration trials next year, including potential treatments for systemic mast cell disease and the most common form of liver cancer.
These trials take years in the best of circumstances. But Blueprint’s Chief Scientific Officer Christoph Lengauer believes they have a good chance at securing “breakthrough status,” a new, accelerated FDA approval process for particularly promising drugs.
That’s because those genomics databases and tools enabled the company to design highly targeted treatments for very specific patient populations from the start, rather than taking shots in the dark.
“If you have a spotlight at a movie theater, you can look at one place or the other place,” Lengauer said. “But if you learn to switch on the lights, you can see the whole room.”
This article originally appeared on Recode.net.