Decoding cancer: Elaine Mardis uses sequencing to study the genomes of diseased cells. Credit: David Torrence

Elaine Mardis
(Washington University, St. Louis) Sequencing the DNA of cancer cells is leading to new ways to treat patients.

Others working on Cancer Genomics
Sam Aparicio, BC Cancer Agency, ­Vancouver
Todd Golub, Broad Institute, Cambridge, Massachusetts
Mike Stratton, Wellcome Trust Sanger Institute, Hixton, U.K.

 

Deciphering the genetics behind the disease

 

 

 

MIT Technology Review, May/June 2011, by Emily Singer  —  In the fall of 2006, a new machine arrived at what’s now known as the Genome Institute at Washington University in St. Louis. It was capable of reading DNA a thousand times as quickly as the facility’s earlier machines, and at far less cost. Elaine Mardis, the center’s codirector, immediately began using it to sequence cancer tissues, scouring their DNA for mutations. Just five years later, Mardis and her collaborators have sequenced both cancerous and healthy tissue from several hundred patients and identified tens of thousands of mutations. Some of the findings have led to new approaches to treating cancer, while others have opened new avenues of research.

Cancer develops when cells accumulate genetic mistakes that allow them to grow and divide faster than healthy cells. Identifying the mutations that underlie this transformation can help predict a patient’s prognosis and identify which drugs are most likely to work for that patient. The information could also identify new targets for cancer drugs. “In a single patient, you have both the tumor genome and the normal genome,” Mardis says. “And you can get at answers much more quickly by comparing the two.”

In 2008, Mardis and her team became the first to publish the sequence of a cancer genome, derived by comparing the DNA of healthy and cancerous cells in a patient with a bone marrow cancer called AML. Further studies have suggested that patients with mutations in a particular gene may fare better with bone marrow transplants than with traditional chemotherapy, a less risky treatment that physicians usually try first. Mardis predicts that soon all AML patients will be genetically tested, allowing their physicians to make more informed decisions about treatment.

As the cost and speed of DNA sequencing have dropped—Mardis estimates that sequencing genomes from a patient’s cancerous and healthy tissue today costs about $30,000, compared with $1.6 million for the first AML genome—the technology is being applied to oncology more broadly. Research groups have now sequenced the genomes of multiple cancers, and in a handful of cases, they have used the results to guide treatment decisions for a patient (see “Cancer’s Genome,” January/February 2011). A few companies are now offering cancer genome analysis to researchers, and at least one is planning to offer the service to physicians and patients.

The decreasing cost of sequencing also means that Mardis can use the technology in drug development and testing. Her latest project is part of a clinical trial assessing hormone therapy for breast cancer. She has developed a preliminary genetic profile of cancers most likely to respond to a popular set of drugs called aromatase inhibitors, which are given to most breast cancer patients whose tumor cells have estrogen receptors on the surface. The goal is to identify the patients who will benefit from the drugs and those who won’t. (Preliminary evidence suggests that only about half the patients in the trial respond to the drugs.)

Understanding cancer genomes isn’t easy. Mardis’s team had to invent techniques to distinguish the rare cancer mutations from the mistakes that routinely occur when sequencing DNA. And scientists must figure out which mutations are actually driving the growth of the tumors and which are harmless. Then comes what might be the most challenging part: determining how the mutations trigger cancer. Mardis says she is leaving that challenge to the scientists around the world who are working to understand the mutations that she and others have identified. “It’s really gratifying to see others pick that up,” she says.

A Vaccine to Attack Cancer Early

Early Intervention: In multiple myeloma, cancerous plasma cells, like the ones pictured here, cause disease in the bones, blood, and immune system.
Credit: Nephron, Creative Commons (BY-SA 3.0)

 

 

 

A startup is developing the first vaccine to target patients before they develop cancer

 

 

 

MIT Technology Review, May 9, 2011, by Courtney Humphries  —  A startup is developing the first vaccine to target patients before they develop cancer.

 

Most cancer vaccines are intended to rally a patient’s immune system to fight cancers that have already progressed. But the startup company OncoPep, based in North Andover, Massachusetts, is developing a vaccine designed to prevent one kind of cancer—multiple myeloma—by treating patients who have only a precursor of the disease.

Multiple myeloma is a cancer of blood plasma cells. It develops when abnormal plasma cells in bone marrow multiply and accumulate, eventually damaging bones and other tissues in the body, and finally overwhelming the immune system. Currently, treatments can extend the lives of patients with the cancer but not cure it.

The company’s approach grew out of research by Kenneth Anderson, Nikhil Munshi, and Jooen Bae at the Dana-Farber Cancer Institute in Boston. The researchers deployed a combination of peptides—small pieces of protein—that are known to be specific to multiple myeloma cells and are important for their survival. The goal is to train the immune system to recognize and attack cancer cells bearing these peptides; the vaccine would also contain substances designed to boost immune response.

Plans call for the vaccine to be administered to people diagnosed with smoldering multiple myeloma, a condition in which plasma cells are unusually abundant and produce abnormal proteins but cause no symptoms of disease. Currently, patients with SMM are not treated. Although a majority of them go on to develop symptomatic cancer, it may take many years. Anderson hopes that the ability to detect the cancer in this early phase will make possible early, effective intervention. “The idea would be to prevent the development of an active cancer,” he says. Administering the vaccine to patients before they have received other, possibly debilitating cancer treatments, and while their immune systems are healthy, may give it a better chance of working.

Doris Peterkin, CEO of OncoPep, says that like several other experimental cancer vaccines in development, this one will be matched to people with a particular immune-system type: HLA type A2, the most common type in the U.S. Peterkin says the vaccine is most likely to be effective in these patients because the peptides are have a better chance of triggering an immune response in them.

Ronald Levy, an oncologist and cancer researcher at Stanford University, says that despite the advantages of vaccinating early, targeting this early stage of the disease may pose practical problems in testing the vaccine. Although nearly 80 percent of patients with SMM go on to develop multiple myeloma, they do so at a rate of only about 10 percent per year—so it may take a while to collect enough patients to test the vaccine. And limiting the vaccine to people with a particular HLA type will narrow the already small field. Levy says that the ultimate test of the vaccine’s success will be how well its chosen peptides provoke a specific immune response against the cancer, which has been the challenge for all peptide-based cancer vaccines.

Developing Cancer Drugs Based on Genomics

Chris Varma, Blueprint Medicines President and Cofounder.
Credit: Conrad Warre

 

 

 

A new startup, funded with $40 million from Third Rock Ventures, will develop drugs aimed at molecularly defined cancers.

 

 

MIT Technology Review, May 9, 2011, by Emily Singer  —  Blueprint Medicines, a startup based in Cambridge, Massachusetts, plans to use the growing amount of genomic information about cancer to create new drugs targeted at the mechanisms that drive specific subtypes of the disease. The company, which announced its creation last week with $40 million in funding from Third Rock Ventures, reflects a growing trend toward defining cancers not by their location in the body but by the particular collections of genetic mistakes that enable tumor cells to grow out of control.

“How the community, both academic and industry, understands cancer is really shifting from largely a pathology-centric viewpoint—classifying cancers based on what we can see in the microscope—to a molecular viewpoint,” says Chris Varma, the company’s president and cofounder. “What we find is that the mechanisms that are driving cancer come up again and again in different environments. The same mechanism responsible for some breast cancers could be driving a subset of brain cancer or melanoma.”

The growing understanding of cancer genetics has enabled researchers to develop an increasing number of drugs designed to zero in on cancer cells. Varma says Blueprint will use genomics and novel chemistry to develop such drugs in a more systematic way, targeting a broader range of molecular mistakes.

In addition to Varma, cofounders include Nicholas Lydon and Brian Druker, who led the development of Gleevec, one of the first targeted cancer drugs; Scott Lowe, deputy director of the Cold Spring Harbor Laboratory Cancer Center; and David Armistead, a biotech entrepreneur.

Genomic data on cancer has been pouring in to public databases over the last few years, thanks to projects such as the Cancer Genome Atlas, an NIH-funded effort to read the entire DNA sequence of various cancers. “There are now literally hundreds of genome efforts on various types of cancer,” says Lowe, “and all of this data is in the public domain and can be readily accessed.”

One of Blueprint’s goals will be to use this information to identify new drug targets. “Right now, we have lot of experience in identifying these alterations; we can catalogue and sequence genomes and identify changes present in particular cancers,” says Michael Hemann, a cancer researcher at MIT who isn’t involved with Blueprint. “The problem is, what do we do with that information? Which of these changes are relevant, and what do we do about it? For example, cancer cells can accumulate many mutations, some that drive abnormal growth and some that have no effect. And scientists need to identify which is which.”

Blueprint is building a platform that will initially use computational algorithms to analyze genomic data for potential molecular mistakes linked to cancer. For example, they would detect whether multiple data sets drawn from cancers of different types reflect mutations in the same enzymes. Researchers would then run tests on cells or animals to determine which of the mutations identified actually drive the growth of cancer cells and are thus the most promising targets for cancer drugs.

The company is also building a proprietary library of chemical compounds called kinase inhibitors—molecules that block activity of kinase enzymes, which have been linked with cancer. Armistead says the researchers will use computational modeling and x-ray crystallography to create a library of structures and then test the compounds’ ability to inhibit different kinases. They plan to generate and screen the library within the next 12 to 18 months. “We also have a short list of targets we already have interest in, which we will begin working on immediately,” says Armistead.

Roche

 

Roche Pharma Research Institute Building 92 Basel
(Herzog & de Meuron, completed 2000), Wettstein, Kleinbasel, Basel, Switzerland.

 

 

 

Why Roche is Important: Researching Drugs that target genetic mutations unique to cancer cells may be more effective than ones that act more broadly.

Key innovation:A new drug blocks the effects of a mutation thought to be present in as many as 8 percent of all cancers.

Technology:

Drugs that target genetic mutations unique to cancer cells may be more effective than compounds that act more broadly, and Roche has a number of such drugs in development. Last summer, it published promising results from a new drug that blocks the effect of a mutation thought to be present in 40 to 60 percent of malignant melanomas, and up to 8 percent of all cancers. In October, the U.S. Food and Drug Administration gave approval to a drug developed by Genentech, which was acquired by Roche in 2009, that blocks a specific protein associated with a certain type of stomach cancer.

Market:

Cancer drugs represent the majority of revenue for Roche and Genentech’s drug Avastin, now widely prescribed to help slow the growth of tumors by cutting off their supply of blood, did over $6 billion in sales in 2010.

Strategy:

Through acquisitions and partnerships, Roche has become one of the leaders in the push to use genetic information to develop drugs to treat a wide range of diseases. Through Genentech, the company has licensed a drug-delivery system developed by startup Seattle Genetics that uses antibodies to deliver cancer-killing drugs to targeted cells, potentially reducing the toxic side effects of chemotherapy medications.

 

Public Company: Roche

www.roche.com
Founded: 1896
Employees: 81,500
Revenues: $48.8 billion
R&D: $10.3 billion

Figures are for the company’s last fiscal year.

Management:

Severin Schwan (CEO)

Pascal Soriot (COO pharmaceuticals)