Monday, November 26, 2012
At Memorial Sloan Kettering, new technologies to study gene changes in cancer cells are accelerating the development and implementation of more-effective treatments.
This is the second part of a two-part story. The first part focused on how cancer genomics research is informing patient care in a number of cancer types.
Memorial Sloan Kettering is gearing up for the next phase of cancer genomics discovery, in which more-streamlined and affordable technologies to study the DNA of cancer cells are expected to accelerate the development and implementation of personalized treatments.
For the past three decades, Memorial Sloan Kettering physicians have asked their patients for permission to archive samples of cancer cells along with the patients’ clinical history. Today, a bank containing samples from tens of thousands of patients — consisting of excess material that in most hospitals normally would be discarded — provides scientists with an invaluable resource that has the potential to benefit future patients.
In discovering and investigating gene alterations in banked tissue samples, researchers have increasingly been able to look into the complex mechanisms that may have caused the diseases to form or progress, or made some patients’ cancer able to elude currently used treatments. These investigations have resulted in more-effective therapies and diagnostic tools in some diseases, including certain types of lung cancer, colorectal cancer, melanoma, and other cancers.
Similar advances have yet to occur for most cancers, but scientists are hopeful that genomics research will fuel important discoveries at a much faster pace in the future. With the arrival of modern technologies known as next-generation DNA sequencing, researchers are now able to map the entire genome of a patient’s tumor, or parts of the genome, more quickly and inexpensively.
“We will soon be able to maximize the amount of knowledge that can be extracted from a tissue sample,” says molecular pathologist Marc Ladanyi. “This is greatly expanding our capacity to study sets of cancer samples retrospectively and to optimize treatments for individual patients.” Together with computational biologist Chris Sander, Dr. Ladanyi heads one of the Genome Data Analysis Centers of The Cancer Genome Atlas (TCGA) — a nationwide effort to catalogue genetic changes and molecular profiles in more than 20 major types of cancer.
Enhanced Sequencing Capabilities
Compared to traditional DNA sequencing methods, next-generation sequencing scales up the process considerably, producing millions or billions of sequences at once. “We can analyze more samples at once, look at more genes at once, and identify different classes of mutations,” Dr. Ladanyi explains.
“We can also look deeper into a tumor sample,” adds Agnès Viale, who heads Memorial Sloan Kettering’s Genomics Core Laboratory. Most tumors are heterogeneous, which means they contain a mix of different populations of cancer cells with distinct genetic profiles, as well as different types of noncancerous cells that infiltrate the tumor. “If a mutation is present only in a tiny percentage of the cells in a sample, next-generation sequencing allows us to detect that mutation more easily,” she explains.
At the same time that technologies are improving, the cost of DNA sequencing is plummeting. As an example, Dr. Viale likes to recall the $3 billion price tag of the international Human Genome Project, which began in 1990 and took 13 years to complete. “Today, we are able to sequence an entire genome for less than $5,000 in about ten days,” she says.
During the past five years, the Genomics Core has continually been enhancing its capabilities by purchasing the latest in next-generation sequencing. With the recent addition of an instrument called Ion Proton™ — acquired in partnership with the New York Genome Center and Life Technologies Corporation — Dr. Viale is hoping to soon see the average cost of whole genome sequencing reduced to $1,000 and the time of the process shortened to a couple of hours.Back to top
A Growing Overload of Data
However, in spite of these technology advances, cancer genomics remains an expensive and time-consuming endeavor. Dr. Sander notes that with the falling costs and increasing speed of DNA sequencing, researchers are generating a deluge of valuable information that is expensive to store and complex to analyze and interpret.
“The community of cancer researchers is now addressing the challenge of translating a growing amount of molecular profiles into biologically meaningful insights,” he says, “with the aim to benefit patients through personalized therapy.”
Dr. Sander and a team of computational scientists led by Nikolaus Schultz are developing computational methods to map out cancer-causing molecular pathways. Their public, Web-based research tool — called the cBio Cancer Genomics Portal — makes data from TCGA and international cancer genomics projects available to a broad community of clinicians and scientists, and also makes this data easier to navigate and explore.Back to top
Another challenge investigators are grappling with is to make as many tissue samples available for DNA sequencing as possible. “We are optimizing our protocols and computational methods to be able to analyze the vast majority of clinical samples, which may contain very small amounts of cancer cells or may have been stored using preservatives that can reduce the quality of the DNA,” says Michael Berger, a genomics researcher in the Department of Pathology.
For example, while surgery of primary tumors often yields high-quality samples, it is more difficult to analyze DNA from metastatic tumors. As these advanced tumors often are inoperable, only small samples obtained by needle biopsy are available for diagnosis and genetic analysis.
Dr. Berger and his colleagues have developed a cancer genomics approach called MSK-IMPACT™, by which 275 select genes in a tumor are captured and sequenced on an instrument called Illumina HiSeqTM. The genes are ones that have previously been implicated in the development or behavior of tumors, and some can be targeted with existing drugs or monitored with clinical tests.
“Targeted sequencing makes genomic research on biopsy samples or low-quality tissue more feasible,” he explains. “And in some research projects, we have better chances of making clinically relevant discoveries if we focus on deep sequencing of these previously characterized genes in many specimens, rather than broadly analyzing the entire genome.”Back to top
Whole Genome Sequencing
However, sequencing the whole genome of a patient’s cancerous tissue is warranted in some cases, and may lead to significant discoveries. As an example, Dr. Berger refers to a recent study he participated in.
The findings were made after an early-stage clinical trial in which advanced bladder cancer patients were given everolimus (Afinitor®), a targeted therapy already used in the treatment of kidney cancer, among other cancer types. The drug did not help the vast majority of patients enrolled in the trial. However, the doctors were encouraged by the outcome of one patient, whose condition radically improved.
The researchers sequenced the entire genome of the patient’s tumor and uncovered a previously unknown mutation in a gene called TSC1 that was making the tumor sensitive to the drug.
“This tells us that everolimus might be an option for an estimated 10 percent of bladder cancer patients whose tumors have TSC1 mutations, even though the drug is not effective in most patients with this disease,” says physician-scientist David B. Solit, of the Human Oncology and Pathogenesis Program. He led the investigation, which was published in Science in August.Back to top
Toward More-Advanced Cancer Pathology
To date, cancer genome sequencing has mainly been conducted as part of research studies, and only in rare cases to treat or diagnose patients. “But in the near future, genomics approaches will be used in the clinic routinely,” says pathologist Cyrus V. Hedvat, Acting Chief of Memorial Sloan Kettering’s Molecular Diagnostics Service. He notes that Memorial Sloan Kettering is on the front line of this development.
Currently, the service performs about 12,000 genetic tests on tumors or blood samples yearly, mainly to help physicians determine which type of treatment a patient is likely to benefit from. The tests are being done using a variety of technologies including one called Sequenom, but these may soon be replaced by newer diagnostic tools based on next-generation sequencing.
While Sequenom is used to efficiently look for the most common mutations that occur within eight different genes — but only within small regions of these genes, called mutational hotspots — the new technologies will make the molecular characterization of tumors far more comprehensive. Drs. Berger, Hedvat, and Ladanyi are developing clinical applications of MSK-IMPACT™ and similar approaches, which could make it possible to rapidly detect common or rare mutations in dozens to hundreds of cancer-associated genes at a time.
However, more work remains before genome sequencing diagnostics can be put into routine clinical practice. “We need to carefully optimize the technologies, which are brand-new and not flawless, and require powerful computer resources and bioinformatics personnel who can help process and analyze huge amounts of data,” Dr. Hedvat notes.
“What’s truly exciting is that, in addition to detecting the most-prevalent mutations in some of the most-common cancer types, we are increasingly able to identify rare mutations that might be clinically significant for small groups of patients,” he adds. “As more drugs are developed to target these rare gene changes, we will be able to offer individualized treatment to a growing number of people.”Back to top