Sequencing Projects Offer Renewed Hope for Cancer Researchers

Sequencing Projects Offer Renewed Hope for Cancer Researchers

 

Cancer is a formidable illness. The World Health Organization predicts that it may overtake heart disease as the number one killer of humans by 2010. Despite this grim forecast, there is renewed hope in the cancer research community from early results of cancer genome sequencing projects targeting brain, lung and leukemia that have provided the most comprehensive look yet of the genetic glitches responsible for these deadly diseases.

Cancer is a genetic disease; it is caused by mistakes accumulated in genes over a person's lifetime. These mistakes, or mutations, disrupt healthy cells turning them into tumor cells that can quickly grow out of control. Researchers, equipped with sequencing technologies and new analytic tools only recently up to the task, are now able to sequence a long list of suspected genes and even entire genomes of cancerous tissue and compare it to healthy tissue to reveal mistakes in the DNA. Researchers believe this information can be exploited to design new and improved diagnostics and treatments for many cancers.

In the last six months, projects supported in part by the National Human Genome Research Institute (NHGRI) have published landmark papers detailing the genetic landscapes of the most common forms of brain cancer (glioblastoma) from The Cancer Genome Atlas (TCGA), in partnership with the National Cancer Institute, and lung cancer (lung adenocarcinoma) from the Tumor Sequencing Project. Furthermore, a research team led by the Genome Sequencing Center at Washington University in St. Louis, one of NHGRI's major sequencing centers, made a major breakthrough by using next-generation sequencing technologies to sequence the entire genome of a cancer patient. The patient had died of acute myeloid leukemia (AML).

These studies confirmed many genetic mutations already known to play a role in cancer. More importantly, they also identified a number of human genes that no one previously suspected would be involved in each of the deadly cancers.

One particularly exciting finding with the potential for rapid clinical impact centers on glioblastoma (GBM) and the MGMT gene. Physicians already know that GBM patients whose tumors have an inactivated, or methylated, MGMT gene respond better to temozolomide, an alkylating chemotherapy drug. By integrating methylation and sequencing data with clinical information about sample donors, the TCGA multi-dimensional analysis found that in patients with MGMT methylation, alkylating therapy may lead to mutations in genes that are essential for DNA repair, commonly known as mismatch repair genes. Such mutations then lead to the subsequent emergence of recurrent tumors that contain an unusually high number of DNA mutations, and that may be resistant to chemotherapy treatment.

If follow-up studies confirm such a mechanism, researchers say first- or second-line treatments for such GBM patients may involve therapies designed to target the results of combined loss of MGMT and mismatch-repair deficiency. The new findings also may help clinical researchers figure out the best ways to combine alkylating chemotherapy drugs with the next generation of targeted therapeutics. After identifying the many complex genetic mutations, each of the project teams proceeded to examine their impact on biological pathways to determine those most crucial in each cancer. A biological pathway is usually defined as a series of chemical actions within a cell that are mediated by enzymes in some sequence of chemical reactions that convert one biological molecule into another. Enzyme production and function are controlled by genes, whether the enzyme is made from protein or RNA, the chemical cousin of DNA.

Biological pathways also can be viewed more broadly as any network of interconnected chemical reactions carried out by any number of biological components in the human body, including individual genes, molecules, cells and entire organs. When something goes wrong in a biological pathway, it can lead to a disease.

While there are many genetic mutations involved in cancer, possibly thousands of mutations in hundreds of genes, researchers have found that cancer's genetic complexity can be reduced by looking at the affected biological pathways. For drug developers, this could be good news. Rather than targeting dozens of genes, cancer treatments could instead focus on fewer biological pathways. Imagine a hockey goalie attempting to block multiple shots going into the net. If the goalie skates out to block each individual shot, chances are the other shots will go in. Instead, the goalie could feasibly block more shots by standing at the critical spot in front of the net where all the shots were bound to intersect. While no cancer drugs have been developed to date that focus exclusively on pathways, this promising strategy is now being pursued by researchers.

Knowing which pathways are disrupted in each tumor subtype will result in customized treatments in the future for cancer patients, says Brad Ozenberger, Ph.D., a member of the TCGA project team. For instance, three interconnected pathways were found to be disrupted in the brain tumors, suggesting a combination of drugs targeting all three pathways may present a successful treatment strategy for some patients.

The pathway research also revealed some commonality among different cancers that could open the door to treatments already being used for other cancers. For example, chemotherapy drugs known to inhibit the kinase insert domain receptor (KDR), such as sorafenib and sunitinib which are used to treat kidney cancers, might be tested in the relatively small percentage of lung adenocarcinoma patients whose tumors have mutations that activate the KDR gene.

It will now fall to laboratory scientists to turn this important information into new life-saving therapies and diagnostics for cancer. For example, researchers in NHGRI's Division of Intramural Research (DIR) have already started actively looking at biological pathways involved in many cancers to uncover clues that might contribute to the development of new diagnostics and therapies for improving patient survival.

For example, Yardena Samuels, Ph.D., an investigator in DIR's Cancer Genetics Branch, is using DNA sequencing technologies and whole-genome genotyping to identify novel mutations in gene families that regulate signal transduction (a type of biological pathway) in a deadly type of skin cancer, late-stage cutaneous melanoma. Once novel mutations are identified, the Samuels' lab evaluates the functional, biochemical and clinical aspects of the most highly mutated gene members. The ultimate goal is to provide doctors at the NIH Clinical Center with information they can use to tailor therapy to an individual cancer patient's genetic profile.

Dr. Samuels's work examines cancer on a smaller scale than TCGA, but has uncovered important and complementary clues. She also believes that her research would benefit from a cancer sequencing project targeting a large number of melanoma tumors, potentially uncovering even more information that could be turned into the next breakthrough treatment.

As genome sequencing and other technology costs decline and analytical tools improve, more and more cancer genomes will be studied to provide valuable data to scientists like Dr. Samuels. In fact, Dr. Ozenberger predicts that cancer genome projects will soon shift to sequencing whole genomes similar to the AML cancer patient's genome, rather than being limited to just targeting individual genes. Researchers believe as they sequence additional cancer genomes they'll find that various cancers share common genetic characteristics - knowledge that will improve the ability of researchers and doctors to more efficiently diagnose and treat cancer in the future.

In addition to brain cancer, the TCGA is also studying ovarian and squamous cell lung cancer. TCGA plans to expand the pilot project to provide genomes of more than 20 different cancers beginning in 2009.

In addition, the International Cancer Genome Consortium recently announced at least eight cancer genome projects being undertaken by its members including pancreatic, stomach, liver and breast cancers.

More information is available about TCGA at The Cancer Genome Atlas.