Getting down to basics

Researchers dig deep into the genome, not just to establish the causes of cancer, but also the best approaches to treatment

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Since the completion of the Human Genome Project in 2003, genomics has exploded as a research area for understanding human disease and driving therapeutic discovery and development efforts, and it has spawned a slew of 'omics children in the form of proteomics, metabolomics and more.

One area where this boon of genetic information has been most welcomed is an area of research already crowded with many players—but few real cures—ranging from the corporate to the public to the academic: oncology.

Oncology researchers looking for new and better ways to treat cancer recently got what may be some of their best early 'omics news since the Human Genome Project published initial results in 2000, with the announcement this summer that the largest study correlating genetics with cancer treatments released its first results.

The cross-Atlantic collaboration, dubbed the Genomics of Drug Sensitivity in Cancer project, is driven primarily by the U.S.-based Massachusetts General Hospital Cancer Center and the U.K-based Wellcome Trust Sanger Institute. In mid-July, the researchers described their initial data set regarding the responses of 350 cancer samples to 18 anticancer therapeutics, publishing the information for free on the Genomics of Drug Sensitivity in Cancer website in the hopes that it will aid oncology researchers worldwide in better understanding cancer genetics and improving treatment regimens.

Dr. Andy Futreal, co-leader of the Cancer Genome Project at the Wellcome Trust Sanger Institute, calls this initial output from the project "our first glimpse of this complex interface where genomes meet cancer medicine," but stresses that this really is only the beginning, as the project hasn't even yet met its halfway point—and there will be much more work done to further refine the overall genomics picture, add more data and produce a carefully curated set of data that will enable researchers both to develop better therapies for cancer and improve clinical decisions and patient response with existing ones.

"We need better information linking tumor genotypes to drug sensitivities across the broad spectrum of cancer heterogeneity, and then we need to be in position to apply that research foundation to improve patient care," says Dr. Daniel Haber, director of the Cancer Center at Massachusetts General Hospital and Harvard Medical School. "The effectiveness of novel targeted cancer agents could be substantially improved by directing treatment towards those patients that genetic study suggests are most likely to benefit, thus 'personalizing' cancer treatment."

The even bigger picture

The five-year Genomics of Drug Sensitivity in Cancer project got its start in late December 2008 with the goal of testing the sensitivity of 1,000 cancer cell samples to 400 known and novel molecular anticancer treatments, then correlating these responses to the genes known to be driving the cancers.

The results are intended to provide a catalog of the most promising treatments for each of the cancer types based on the specific genetic alterations in these cancers. The hope since the start of the project, Futreal notes, is that such knowledge will empower more informative clinical trials and aid the introduction of more targeted agents into the clinic.

The researchers note that it is well known that how a patient responds to anticancer treatment is determined in large part by the combination of mutations in her or his cancer cells. Thus, the better this relationship is understood, the better treatment can be targeted to the particular tumor.

The researchers are looking not only at responses to single drugs but also drug combinations, and they have not simply focused on commercial drugs but are also looking at some that are still in preclinical development.

Although the work is being split pretty equally between the two institutions, it is designed to harness the particular strength of each: previous experience in experimental exposure of cells to molecular treatments at Massachusetts General Hospital Cancer Center and skills in large-scale genomics, sequencing and informatics at the Sanger Institute.

To make the study as comprehensive as possible, the researchers have selected cell lines that include common cancers such as those of the breast, colorectal system and lung. Each cell line has been genetically fingerprinted, and the researchers will take promising leads from the cancer samples in the lab to be verified in clinical specimens, so that the findings can be used to design clinical studies in which treatment will be selected based on a patient's cancer mutation spectrum.

Among the findings in the first data release in July was confirmation of several genes that predict therapeutic response in different cancer types. These include sensitivity of melanoma, a deadly form of skin cancer, with activating mutations in the gene BRAF to molecular therapeutics targeting this protein, a therapeutic strategy that is currently being exploited in the clinical setting.

"It is very encouraging that we are able to clearly identify drug-gene interactions that are known to have clinical impact at an early stage in the study," says Dr. Ultan McDermott, faculty investigator at the Wellcome Trust Sanger Institute. "It suggests that we will discover many novel interactions even before we have the full complement of cancer cell lines and drugs screened."

McDermott is proud not just of the fact that the project is studying more gene mutation-drug interactions than any previous work but even more so that mechanisms are in place for ensuring rapid dissemination of the results to the global research community to enable more collaborative oncology research.

"Further results from this study should identify interactions between mutations and drug sensitivities most likely to translate into benefit for patients," McDermott notes. "At the moment we do not have sufficient understanding of the complexity of cancer drug response to optimize treatment based on a person's genome."

"This significant and strategic project is aimed squarely at providing the first step towards tailored cancer therapy," adds Dr. Ted Bianco, director of technology transfer at the Wellcome Trust. "The ultimate target is to give doctors the tools to identify the best therapy for each individual patient according to the genetic characteristics of their particular tumor, rather than basing these decisions solely on where the tumor has developed."

Root causes

But the Genomics of Drug Sensitivity in Cancer project isn't the only game in town, notes Dr. Mark Walport, director of the Wellcome Trust.

"The pace of research in human genetics is breathtaking," he notes, commenting that the Human Genome Project has enabled the identification of the mutations that cause certain cancers, but that's just a starting point. He notes that another effort that also got its start in 2008, just like Genomics of Drug Sensitivity in Cancer, will play a critical role in oncology research.

"Following the work of Professor Mike Stratton at the Sanger Institute and others, an international cancer genome project is underway that will identify the mutations that cause the 50 commonest types of cancer around the world," Walport says. "The challenge is to use new genetic knowledge about the causes of cancer to find new treatments and this project aims to do just that."

That project is the International Cancer Genome Consortium (ICGC), a voluntary scientific organization established to provide a forum for collaboration between the world's leading cancer and genomics researchers looking at tumors and tumor sub-types. It is considered to be one of the most ambitious research efforts in the biomedical research arena since the Human Genome Project. The 50 cancers being targeted are those considered to be the most important worldwide, affecting a diversity of organs including blood, brain, breast, colon, kidney, liver, lung, pancreas, stomach, oral cavity and ovary. To do this, the ICGC is carrying out systematic studies of more than 25,000 cancer genomes (500 cancer samples in each of the 50 tumor classes) at the genomic, epigenomic and transcriptomic levels.

Studies of breast, liver, and pancreatic cancer have already generated datasets that are now available on the ICGC website. The genomic analyses of the tumors were conducted by ICGC members in the United Kingdom (breast cancer), Japan (liver cancer) and Australia and Canada (pancreatic cancer).

The ICGC's work "will profoundly alter our understanding of the development of human cancer, across the spectrum of tumor types," predicts Paul Nurse, a cancer researcher and 2001 Nobel Laureate for Physiology or Medicine. "The worldwide, coordinated nature of the project and the plans for data release will facilitate efficient deployment of resources and ensure that all cancer researchers can use the information generated in a timely manner."

"The ability to identify the genetic changes in cancer is leading to new ways to devise
therapies directed at the underlying cellular mechanisms of cancer and to target the right
therapies to the right patients," says Dr. Eric S. Lander, president and director of the Broad Institute of Harvard and MIT and a member of ICGC. "We are moving into an era where the prescription for cancer treatment should be based on the genetics of each patient's tumor."

As Futreal and others notes, both the Genomics of Drug Sensitivity in Cancer project and the ICGC's work are benefiting greatly from the rapidly falling cost of genomic sequencing. The $1,000 genome may not be here yet, but the Genomics of Drug Sensitivity in Cancer was funded with only $13 million initially, something that would have been unthinkable when the multibillion-dollar Human Genome Project began.

Other efforts

While not all of them are as ambitious or far-reaching as the two efforts noted above, many other genomic-oriented efforts are also underway, all of them adding to the mountain of knowledge in the oncology arena.

In 2006, for example, the National Cancer Institute and the National Human Genome Research Institute selected researchers and laboratories that would participate in their Cancer Genome Atlas (TCGA), a project to catalog genetic mutations responsible for cancer to help improve the ability to diagnose, treat and prevent cancer through a better understanding of the molecular basis of the disease in its many forms. The initial goal of the project was to provide systematic, comprehensive genomic characterization and sequence analysis of three types of human cancers: glioblastoma multiforme, lung cancer and ovarian cancer.

The project is said to be distinct from many, not just in terms of the size of the patient cohort interrogated, but also the number of different techniques used to analyze the patient samples, including gene expression profiling, copy number variation profiling, SNP genotyping, genome wide methylation profiling, microRNA profiling and exon sequencing of at least 1,200 genes.

More recently, in June, Life Technologies Corp. announced at the Consumer Genetics Conference in Boston the creation of the Genomic Cancer Care Alliance, the founding partners of which also include Fox Chase Cancer Center, Scripps Genomic Medicine and the Translational Genomics Research Institute (TGen).

The alliance will launch a pilot study aimed at determining whether whole-genome sequencing can better guide treatment decisions across a number of difficult-to-treat cancers, building upon a research trial announced earlier this year by Life Technologies, TGen and contract research organization US Oncology to sequence the genomes of 14 patients diagnosed with triple-negative breast cancer whose tumors have progressed despite multiple other therapies. In contrast to the breast cancer trial, this larger study will reportedly be the first one to evaluate the use of whole-genome sequencing information in guiding treatment decisions across a wide range of cancer types. The alliance expects the study to begin enrolling patients late this year.

"This is a groundbreaking initiative for oncologists and their patients that should demonstrate how whole-genome sequencing with analytics and counseling can identify a treatment plan customized specifically for each seriously ill patient," says Dr. Paul Billings, the alliance's chief medical officer. "There is an urgent need to define and validate a complete medical workflow for genomic-based cancer care."

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