The Cancer Genome Atlas (TCGA) — a collaborative effort funded by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) — has opened up the new field of “precision medicine” (AKA “genetically informed medicine” or “personalized medicine”) — phrases that describe how the availability of genetic information about a person’s disease can be used to diagnoses and treatment informed by and tailored to an individual’s specific genetic makeup and that particular disease variant.
A National Cancer Institute article entitled: “Cancer Genome Atlas, Impact of Cancer Genomics on Precision Medicine for the Treatment of Cancer” outlines how since cancer is a disease of the genome, as more is learned about cancer tumors, the more scientists are finding that each tumor has its own set of genetic changes. This greater understanding of genetic changes in are in cancer cells is facilitating development of more effective treatment strategies tailored specifically to the genetic profile of each individual patient’s cancer.
The article outlines how the relatively new field of cancer genomics research is focused on advancing personalized medicine through the DNA sequencing and analysis of patient tumors to find new genetic alterations associated with specific cancers, and that providing researchers with comprehensive catalogs of the key genomic changes that take place in various major types and subtypes of cancer will support advances in developing more effective ways to diagnose, treat and prevent the disease.
Examples cited of how genomic information has already helped shape development and utilization of some of the newest cancer treatments include the drug imatinib (Gleevec), which was designed to inhibit an altered enzyme produced by a fused version of two genes found in chronic myelogenous leukemia. Another instance is the breast cancer drug trastuzumab (Herceptin), which works only for women whose tumors have a particular genetic profile called HER-2 positive. Studies have also found that lung cancer patients whose tumors are positive for EGFR mutations respond to the drugs gefitinib (Iressa) and erlotinib (Tarceva) which target this mutation.
On the other hand, it’s been determined that colon cancer patients whose tumors have a mutation in a gene called KRAS derive little benefit from the drugs cetuximab (Erbitux) and panitumumab (Vectibix). The type of genomic information generated by TCGA and other cancer genomics projects will drive research to develop similar treatment strategies that will be most effective for a given set of genomic changes.
In June, investigators in The Cancer Genome Atlas (TCGA) Research Network reported discovery of a connection between how tumor cells use energy from metabolic processes and the aggressiveness of the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC), demonstrating that normal metabolism is altered in ccRCC tumor cells, and involves a shift from using one metabolic pathway to another. This change – termed a metabolic shift – correlates with tumor stage and severity in some cases.
The scientists also found mutations in a pathway that may cause increased aggressiveness in this cancer — their findings providing new insight into underlying disease mechanisms and potential treatments as well as better understanding of how some cancer cells can shift from using normal metabolic pathways to alternative pathways, thereby providing a growth advantage to tumor cells.
W. Marston Linehan, M.D., chief of the NCI Urologic Oncology Branch and one of the study’s leaders, quoted in a recent TCGA release, sees several implications from the results. “The finding of a metabolic shift in the aggressive tumors could provide the foundation for the development of a number of novel approaches to therapy for patients with advanced kidney cancer,” said Dr. Linehan. The results of this study were published online June 23, 2013, in Nature.
In a TCGA article “The New Backbone of Clinical Trial Design,”Dr. Douglas A. Levine, head of the Gynecology Research Laboratory at the Memorial Sloan-Kettering Cancer Center in New York observes that most scientists would now agree that The Cancer Genome Atlas (TCGA) is a transformative program in cancer biology, at least insofar as defining the genomic landscape for a variety of malignancies in a reliable and robust manner. Dr.Levine notes that research begets research, and TCGA is no exception, with even the most nascent scientists able to imagine countless additional outstanding analyses that can be performed with TCGA data.
“A major contribution that TCGA has made to date,” says Dr. Levine, “is in the design of molecularly targeted clinical trials. Prior to the widespread availability of reference genomic data, clinical trials of targeted therapeutics were based on a comprehensive review of the limited literature, generally indicating specific genomic events identified in a relatively small and sometimes non-uniform patient population. With TCGA’s data, now the starting point is often a survey of relevant events in the specified disease. As characterizations of more cancer types are completed, similarities and differences in event types for a given pathway or target can be highlighted across varied tumors types.”
“It’s likely that more than half of tumors have some alteration we can target with a drug,” says John V. Heymach, an Associate Professor and lung-cancer specialist at Houston’s MD Anderson Cancer Center, told the Wall Street Journal this week. “They may not all have the same success, but we know that in many cases, a targeted agent will work very well.”
The central focus at the Heymach laboratory is to conduct translational and basic research that advances the development of targeted therapeutic agents, particularly angiogenesis inhibitors, for non-small cell lung cancer (NSCLC) and other solid tumors, increase understanding of how oncogenic pathways can lead to metastatic spread and resistance to anticancer therapies, and to develop predictive markers for identifying which patients are likely to respond or develop resistance to targeted agents.
Dr. Heymach notes that they have taken a systems biology approach to develop proteomic, genomic, and gene expression profiles in NSCLC cell lines and tumors and have used this to identify key pathways or processes driving tumor progression and drug resistance. This includes extensive profiling of more than 100 cell lines and tumor specimens which the researchers can then correlate with clinical outcomes.
Cancer genome sequencing is allowing the NCI to focus on ushering in the era when tailored prevention and treatment strategies, based on the unique characteristics of each person and tumor, become standard practice in research-based clinics and community settings. Understanding of the unique characteristics of cancer cells and how they are different from normal cells can result in treatments targeted to specific types of cancer cells rather than at all of the cells within the body, which for example should diminish the sometimes devastating side effects of chemotherapy. The promise of genetically informed or precision medicine points to patients receiving treatments in their local communities that target the unique characteristics of their specific tumors, resulting in fewer side effects, and allowing patients to experience a higher quality of life during treatment.
Toward achieving this end, the NCI says it is spearheading an innovative platform of activities to enhance the full spectrum of cancer research and accelerate the translation of scientific discoveries in the laboratory into better treatments in the clinic.
This NCI graphic provides an overview with more information about these activities.
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In a PLOS Genetics Open Access research article entitled “High-Precision, Whole-Genome Sequencing of Laboratory Strains Facilitates Genetic Studies,” co-authors Anjana Srivatsan, Yi Han, Jianlan Peng, Ashley K. Tehranchi, Richard Gibbs, Jue D. Wang, and Rui Chen — all scientists at the Baylor College of Medicine Department of Molecular and Human Genetics in Houston — note that completion of the whole-genome sequencing of many organisms, ranging from bacteria to humans, has transformed the way in which biological research is conducted, observing that genome sequencing is mostly used as a resource to obtain the reference sequence information of laboratory species, and its full applications in genetic research remain unexplored, due to its time-consuming and expensive nature.
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