Researchers have found that a common form of kidney cancer known as clear cell renal cell carcinoma (ccRCC) expresses a metabolic shift going from normal metabolism to making use of a metabolic pathway that promotes tumor cell growth. This metabolic shift can be correlated with cancer cell stage and in some cases severity of the cancer. This was discovered by a group of investigators at The Cancer Genome Atlas (TCGA) Research Network.
The research was funded by National Institutes of Health-led institutes that include the National Human Genome Research Institute (NHGRI) and the National Cancer Institute (NCI). This study was published in Nature (June 23, 2013).
The director of NIH, Francis S. Collins commented:
“Because of TCGA’s comprehensive characterization of kidney tumors and correlating that with patient survival data, researchers now can begin applying this knowledge to validating prognostic biomarkers and identifying new therapeutic strategies for this disease.”
According to Richard A. Gibbs, Ph.D., a lead researcher in the project and director of the Human Genome Sequencing Center at Baylor College of Medicine, Houston, “The molecular analysis of this disease impacts understanding of all cancers through furthering insights into the role of metabolic perturbation in malignancy.”
These researchers also found mutations in a particular pathway that may be involved with augmenting aggressiveness in ccRCC. Considering mutations and making use of an alternate metabolic pathway has brought about new insights to the disease mechanism and possible therapies. It is known that changes in metabolic enzymes promote tumor growth and generate poor patient outcomes in ccRCC.
Researchers were able to study close to 450 ccRCC tumors. They matched each tumor with a normal sample from the same patient and looked at the levels of specific proteins expressed in tumor cells. They observed low levels of AMPK and elevated levels of acetyl-CoA carboxylase, which is linked to poor patient outcomes. AMPK stands for AMP activated protein kinase and it is a master metabolic regulator in cellular energy. Acetyl CoA carboxylase is an enzyme that is important for synthesis of fatty acids.
NCI Director Harold Varmus suggested:
“Earlier findings from the characterization of other types of cancers have given us important clues as to how to design better therapies for these cancers. The new results from the TCGA analysis of clear cell renal cell carcinomas provide an explanation for how mutations in certain genes can alter chromosome chemistry to produce changes in enzyme levels that affect cell metabolism in ways correlated with clinical outcomes. These findings will stimulate some novel ideas about therapies for other lethal cancers.”
The following video provides an overview of adverse outcomes in clear cell renal cell carcinoma:
Researchers found that there was a decrease in factors that are involved in activating tumor suppressor genes. They also found that factors that turn on genes that inhibit P13K pathway were actually blocked. These findings suggest that the P13K/AKT/mTOR pathway has potential as a therapeutic target where inhibitory drugs can be used.
According to Eric Green, M.D., Ph.D. (Director NHGRI), having availability of large datasets coming from anaylses of hundreds of tumors enables researchers to gain new insights into cancer biology. These datasets have advanced our understanding of ccRCC greatly.
Clearly, the TCGA data has provided information into the abnormal processes in the development of kidney cancer and the complexity of metabolic shifts and where these pathways cross. In general, advanced kidney tumors tend to be chemotherapy resistant. These new insights will be helpful in developing new therapies that will work.
Potential outcome and future benefits from the findings:
The researchers suggest that knowing the actual site and mechanism of alterations in the PI3K pathways may help in formulating and designed inhibitor drugs.
The Chief of the NCI Urologic Oncology Branch and one of the study’s leaders, W. Marston Linehan, discussed his expectations from the study in these words:
“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.”
The research team suggested that new treatment modalities are essential, since old therapies are insufficient at producing quality results in advanced cancer stages. Investigators also studied various processes and compiled data involving kidney cancers and other tumor pathways.
About Clear Cell Renal Carcinoma:
According to the latest statistics of NCI, it has been estimated that by the end of 2013, 65,000 people in United States will be diagnosed with clear cell renal carcinoma. In addition, over 13,000 people will die from the advanced disease. Although current therapies are successful at treating over 50% of the early stage renal cancer, most of the patients with advanced disease have the worst outcome.