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Cancer Currents Blog: Colorectal Cancer Survival Linked to Primary Tumor Location - National Cancer Institute

Colorectal Cancer Survival Linked to Tumor Location - National Cancer Institute

National Cancer Institute

05/27/2016


In patients with metastatic colorectal cancer, the location in the colon where the tumor originated appears to strongly influence how long patients live, according to a new study.

The study—a retrospective analysis of data from a large NCI-funded phase III clinical trial—found that patients whose cancer originated in the left side of the colon (distal colon) lived more than a year longer after initial treatment than patients whose disease originated in the right side of the colon (proximal colon).


National Cancer Institute

Colorectal Cancer Survival Linked to Primary Tumor Location



May 27, 2016 by NCI Staff
Credit: National Cancer Institute / Terese Winslow
In patients with metastatic colorectal cancer, the location in the colon where the tumor originated appears to strongly influence how long patients live, according to a new study.
The study—a retrospective analysis of data from a large NCI-funded phase III clinical trial—found that patients whose cancer originated in the left side of the colon (distal colon) lived more than a year longer after initial treatment than patients whose disease originated in the right side of the colon (proximal colon).
The study also linked tumor location to the likelihood of benefit from specific targeted therapies used to treat patients with colorectal cancer. Patients with left-sided primary tumors are more likely to benefit from the targeted therapy cetuximab (Erbitux®), the study suggests, whereas patients whose tumors originated in the right colon may be better off receiving bevacizumab (Avastin®).
The findings support the idea that “colorectal cancers that originate on the right side should be treated differently than colon cancers originating on the left,” said the study’s lead investigator, Alan Venook, M.D., of the University of California, San Francisco.
Other investigators, however, caution that further confirmation is needed from prospective studies that provide more information about the underlying biology that may account for the observed survival differences.
Dr. Venook and his colleagues reported their study findings at a May 18 American Society for Clinical Oncology (ASCO) press briefing in advance of their presentation early next month at the ASCO annual meeting in Chicago.

Building on Earlier Evidence

In CALGB/SWOG 80405, the clinical trial on which this retrospective analysis was based, patients were randomly assigned to primary treatment with either cetuximab or bevacizumab in combination with one of two commonly used chemotherapy regimens (FOLFIRI or FOLFOX). Results from the trial, presented in 2014, showed no difference in overall or progression-free survival between the treatment groups.
Several previous studies had suggested, however, that tumor location in the colon may be an important clinical and biological consideration, Dr. Venook explained during the briefing. But uncertainty about its influence remained, he added, “because of the nature of the studies and [their] small numbers.”
The more than 44,000 biological samples collected in the CALGB/SWOG 80405 trial (from tumors and normal tissue), provided an ideal resource to further investigate differences between left- and right-sided colorectal cancers, Dr. Venook said.

Therapy Choice May Matter

The researchers focused their analysis on the 971 patients in the trial whose tumors had the wild-type, or normal, form of the KRAS gene. (Patients whose tumors have wild-typeKRAS are more likely to respond to cetuximab than patients whose tumors have mutations in KRAS, who don’t respond at all to the therapy.)
Although patients whose tumors originated in the left colon lived substantially longer after treatment than patients whose tumors originated in the right colon, the survival improvement for patients treated with cetuximab was more pronounced. And patients with right-sided tumors had better outcomes when treated with bevacizumab. (See the table below.)
Median Overall Survival by Tumor Location and Therapy
Left-Sided TumorsRight-Sided Tumors
All Patients33.3 months19.4 months
Patients Treated with Cetuximab36 months16.7 months
Patients Treated with Bevacizumab31.4 months24.2 months
The survival difference associated with the two drugs was a “dramatic finding,” Dr. Venook said. “I think that was really surprising to most … or all of [the study investigators], given our belief beforehand that [the treatment drug] was not likely to really make a big difference.”

A ‘Surrogate Marker’

Findings from another study to be presented at the ASCO meeting also found that patients with advanced forms of colorectal cancer (stages III and IV) that originated in the left colon survived longer than patients whose tumors originated on the right side.
Although findings from both studies support the idea that primary tumor location is important, Dr. Venook said that location may well be “a surrogate marker” for underlying biological differences between tumors.
Several other studies support the notion that colorectal cancer is “not just one uniform disease,” he continued. For example, based on analyses of genomic data from numerous studies, an international consortium of researchers recently identified four molecular subtypes of the disease, each with distinct molecular features. And results from another study to be presented at the ASCO annual meeting identified molecular characteristics that are seen more frequently in right-sided colorectal tumors.
Given the size of the large bowel, “it’s not surprising that molecular differences exist across it,” said Austin Duffy, M.D., of the Thoracic and Gastrointestinal Oncology Branch in NCI’s Center for Cancer Research.
Dr. Duffy commended the researchers “for highlighting a fairly basic factor [tumor location in the colon] that is usually ignored.” He argued, however, that more data on the molecular makeup of colorectal tumors, relative to their specific location, is needed before any firm conclusions on treatment choice can be reached.
The results and conclusions seen with cetuximab treatment “are largely driven by the differences in the KRAS wild-type population,” Dr. Duffy said. The analysis was confined to the more common KRAS mutations, he continued. Information on other mutations, including less common KRAS mutations associated with lack of response to cetuximab, as well as in the NRAS and BRAF genes, would help to “complete the picture, as these would have also influenced the results,” he said.
Dr. Venook’s research team is performing molecular analyses of patient tumor samples from the CALGB/SWOG 80405 trial and expects to complete their work in the coming months, he said.
Colorectal Cancer Survival Linked to Tumor Location - National Cancer Institute

Visualizing proteins involved in cancer cell metabolism - National Cancer Institute

Visualizing proteins involved in cancer cell metabolism - National Cancer Institute



National Cancer Institute

05/26/2016


Scientists using cryo-electron microscopy have broken through a technological barrier in visualizing proteins with an approach that may have an impact on drug discovery and development, capturing images of an enzyme found in cells at a resolution of 1.8 angstroms.

National Cancer Institute

NIH study visualizes proteins involved in cancer cell metabolism

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  • Posted: May 26, 2016
Contact: 
NCI Press Office
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Rapid advances in cryo-EM technology, from left to right, show improving resolutions in atomic detail of proteins and drug binding sites.
Credit: National Cancer Institute
Scientists using a technology called cryo-EM (cryo-electron microscopy) have broken through a technological barrier in visualizing proteins with an approach that may have an impact on drug discovery and development. They were able to capture images of glutamate dehydrogenase, an enzyme found in cells, at a resolution of 1.8 angstroms, a level of detail at which the structure of the central parts of the enzyme could be visualized in atomic detail. The scientists from the National Cancer Institute (NCI), part of the National Institutes of Health, and their colleagues also reported achieving another major milestone, by showing that the shapes of cancer target proteins too small to be considered within the reach of current cryo-EM capabilities can now be determined at high resolution.
The research team was led by NCI’s Sriram Subramaniam, Ph.D., with contributions from scientists at the National Center for Advancing Translational Sciences (NCATS), also part of NIH. The findings appeared online May 26, 2016, in Cell.
“These advances demonstrate a real-life scenario in which drug developers now could potentially use cryo-EM to tweak drugs by actually observing the effects of varying drug structure— much like an explorer mapping the shoreline to find the best place to dock a boat — and alter its activity for a therapeutic effect,” said Doug Lowy, M.D., acting director, NCI.
Both discoveries have the potential to have an impact on drug discovery and development. Cryo-EM imaging enables analysis of structures of target proteins bound to drug candidates without first needing a step to coax the proteins to form ordered arrays. These arrays were needed for the traditional method of structure determination using X-ray crystallography, a powerful technique that has served researchers well for more than a half century. However, not all proteins can be crystallized easily, and those that do crystallize may not display the same shape that is present in their natural environment, either since the protein shape can be modified by crystallization additives or by the contacts that form between neighboring proteins within the crystal lattice.
“It is exciting to be able to use cryo-EM to visualize structures of complexes of potential drug candidates at such a high level of detail,” said Subramaniam. “The fact that we can obtain structures of small cancer target proteins bound to drug candidates without needing to form 3D crystals could revolutionize and accelerate the drug discovery process.”
Two of the small proteins the researchers imaged in this new study, isocitrate dehydrogenase (IDH1) and lactate dehydrogenase (LDH), are active targets for cancer drug development. Mutations in the genes that code for these proteins are common in several types of cancer. Thus, imaging the surfaces of these proteins in detail can help scientists identify molecules that will bind to them and aid in turning the protein activity off.
In publications in the journal Science last year and this year, Subramaniam and his team reported resolutions of 2.2 angstroms and 2.3 angstroms in cryo-EM with larger proteins, including a complex of a cancer target protein with a small molecule inhibitor. Of note, the journal Nature Methods deemed cryo-EM as the "Method of the Year" in January 2016. “Our earlier work showed what was technically possible,” Subramaniam said. “This latest advance is a delivery of that promise for small cancer target proteins.” For more information on cryo-EM, go to electron.nci.nih.gov.
The National Cancer Institute leads the National Cancer Program and the NIH’s efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER.
The National Center for Advancing Translational Sciences (NCATS) is a distinctly different entity in the research ecosystem. Rather than targeting a particular disease or fundamental science, NCATS focuses on what is common across diseases and the translational process. The Center emphasizes innovation and deliverables, relying on the power of data and new technologies to develop, demonstrate and disseminate improvements in translational science that bring about tangible improvements in human health. For more information, visit www.ncats.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
Selected References
  1. Merk A, Bartesaghi A, Banerjee S, Falconieri V, Rao P, Davis M, Pragani R, Boxer M., Earl LA, Milne, JLS, Subramaniam, S. Breaking cryo-EM resolution barriers to facilitate drug discovery. Cell.  Online May 26, 2016.  In print June 16, 2016. DOI:10.1016/j.cell.2016.05.040

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