Glowing amino acid lights up growing brain cancer

Uptake of tagged glutamine allows scans to spot tumor changes during treatment Nathan Seppa 2:02pm, February 11, 2015 By injecting the amino acid glutamine that’s been tagged with a tracer compound into patients with brain cancer, scientists have devised a technique that might enable doctors to spot growth of such tumors with high accuracy. Glutamine and glucose provide nourishment for malignant cells in patients with glioma, a cancer of glial cells. These support cells for neurons become ravenous for both nutrients when cancerous, so spotting their high uptake with brain scans could provide a way to monitor the cancer. But glucose is also taken up widely by normal tissues in the brain. In contrast, glutamine is voraciously gobbled up by several cancers including glioma, researchers report in the Feb. 11 Science Translational Medicine. Venneti et al/Science Translational Medicine 2015 Tests in mice with glioma show that a glutamine analog toting a telltale radioactive tracer gets taken up readily by glioma cells but not by healthy cells. The tracer shows up in PET, or positron emission tomography, scans. This allows tumor delineation, scientists from Memorial Sloan Kettering Cancer Center in New York City and elsewhere report. In six glioma patients, brain scans revealed that while aggressive brain tumors took up the tagged glutamine readily, stable tumors did so only minimally, if at all. The imaging technique might enable doctors to more clearly track brain cancer growth, the authors say.

New target for personalized brain cancer treatment: PTPRZ-MET fusion protein

 

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Researchers at the University of California, San Diego School of Medicine have identified a new fusion protein found in approximately 15 percent of secondary glioblastomas or brain tumors. The finding offers new insights into the cause of this cancer and provides a therapeutic target for personalized oncologic care. The findings were published this month in the online edition of Genome Research.

Glioblastoma is the most common and deadliest form of brain cancer. The majority of these tumors – known as primary glioblastomas – occur in the elderly without evidence of a less malignant precursor. Secondary glioblastomas occur mostly in younger patients and progress from low-grade, less aggressive precursor tumors to glioblastoma, the most aggressive form of the disease.

“While genomic profiling is yielding improved understanding of primary glioblastoma, our understanding of secondary glioblastoma remains rudimentary,” said Clark Chen, MD, PhD, vice-chairman of Research and Academic Development, Division of Neurosurgery, UC San Diego School of Medicine and a principle investigator of the study. “In this study, we used a technology called RNA-Seq to study the RNA sequences derived from 272 clinical tumor specimens from patients afflicted with secondary glioblastoma or precursor forms of this tumor.”

The study revealed that the RNA sequences of brain cancers become progressively more abnormal as the tumor become more malignant. Specifically, the frequency of aberrant RNAs fusing gene sequences not normally found next to one another increased with tumor grade. Most of these fusion junctions occur in seemingly random locations. However, transcripts involving fusions of the PTPRZ and MET gene were found repeatedly in clinical specimens derived from different patients. The study estimates that 15 percent of the secondary glioblastoma harbor this fusion.

“The recurrent nature of this fusion transcript suggests that the fusion did not arise by chance. Instead, it’s likely that the fusion actively contributes to the biologic behavior of the tumor,” said Chen, who collaborates with a multidisciplinary team at UC San Diego Moores Cancer Center. “Supporting this hypothesis, we demonstrated that glioblastoma cells expressing the PTPRZ-MET fusion are more invasive and patients afflicted with these tumors showed particularly poor survival relative to other secondary glioblastoma patients.”

“One of the most important implications of the work is that inhibitors against the MET oncoprotein are available for clinical use,” said Bob S. Carter, MD, PhD, study co-author and professor of surgery and chief of Neurosurgery, UC San Diego School of Medicine. “Secondary glioblastomas harboring the PTPRZ-MET fusion may be exquisitely sensitive to these inhibitors. Matching MET inhibitors to genotype of the glioblastoma affords us a unique opportunity to personalize oncologic care.”

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Story Source:

The above story is based on materials provided by University of California, San Diego Health Sciences. Note: Materials may be edited for content and length.

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Journal Reference:

1. Z.-S. Bao, H.-M. Chen, M.-Y. Yang, C.-B. Zhang, K. Yu, W.-L. Ye, B.-Q. Hu, W. Yan, W. Zhang, J. Akers, V. Ramakrishnan, J. Li, B. Carter, Y.-W. Liu, H.-M. Hu, Z. Wang, M.-Y. Li, K. Yao, X.-G. Qiu, C.-S. Kang, Y.-P. You, X.-L. Fan, W. S. Song, R.-Q. Li, X.-D. Su, C. C. Chen, T. Jiang. RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas. Genome Research, 2014; DOI: 10.1101/gr.165126.113

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University of California, San Diego Health Sciences. "New target for personalized brain cancer treatment: PTPRZ-MET fusion protein." ScienceDaily. ScienceDaily, 13 October 2014. <www.sciencedaily.com/releases/2014/10/141013152652.htm>.

Longer telomeres linked to risk of brain cancer: Double-edged sword, gene variants may promote overall health while increasing risk of gliomas

 

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New genomic research led by UC San Francisco (UCSF) scientists reveals that two common gene variants that lead to longer telomeres, the caps on chromosome ends thought by many scientists to confer health by protecting cells from aging, also significantly increase the risk of developing the deadly brain cancers known as gliomas.

The genetic variants, in two telomere-related genes known as TERT and TERC, are respectively carried by 51 percent and 72 percent of the general population. Because it is somewhat unusual for such risk-conferring variants to be carried by a majority of people, the researchers propose that in these carriers the overall cellular robustness afforded by longer telomeres trumps the increased risk of high-grade gliomas, which are invariably fatal but relatively rare cancers.

The research was published online in Nature Genetics on June 8, 2014.

"There are clearly high barriers to developing gliomas, perhaps because the brain has special protection," said Margaret Wrensch, MPH, PhD, the Stanley D. Lewis and Virginia S. Lewis Endowed Chair in Brain Tumor Research at UCSF and senior author of the new study. "It's not uncommon for people diagnosed with glioma to comment, 'I've never been sick in my life.'"

In a possible example of this genetic balancing act between risks and benefits of telomere length, in one dataset employed in the current study -- a massive genomic analysis of telomere length in nearly 40,000 individuals conducted at the University of Leicester in the United Kingdom -- shorter telomeres were associated with a significantly increased risk of cardiovascular disease.

"Though longer telomeres might be good for you as a whole person, reducing many health risks and slowing aging, they might also cause some cells to live longer than they're supposed to, which is one of the hallmarks of cancer," said lead author Kyle M. Walsh, PhD, assistant professor of neurological surgery and a member of the Program in Cancer Genetics at UCSF's Helen Diller Family Comprehensive Cancer Center.

In the first phase of the new study, researchers at UCSF and The Mayo Clinic College of Medicine analyzed genome-wide data from 1,644 glioma patients and 7,736 healthy control individuals, including some who took part in The Cancer Genome Atlas project sponsored by the National Cancer Institute and National Human Genome Research Institute. This work confirmed a link between TERT and gliomas that had been made in previous UCSF research, and also identified TERC as a glioma risk factor for the first time.

Since both genes have known roles in regulating the action of telomerase, the enzyme that maintains telomere length, the research team combed the University of Leicester data, and they found that the same TERT and TERC variants associated with glioma risk were also associated with greater telomere length.

UCSF's Elizabeth Blackburn, PhD, shared the 2009 Nobel Prize in Physiology or Medicine for her pioneering work on telomeres and telomerase, an area of research she began in the mid-1970s. In the ensuing decades, untangling the relationships between telomere length and disease has proved to be complex.

In much research, longer telomeres have been considered a sign of health -- for example, Blackburn and others have shown that individuals exposed to chronic stressful experiences have shortened telomeres. But because cancer cells promote their own longevity by maintaining telomere length, drug companies have searched for drugs to specifically target and block telomerase in tumors in the hopes that cancer cells will accumulate genetic damage and die.

Walsh said the relevance of the new research should extend beyond gliomas, since TERT variants have also been implicated in lung, prostate, testicular and breast cancers, and TERC variants in leukemia, colon cancer and multiple myeloma. Variants in both TERT and TERC have been found to increase risk of idiopathic pulmonary fibrosis, a progressive disease of the lungs.

In some of these cases, the disease-associated variants promote longer telomeres, and in others shorter telomeres, suggesting that "both longer and shorter telomere length may be pathogenic, depending on the disease under consideration," the authors write.

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Story Source:

The above story is based on materials provided by University of California, San Francisco (UCSF). The original article was written by Pete Farley. Note: Materials may be edited for content and length.

Newly identified brain cancer mutation will aid drug development

 

June 1, 2014

Duke Medicine

New genetic insights into a rare and deadly form of childhood and young adult brain cancer called brainstem glioma has been identified by an international team of researchers. The researchers identified a genetic mutation in the tumor cells that plays a role in both the growth and the death of a cell. Additionally, the mutation to the newly identified gene may also contribute to the tumor’s resistance to radiation.

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A collaborative effort between Duke Medicine researchers and neurosurgeons and scientists in China has produced new genetic insights into a rare and deadly form of childhood and young adult brain cancer called brainstem glioma.

The researchers identified a genetic mutation in the tumor cells that plays a role in both the growth and the death of a cell. Additionally, the mutation to the newly identified gene may also contribute to the tumor’s resistance to radiation.

The findings, published online in the journal Nature Genetics on June 1, 2014, provide both immediate and long-term benefits. Knowing that this mutation may render radiation ineffective, patients could be spared that therapy. The mutation would also serve as a strong candidate for drug development.

The researchers conducted genetic tests and found that many of the tumor cells had a mutation in a gene called PPM1D, which causes cells to proliferate and avoid natural death. It is the first time this mutation has been found to be a major driving force in the development of brainstem gliomas; it is not evident in other brain tumors.

If tumors have this PPM1D mutation, they do not have another more common genetic mutation to the TP53 gene, a tumor suppressor that, when defective, is linked to half of all cancers.

“This finding has immediate clinical applications, because either mutation - PPM1D or TP53 – cause the tumor cells to be resistant to radiation,” said senior author Hai Yan, M.D., Ph.D., a professor of pathology at Duke University School of Medicine. “Knowing that could spare patients from an ineffective treatment approach.”

Additionally, the PPM1D genetic mutation is a strong candidate for new drug development.

“This finding gives us a clue as to why these particular tumors are growing inappropriately,” said co-author Zachary Reitman, M.D., Ph.D., a research associate at Duke. “These clues may help us to design better treatments for this type of cancer.”

Yan said his lab is working to identify new treatments that could target the PPM1D genetic mutation and shut down its cancer-growing capabilities.

“PPM1D is itself a target for drug development, because the gene mutation causes cells to avoid death and proliferate,” Yan said. “In drug development, it’s easier to turn that growth function off than it is to switch on the cell’s defective tumor suppression mechanism.”

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Story Source:

The above story is based on materials provided by Duke Medicine. Note: Materials may be edited for content and length.

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Journal Reference:

1. Liwei Zhang, Lee H Chen, Hong Wan, Rui Yang, Zhaohui Wang, Jie Feng, Shaohua Yang, Siân Jones, Sizhen Wang, Weixin Zhou, Huishan Zhu, Patrick J Killela, Junting Zhang, Zhen Wu, Guilin Li, Shuyu Hao, Yu Wang, Joseph B Webb, Henry S Friedman, Allan H Friedman, Roger E McLendon, Yiping He, Zachary J Reitman, Darell D Bigner, Hai Yan. Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas. Nature Genetics, 2014; DOI: 10.1038/ng.2995