Frontiers

Breakthrough–The Frontiers of Cancer Research 

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‘GROW OR GO’ SWITCH

Researchers discover brain tumor mechanism

Researchers at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC-James) have discovered a mechanism that regulates the behavior of glioblastoma multiforme cells.

Cancer cells in rapidly growing brain tumors must adapt to periods of energy fluctuation. When glucose levels are high, tumor cells grow and proliferate; when levels are low, the cells grow less and migrate more.

Researchers discovered that the microRNA miR-451 coordinates this “grow-or-go” behavior.

“We found that glioblastoma cells use miR451 to sense glucose availability,” says co-author E. Antonio Chiocca, MD, PhD, professor and chair of Neurological Surgery, and co-leader of the OSUCCC-James Viral Oncology Program. “Levels of miR451 directly shut down the engine of the tumor cell if there is no glucose, or rev it up if glucose is plentiful. This suggests that this molecule might be a useful biomarker to predict a glioblastoma patient’s prognosis. It also might be used as a target to develop drugs to fight these tumors.”

“The change in miR-451 expression enabled the cells to survive periods of stress caused by low glucose, and it caused them to move, perhaps enabling them to find a better glucose supply,” says principal investigator Sean Lawler, PhD, assistant professor of Neurological Surgery. “The migration of cancer cells from the primary tumor, either as single cells or chains of cells, into the surrounding brain is a problem with these tumors. By targeting miR-451, we might limit the tumor’s spread and extend a patient’s life.”

Published in the jounal Molecular Cell.


VICIOUS CIRCLE

Molecular network may be therapeutic target for AML

Researchers at the OSUCCC-James have identified a self-feeding “vicious circle” of molecules that keeps acute leukemia cells alive and growing. Their findings suggest a new strategy for treating acute myeloid leukemia (AML) by tar-geting this molecular network and lowering the amount of a protein called KIT.

The study describes a network of protein and microRNA molecules that, when imbalanced, contributes to increased KIT expression and favors leukemia development. The researchers also were able to target this network with therapeutic drugs.

“We now understand the mechanism responsible for high KIT expression in AML cells, and we believe that targeting that mechanism and reducing KIT levels will prove a more effective therapy than the current standard of care,” says study leader Guido Marcucci, MD.

More than 80 percent of AML cases show elevated KIT expression. Doctors treat AML with standard chemotherapy, but drugs that target and block KIT activity are being tested in clinical trials. These agents, tyrosine kinase inhibitors, bind to the protein and stop disease progression, but they can lose their effectiveness when new mutations that arise from the disease alter the protein.

“Our study suggests that the amount of KIT protein in cancer cells is as important as its activity, and we discovered that the amount of the protein is controlled by a circular network of molecules that has many points of entry,” says senior co-leader Ramiro Garzon, MD. “These findings provide a strong rationale for developing drugs that target the components of this network rather than focusing on the activity of KIT alone.”

Published in the journal Cancer Cell.



MAURA GILLISON, MD, PhD, professor of Internal Medicine, Jeg Coughlin Chair in Cancer Research, and her research team

PAPILLOMA PREDICTOR
HPV in oropharyngeal tumors signifies increased survival

The presence of human papilloma virus (HPV) in oropharyngeal tumors is the most important predictor of patient survival, according to a study at the OSUCCC-James.

This is the first study large enough to show that HPV in tumors accounts for better response to therapy, rather than other favorable factors that may be present, such as young age and small tumors. The second-leading predictor of survival is lifetime smoking history, followed by cancer stage.

The findings suggest that the HPV status and patients’ smoking history may be used, in addition to cancer stage, to determine the aggressiveness of therapy.

“Previous studies indicated a relationship existed between the presence or absence of HPV in oropharyngeal tumors and patient survival, but they couldn’t determine if other favorable factors present in these patients were responsible for their better outcome,” says study leader Maura Gillison, MD, PhD, medical oncologist and head and neck cancer specialist. “These findings close the door on these questions and will allow the field to move forward with clinical trials to determine how we should use molecular and behavioral factors to personalize therapy.”

Gillison says there is insufficient data at this time to indicate how a patient’s therapy should be tailored based on these factors.

The research analyzed the tumors and outcomes of 323 patients with stage III or IV oropharyngeal cancer who were part of a Radiation Therapy Oncology Group clinical trial. Of these, 206 had HPV+ tumors and 117 had HPV- tumors. Three years after treatment, 82 percent of those with HPV+ tumors were alive, compared with 57 percent of those with HPV- tumors.

Published in the New England Journal of Medicine.


An enriched environment inhibits cancer growth in mice. Enrichment stimulates the hypothalamus to produce brain-derived neurotrophic factor (BDNF), which activates the HSA axis. This sympathetic nervous system pathway shuts down leptin production in white adipose tissue (WAT), suppressing cancer growth. Reprinted from Cell, 142:62. Cao L., Liu X., Lin E.-J. D., et al. Environmental and Genetic Activation of a Brain-Adipocyte BDNF/Leptin Axis Causes Cancer Remission and Inhibition. Copyright 2010, with permission from Elsevier.

UP FOR THE CHALLENGE
Stimuli of enriched environment may curb cancer

An animal study led by researchers at the OSUCCC-James shows that living in an environment rich with physical, mental and social stimulation – a setting that causes mild stress – may curb cancer growth.

The researchers discovered that an enriched environment activates the hypothalamic-sympathoneural-adipocyte (HSA) axis, a nervous-system pathway that instructs fat cells to stop releasing leptin into the bloodstream. Overall, the study suggests that environmental or genetic activation of the HSA pathway leads to a marked drop in serum leptin levels, and that this inhibits tumor growth.

“People think cancer survivors should avoid stress, but our data suggest this is not completely true,” says study leader Matthew During, MD, PhD, professor of Neuroscience, of Neurological Surgery and of Molecular Virology, Immunology and Medical Genetics. “The anticancer effect we observed was not due simply to increased activity, but to social and physical challenges that cause mild stress.”

The most dramatic hormonal change observed was the drop in leptin from fat after enhanced housing conditions activated the HSA pathway. The HSA pathway is also present in humans and is likely to be activated by a complex and challenging lifestyle, During notes.

The enriched environment created for this study housed 20 mice in large containers equipped with toys, hiding places and run-ning wheels, along with unlimited food and water. Control mice were housed in groups of five in smaller laboratory containers with unlimited food and water.

The researchers injected human melanoma cells under the skin in both sets of animals. After three weeks, mice in enriched housing had tumors about half the size of those in control mice. After six weeks of enrichment, those tumors had dropped to one fifth the size of those in control animals, and almost 20 percent of enriched-group mice had no visible tumors. All control animals had visible tumors.

Published as the lead cover story in the journal Cell.


INVALUABLE INTERVENTION
Program helps breast cancer patients long after recurrence.

A psychological intervention program for breast cancer patients can reduce the risk of dying if the cancer recurs, new research shows.

The study is the latest in a series at the OSUCCC-James showing that an intervention that teaches patients how to cope with the disease can boost their health, well-being and chances of survival.

In an earlier study, the researchers found that the intervention reduced the risk of dying of breast cancer by 56 percent after a mean of 11 years, and it reduces the risk of recurrence by 45 percent compared with women not receiving the intervention.

The new study shows that women who had a recurrence also benefited from the program. Women with recurrent cancer who received the intervention had a 59-percent reduction in the risk of dying from breast cancer compared with the women who didn’t participate.

“Women who took part in the intervention program do better across the board than others, even if they have a recurrence,” says lead author Barbara Andersen, PhD, professor of Obstetrics and Gynecology, of Psychology and of Public Health. “They learned how to cope with a cancer diagnosis when they were first diagnosed, and those lessons likely helped them deal with recurrence.”

The study is part of the Stress and Immunity Breast Cancer Project at Ohio State, which since 1995 has followed 227 patients treated for stage II or III breast cancer.

Published in the journal Clinical Cancer Research.


REWIRE ACT
Cancer cells show rewired, fragmented microRNA networks

A multicenter study led by scientists at the OSUCCC-James shows that microRNA (miRNA) molecules work together in single, well-connected
networks to control functions in healthy cells, but in cancer cells the networks are rewired and fragmented.

The research introduces a way of discovering cancer genes, identifies new miRNAs that can be used as targets for drug development, and pinpoints possible cancer-related proteins, says study lead Carlo Croce, MD, professor of Molecular Virology, Immunology and Medical Genetics, and John W. Wolfe Chair in Human Cancer Genetics.

MiRNAs are noncoding RNAs that control cell functions such as growth, proliferation and differentiation. Abnormal miRNA expression plays an important role in cancer development. This study found that miRNAs in healthy cells interact in a network that, when mapped, resembles a family tree with dozens to hundreds of members. Each cell type has its own network, with particular miRNAs serving as central hubs within the network.

In cancer cells, the single network is replaced by subnetworks that usually include small detached clusters of two to six miRNAs. “These small groups that exist outside the main network were unexpected,” Croce says. “Some of these miRNA outliers are well-known cancer genes, but the involvement of others in cancer was unknown.”

The study suggests that key cancer genes can be identified on the basis of their relationship to other genes, as well as on their overexpression or loss.

Published in the journal Genome Research.


eeting of the American Society of Hematology, December 2009.

 
11-Oct-10
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