Overactive Marker May Shorten Survival of Brain Tumor Patients
Gerald Hurowitz, M.D.·Published 11 April 2013·11 min read
Key points
Researchers may have discovered a more accurate way to predict how long patients with the deadliest form of brain cancer will live, according to an analysis by researchers from the University of Alabama at Birmingham (UAB) published today in the journal PLOS ONE.
And each of those can come in faster growing or more slowly growing forms.
Sometimes brain tumours are diagnosed at an advanced stage.
Most studies on CcO to date have focused on its role in a chain reaction in which the mitochondria, the powerhouses of human cells, produce energy.
Researchers may have discovered a more accurate way to predict how long patients with the deadliest form of brain cancer will live, according to an analysis by researchers from the University of Alabama at Birmingham (UAB) published today in the journal PLOS ONE. The authors say the finding could better inform physician recommendations on the most appropriate treatment strategy for patients with aggressive brain tumors.
The new analysis examined tumors from patients with glioblastoma multiforme (GBM), who survive 12-15 months on average with the current combination of surgery, radiation and the chemotherapy temozolomide. GBM’s deadliness is due not only to its staggering growth rate and location in the brain, but also to how quickly GBM cells become impervious to treatment.
While radiation and temozolomide usually kill most GBM cells, those that survive can quickly multiply to fill the void. Tough, treatment-resistant tumor cells soon comprise most of the recurring tumor, and 90 percent of recurring tumors show no response to temozolomide. At this point, patients have few options, most of which merely bring comfort before death.
Into this grim picture comes the current study result, which found that the 25 to 30 percent of GBM patients whose tumor cells have an overactive version of the enzyme cytochrome c oxidase (CcO) live less than half as long as patients with a less active version.
"Our study reports for the first time the role of cytochrome c oxidase as a prognostic marker in GBM patients' tumor tissues," said Corinne Griguer, Ph.D., associate professor in the Division of Neurosurgery within the UAB School of Medicine and study leader. "High CcO activity comes with a 25-fold increase in risk of death."
Presently, all patients with GBM tumors are lumped together in various prognostic models. The current study found, however, that patients with highly active CcO lived six months on average, whereas those whose tumors had lower CcO activity, closer to levels in normal tissues, lived 14 months.
The team investigated the relation between tumor CcO activity and survival times of 84 patients diagnosed with primary GBM and treated at UAB. They found that patient survival time tracked closely with CcO enzymatic activity, and without regard to subsequent therapies. Analysis of tumor tissue from a second group of European GBM patients yielded nearly identical results.
Types of brain tumours
There are many different types of brain tumours. And each of those can come in faster growing or more slowly growing forms. So there is no single situation we can describe here.
Some people have slowly growing brain tumours that cannot be cured. But with a very slow growing tumour, you may live for many years before the tumour causes any serious effects. Depending on your age when you are diagnosed, the tumour may eventually cause your death. Or you may live a full life and die from something else. It depends on the type of tumour, where it is in the brain and how well it responds to treatment.
Written and revised by
Gerald Hurowitz, M.D.
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Other people have fast growing tumours that may respond well to treatment, but then come back.
Treatments
Sometimes brain tumours are diagnosed at an advanced stage. The tumour may be too advanced to be cured with treatment. But treatment may shrink the tumour, and so slow down its progress.
In some situations, your specialist may think that a long course of radiotherapy or major surgery may not help you, or may even make matters worse. If this is the case, your specialist will talk this through with you. Depending on the type of brain tumour you have, if you are too ill to be up and about and looking after yourself when you are diagnosed, you are less likely to be helped by intensive radiotherapy. It may even increase your problems so that you can do less for yourself after the treatment than before.
Similarly, with surgery, you have to be fit enough to be able to make a good recovery from your operation. The more ill you are, the more likely you are to spend longer in hospital getting over your treatment. If your specialist suggests that intensive treatment may not help you, it is because your specialist wants to help you to make the most of the time you have. And they may be reluctant to give you treatment that overall may make matters worse for you and your family.
Of course you can still have other treatment to help to control your symptoms and keep you as well as possible for as long as possible. A shorter course of radiotherapy may slow down or even shrink your tumour, helping you to feel better for longer.
Why CcO?
Most studies on CcO to date have focused on its role in a chain reaction in which the mitochondria, the powerhouses of human cells, produce energy. CcO, with the help of oxygen, turns sugar from food into energy needed for survival in a series of chemical reactions that use a process called oxidative phosphorylation (OxPhos). Energy mechanisms become relevant because of how cancer cells use energy as they seek to survive and resist therapy.
Different types of brain tumour
There are many types of benign brain tumours and primary malignant brain tumours. Many are very rare. The following is a brief description of the most common types. Meningioma
Meningiomas are usually benign. They grow from cells in the meninges (the tissues that surround the brain). Medulloblastoma
These are high-grade malignant tumours that grow in the cerebellum. They are uncommon in adults, but are one of the two most common brain tumours in children. The other is astrocytoma in the cerebellum. Gliomas
These are malignant primary brain tumours that arise from glial cells. There are various types, depending on the cell of origin - for example:
Astrocytomas (originating from astrocyte cells.) There are various types of astrocytoma. They include: Low-grade astrocytomas. Anaplastic astrocytoma. This is a high-grade tumour. Glioblastoma multiforme. This is a high-grade tumour which tends to grow quite quickly. It is the most common type of primary malignant brain tumour in adults. Oligodendrogliomas (originating from oligodendrocytes). These can vary in their grade. Ependymoma (originating from ependymal cells). These are rare, but are usually low-grade.
Primitive neuroectodermal tumours (PNETs)
These are very similar to medulloblastomas and mainly occur in children. Pituitary tumours
There are various types of tumour which arise from the different cells in the pituitary gland. They tend to be benign. However, the cells of the tumour may produce large quantities of hormones which can cause various symptoms. As they grow, they may also cause pressure symptoms. The optic nerves (the nerves of sight) are near to the pituitary and so a growing pituitary gland tumour may press on an optic nerve and affect vision. Acoustic neuroma (schwannoma)
This is a benign tumour which arises from Schwann cells which cover the nerve that goes to the ear. Symptoms can include deafness on the affected side and vertigo. Other
There are various other rare types of benign and primary malignant brain tumours.
The current study is among the first to examine the role of CcO in mechanisms that determine how cancer cells use energy. The team found that cancer cells with higher CcO activity generate more energy and are better able to survive chemotherapy.
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In addition, CcO plays a second role in cancer cell survival through its interaction with a protein called cytochrome c. If cytochrome c is not kept busy in the mitochondria by constant interaction with active CcO, it is available for release into the cytoplasm where it can trigger the cell to self-destruct.
Normal human cells are pre-programmed to self-destruct to protect the body when they become infected or are severely damaged by diseases, including cancer. In terms of evolution, it makes sense that a self-destruct mechanism would be "wired" through the energy producing machinery that keeps cells alive, and that cancer cells must disconnect this wiring to survive.
When temozolomide interferes with cancer cells' ability to copy DNA, a vital step in cell growth, signals such as cytochrome c go out telling the cell to self-destruct. If highly active CcO is present, however, cytochrome c is less available for self-destruction signaling because it is already engaged in the mitochondria making energy for the threatened cancer cell, said Griguer.
Combine with current measures?
A marker in current clinical use to predict each patient's survival benefit from temozolomide is the activity of the enzyme O6-methylguanine-DNA methyltransferase (MGMT). When temozolomide damages a cancer cell, MGMT repairs the damage. If the gene for MGMT is shut down or silenced, however, by a process called methylation, the damage cannot be repaired and cancer cells die. MGMT methylation varies patient to patient.
Silenced MGMT should let chemotherapy-induced damage to cancer cells remain in place, but it does not perfectly predict outcomes, said Griguer. For instance, her new analysis found that in people with high CcO activity, there is no difference in the number of those with high or low MGMT methylation. The two markers did not agree, and further research is needed to understand why.
In people with low CcO activity, on the other hand, those with unmethylated MGMT lived for 6.7 months, while those with methylated MGMT lived 14 months. The two measures tended to agree in this group, and using them together may improve predictions.
Previous cancer cell studies in Griguer's lab had interfered with CcO activity by shutting off related genes or blocking its action with drugs. While they demonstrated in principle that CcO blockade counters chemoresistance, the drugs and methods used do not lend themselves to clinical use. Thus, an effort underway in her lab seeks to identify drug candidates for human testing.
Outcomes of all brain tumour treatment
With brain tumours, the likely outcome of treatment depends mainly on the following factors.
The type of tumour Grade of the tumour cells Position in the brain The size of the brain tumour Age at diagnosis for children and for some adult brain tumours How ill you are when you are diagnosed
Overall, for all types of malignant brain tumours in adults, more than a third of people diagnosed (36%) live for at least a year. About 15 out of every 100 people diagnosed (15%) live for more than 5 years after diagnosis. Just under 10 out of every 100 people diagnosed (10%) live for more than 10 years after diagnosis. Women seem to do slightly better than men but we don't know why this is.
The figures are better for younger people. For people under 40, around 1 in 2 of all those diagnosed (50%) live for more than 5 years after their diagnosis. For children the survival rates more than doubled between the 1960's and the early 2000s. Now, 65 out of every 100 children diagnosed with a brain tumour (65%) live for more than 5 years after diagnosis.
Different types of brain tumours respond differently to treatment. Some respond better to radiotherapy than others, for example. Grade is one of the most important factors for some types of tumours. But for others the appearance of the cells is much less likely to predict how the tumour will respond to treatment. Generally, fast growing tumours are much more likely to come back after treatment than slow growing tumours.
Some parts of the brain are more difficult to operate on than others. Because the brain controls all the functions of the body, it is not possible to remove large parts of it or very crucial parts of it without causing major problems. Unlike other types of cancer, it isn't always possible to remove the whole tumour, together with a safety margin of healthy tissue around it. This may affect the risk of the cancer coming back.
In some situations, surgery can be life threatening. If a brain tumour is growing in the nerves that control your sight (optic nerves) or in the brain stem, or is close to or surrounding major blood vessels, it may not be advisable to try to completely remove it - or even operate at all. In these situations, radiotherapy or chemotherapy may be better options for treatment. The outlook will then depend on how well the tumour responds to those treatments.
"Giving some GBM patients bad news about their prognoses without also giving them better treatment options doesn't seem right to me," said Griguer. "That's why our ultimate goal is to use the same mechanism that predicts shorter survival in some to design drugs that target cells not killed right away by chemotherapy."
About the research team
Along with Griguer, authors of the study within the UAB Division of Neurosurgery were G. Yancey Gillespie, Ph.D., Amber Gordon, Ph.D., James Markert, M.D., M.P.H., and Claudia Oliva, Ph.D. Important contributions were also made by Hassan Fathallah-Shaykh, M.D., Ph.D., within the UAB departments of Neurology and Mathematics and Alan Cantor, Ph.D., in the UAB Department of Medicine and Division of Preventive Medicine, as well as by Ivan Radovanovic, M.D., Ph.D, and Virginie Clement-Schatlo, Ph.D., from the University of Geneva in Switzerland.
The research was funded in part by grants from the National Institute of General Medical Sciences (NIGMS), the National Center for Advancing Translational Sciences (NCATS and the National Cancer Institute (NCI) [R21 CA 139290 (Griguer), R01 CA 160821 (Griguer) and P20 CA151129 (Gillespie, Markert)]. Further funding was provided by a grant from the Alabama Drug Discovery Alliance, which was supported in part by the UAB Comprehensive Cancer Center (P30 CA13148), the UAB Center for Clinical and Translational Science (UL1 RR025777) and Southern Research Institute.
The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health and the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government.
About UAB
Known for its innovative and interdisciplinary approach to education at both the graduate and undergraduate levels, the University of Alabama at Birmingham is the state of Alabama's largest employer and an internationally renowned research university and academic health center; its professional schools and specialty patient-care programs are consistently ranked among the nation's top 50.
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Source Newsroom: University of Alabama at Birmingham
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