Overactive Marker May Shorten Survival of Brain Tumor Patients
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.
###
Source Newsroom: University of Alabama at Birmingham