21st Century Science Initiative Grant: Researching Brain Cancer
Houston, TX, USA
Researcher: Mostafa W. Gaber, Ph.D.
Grant Title: Identifying preclinical imaging markers of radiation side effects: An animal brain tumor model to correlate radiation-induced imaging changes, neurogenesis and cognitive impairment
Grant Type: Research Award
Program Area: Researching Brain Cancer
Duration: 3 years
Cancer in children is much less common than it is in adults1. Yet when we consider the consequences in terms of net years of disability and years of life lost, pediatric cancer's impact on public health is disproportionate to its incidence. Brain tumors are the most common solid tumors in childhood and radiotherapy (RT) is the mainstay for the treatment of many brain tumors in children. While achieving increased rates of long-term survival, this has come at some risk to the development of these children. It has been estimated that children treated with radiation for medulloblastoma, for example, on average suffer a decline in intelligence on the order of a standard deviation (15 IQ points) over a 4 year period in one study2. To put this in perspective, this corresponds to a decline from the 50th to the 16th percentile in global cognitive functioning, which is a substantial, irreversible change in cognitive functioning with major implications for educational achievement and adaptive success in all areas throughout the lifespan. A recent paper by Ris et. al.,3 reported the long-term outcomes of adult survivors of pediatric brain tumors and found that, compared to healthy siblings, survivors were less likely to be fully employed, have a college education, and earning over $20,000 per year. Survivors also reported higher levels of global distress and depression than their siblings. This portends a life of challenges to children treated for brain tumors that could be partially averted and/or mitigated by improved treatments informed by research of the type proposed here. Improving our understanding of the factors that place these children at higher or lower risk for late-effects is critical to informing the development of less toxic treatments.
At the human level, changes in imaging following radiotherapy and how these relate to neurobehavioral morbidity is only generally understood. For example, changes in cerebral white matter have been correlated with IQ declines4. Ongoing research, including an NCI sponsored R01 by one of the co-investigators (DM. Ris) is aimed at relating imaging changes over time to subsequent neurodevelopment in a sample of children treated for brain tumors. This line of research would be greatly enhanced by an animal model of radiation effects on behavior, as proposed here. For example, recent research suggests that preservation of the neural stem cell compartments in irradiated rats may improve behavioral outcome on such tasks as the Morris water maze5. Further, reseach has shown that exercise enhances brain health by reducing inflammation6, increasing angiogenesis7 and enhancing proliferation and survival of neuronal progenitors8. Thus, exercise may counteract radiation-induced decrements in hippocampal neurogenesis5.
The discovery of early imaging markers of behavioral toxicity will contribute to our understanding of the mechanisms of late-effects as well as early interventions that might mitigate these effects. Such a coordinated program can design and investigate neurobehavioral end-points in animals that correlate with imaging markers as well as align with the neurobehavioral phenotype of children treated with radiation (e.g. deficits in attention, working memory, and processing speed). A translational paradigm of pediatric brain tumors with behavioral end-points executed in conjunction with research at the human level is virtually unprecedented and promises new discoveries of the pathophysiology, prediction, and intervention for late-effects in children treated for brain tumors.
1. We will test the hypothesis that late cognitive changes are related to imaging markers of radiation toxicity.
1.1. We will identify imaging predictive signatures of cognitive changes using a fractionated irradiation scheme (we will test two different schemes as outlined in the design section).
1.2. The model will include the effect of tumor presence on treatment side effects thereby providing us with a preclinical tool to test interventions that can abrogate treatment side effects.
1.3. To achieve our goal we will correlate time of onset and kinetics of imaging changes to pathological and neurocognitive changes.
When completed aim 1 would have established: i) a set of imaging markers of RT-toxicity; ii) pathological markers of neurogenesis impairment; iii) a set of cognitive tests in which we have charted the time course of significant changes in cognition.
2. We will test the hypothesis that exercise will reduce radiation-induced brain microvascular inflammation, limit neurogenesis impairment and cognitive decline and that these changes can be detected using our imaging markers established in aim 1.
2.1. Establish our exercise regimen.
2.2. Conduct cognitive and behavioral measurements following exercise regimen.
2.3. Measure the histological effect of exercising on radiation-induced neurogenesis impairment.
When completed aim 2 would have: i) tested the predictive power of our set of imaging markers; ii) tested the role of exercise in reversing radiation-induced cognitive decline; iii) investigated the role of exercise in protecting neurogenesis in subjects treated with cranial-RT.
The effects of irradiation on brain tissue are characterized on the basis of clinical deficits and associated with vascular and parenchymal damage. This damage is mediated by host and treatment related factors and the inherent sensitivities of specific functional anatomic compartments. We have developed a braintumor model that is useful in studying RT side effects. Our model uses C6-GFP glioma cells implanted in the rat brain and irradiated using a hypo-fractionation RT scheme. In the model untreated C6 implanted rats die within 20 days of tumor injection while RT treated animals survive with almost no loss. This RT-response offers a clinically relevant RT toxicity model that allows us to study the combined effect of tumor and RT on brain tissue.
Radiation side effects. RT-induced central nervous system injury is usually divided into three categories: acute (within days), early (1-6 months post treatment), and late. Late RT damage is associated with changes in neuropsychometric or neuroendocrine function, and vascular events9. Brain tumor patients treated with cranial RT have been reported to suffer from late-term toxicity such as decreases in motor/sensory coordination, altered hypothalamic hormone levels, delayed growth and development, IQ deficits, memory loss, behavioral problems, and lower academic achievement10. Several preclinical and clinical studies have demonstrated that RT dose and volume influence cognitive outcomes11-13. The chronological division of RT injury does not necessarily reflect a mechanistic disparity14-16. Late RT injury is likely to be related to early events that initiate a cascade of events leading to the observed changes 17,18. We, and others, have shown that RT induces an inflammatory response as indicated by an increase in TNF-α, ICAM-1 signaling, and astrocyte activation in the brain 19-22 after treatment with single and fractionated RT23,24. Prolonged gliosis can create glial scar sites, which has been theorized to inhibit axonal regeneration or remyelination25,26. We22,27 have demonstrated that this inflammation response is related to an increase in blood brain-barrier permeability following RT, and that it is abrogated when treated with TNF-α or ICAM-1 mAbs22.
RT affects neurogenesis. Neurogenesis is a highly regulated process that is affected by a widespread variety of exogenous and endogenous stimulus28-32. It has been shown that RT has a detrimental effect on neurogenesis33,34. Neurogenesis in the dentate gyrus (DG) of the hippocampus has been implicated in learning and memory. Neurogenesis is reported to be important for spatial learning,35,36 which is a hippocampal-dependent task 37,38. DG is particularly adapted to maintain and transmit the information received from the enthorinal cortex, specifically aimed to encode small inputs into the place cells within the hippocampal circuitry. Thus, impaired neurogenesis can easily be tested by Morris water maze, a well-established behavioral paradigm for spatial learning. Ablation of hippocampal neurogenesis in rodents by different means (genetic, pharmacological, or RT) results in lower scores in tasks that involve memory and learning.
RT affects growth hormone (GH) deficiency. GH deficiency is usually caused by the loss of growth hormone-releasing hormone neurons in the arcuate nucleus of the hypothalamus, and the condition tends to worsen over time39. The true incidence of GH deficiency after central nervous system (CNS) RT is unknown; however, evidence suggests that hypothalamic RT at doses at or >2Gy will impair GH release40 and that doses used to treat primary brain tumors (>50Gy) will often result in GH deficiency41.
FUTURE DIRECTIONS The long-term goal of our work is two fold. First, we want to identify a set of imaging markers of radiation side effects that are predictive of cognitive impairment. Second, we will use our imaging/cognitive paradigm to test interventions that can ameliorate these cognitive deficits and protect the brain against late RT-induced toxicity. To achieve this goal, the PI has assembled a strong interdisciplinary team which put together the current proposal. This project will be used as a springboard to construct the imaging/cognitive model and build future collaborations with oncologists, geneticists, and drug developers to achieve the long-term goal stated above.
- Ris MD: Lessons in pediatric neuropsycho-oncology: what we have learned since Johnny Gunther. J Pediatr Psychol 32:1029-37, 2007
- Ris MD, Packer R, Goldwein J, et al: Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children's Cancer Group study. J Clin Oncol 19:3470-6, 2001
- Zebrack BJ, Gurney JG, Oeffinger K, et al: Psychological outcomes in long-term survivors of childhood brain cancer: a report from the childhood cancer survivor study. J.Clin.Oncol. 22:999-1006, 2004
- Mulhern RK, Reddick WE, Palmer SL, et al: Neurocognitive deficits in medulloblastoma survivors and white matter loss. Ann Neurol 46:834-41, 1999
- Rola R, Raber J, Rizk A, et al: Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp Neurol 188:316-30, 2004
- Cotman CW, Berchtold NC, Christie LA: Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 30:464-72, 2007
- Swain RA, Harris AB, Wiener EC, et al: Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat. Neuroscience 117:1037-46, 2003
- van Praag H, Kempermann G, Gage FH: Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2:266-70, 1999
- FitzGerald TJ, Aronowitz J, Giulia Cicchetti M, et al: The effect of radiation therapy on normal tissue function. Hematol Oncol Clin North Am 20:141-63, 2006
- Surawicz TS, Davis F, Freels S, et al: Brain tumor survival: results from the National Cancer Data Base. J.Neurooncol. 40:151-160, 1998
- Merchant TE, Kiehna EN, Li C, et al: Modeling radiation dosimetry to predict cognitive outcomes in pediatric patients with CNS embryonal tumors including medulloblastoma. Int J Radiat Oncol Biol Phys 65:210-21, 2006
- Merchant TE, Kiehna EN, Li C, et al: Radiation dosimetry predicts IQ after conformal radiation therapy in pediatric patients with localized ependymoma. Int J Radiat Oncol Biol Phys 63:1546-54, 2005
- Grill J, Renaux VK, Bulteau C, et al: Long-term intellectual outcome in children with posterior fossa tumors according to radiation doses and volumes. Int J Radiat Oncol Biol Phys 45:137-45, 1999
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- Wilson CM, Gaber MW, Sabek OM, et al: Radiation-induced astrogliosis and bloodbrain barrier damage can be abrogated using anti-TNF treatment. Int J Radiat Oncol Biol Phys 74:934-41, 2009
- Yuan H, Gaber MW, Boyd K, et al: Effects of fractionated radiation on the brain vasculature in a murine model: blood-brain barrier permeability, astrocyte proliferation, and ultrastructural changes. Int J Radiat Oncol Biol Phys 66:860-6, 2006
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