David R Grosshans, MD, PhD - US grants

In recent decades, the cure rates for adult and childhood brain tumors have improved. Unfortunately, many survivors now live with life-long side effects from the treatment itself. Radiation therapy is particularly damaging to the brain and results in long-term cognitive deficits. The majority of both laboratory and clinical investigation has focused on the negative effects of radiation on memory. The hippocampus, a brain structure important in memory formation where postnatal neurogenesis occurs, has been the sole focus. While memory is of great importance, deficits in attention and executive function may be equally debilitating for patients. Other brain areas, including the frontal cortex, control these functions and radiation effects on these non-neurogenic brain areas have been ignored. Moving outside the hippocampus to areas of the brain where neurogenesis does not occur, exciting new preliminary data indicate that neurons in the pre- frontal cortex are also susceptible to radiation-induced dysfunction. This challenges commonly held notions regarding the molecular and cellular mechanisms that underlie radiation-induced cognitive dysfunction. Such findings have the potential to explain fundamental aspects of radiation-induced cognitive decline. To identify such mechanisms we will use unique resources including simultaneous imaging and electrophysiological recordings of synaptic activity with radiation as well as in vivo assessments of persistent alterations in synaptic plasticity and dendritic structure in transgenic animals. In this proposal we will examine the role of acute glutamate toxicity following radiation, explore how synaptic function changes in the frontal cortex and determine the mechanisms leading to long lasting synaptic dysfunction. We will conduct the following aims; (1) define the role of glutamate toxicity and oxidative stress in the prefrontal cortex following radiation, (2) establish an animal model of radiation-induced attention and executive deficits and correlate these with alterations in synaptic function, (3) identify the role of epigenetic mechanisms in long lasting changes in synaptic structure and function following radiation. Knowledge of the early and late mechanisms involved will allow for the development of more effective preventative treatments or even reversal of pre-existing radiation-induced deficits.

Project Summary/Abstract Cure rates for childhood cancers have improved. Unfortunately, many survivors now live with life-long side effects from treatment itself. Radiation therapy, used for brain tumors, is particularly damaging. The most serious side effect is necrosis which can result in weakness, paralysis or even death. Proton therapy is an increasingly popular radiation modality. Proton therapy reduces exposure to normal tissues and the reby may decrease the incidence of cognitive deficits following radiation. However, recent studies, including our own suggest that certain areas of proton beams may be more damaging to brain tissue than others potentially leading to higher rates of necrosis. Here we will develop high accuracy models to correlate necrosis with the physical parameters of proton beams. These models will include multi-cell type human brain ?organoids? as well as rodent animal models. Using these models as well as clinical data, we will identify the physical factors of proton therapy which may lead to necrosis. This is significant in that this data may be used to design safer proton therapy treatments in which the most biologically effective portions of beams are solely placed within the tumor. This should reduce necrosis and improve disease control. In a second component of our study, we will examine the molecular mechanisms of necrosis. Rather than being simple dis-organized death, we will determine if radiation induces an orderly programmed cell death pathway. We will conduct the following aims; (1) relate the physical factors of proton beams with biological response, (2) explore the cellular and molecular mechanisms of radiation induced brain damage and (3) validate the clinical consequences of variability in the effectiveness of proton beams. The knowledge gained will quickly influence the treatment of brain tumor patients and expedite the clinical introduction of agents and approaches to combat the negative effects of radiation on the brain.

PROJECT SUMMARY/ABSTRACT Radiation plays a central role in the management of the most lethal central nervous system malignancy, glioblastoma (GBM), yet local control rates, and hence survival, remain dismal for this disease. Even novel therapies, such as immunotherapy, have not shown efficacy in the treatment of GBM. Meanwhile, radiation dose escalation studies have demonstrated improved local control. However, dose escalated treatments are hindered by the increased incidence of radiation induced brain necrosis in surrounding tissues. High LET particle therapy holds the potential to both increase tumor cell kill and decrease normal tissue toxicity, yet the data required to develop models for clinical treatments regarding the biological effectiveness of high LET beams on normal brain tissue and GBM cells is sparse. This fact is especially true when considering results reported utilizing the appropriate environment for the origination and growth of GBM cells ? the human brain. We have implemented recently developed high accuracy models which are truly beginning to recapitulate the native GBM niche in order to correlate both necrosis induction and progression and tumor cell response with the physical parameters of particle beams. These models include multi-cell type human brain organoids (cerebral organoids) as well as immune-competent orthotopic rodent models. Using these models, we will identify the physical factors of particle beams which may lead to necrosis. This is significant in that this data will aid the design of safer treatments by reducing necrosis and improving disease control. In the second component of our study, we will examine the molecular mechanisms of necrosis and neuroinflammation. Rather than being a simple accidental, disorganized death, we will determine if radiation induces an orderly programmed cell death pathway. Overall, we will conduct the following aims; (1) identify the optimal particle and fractionation for treatment of GBM, (2) explore the cellular and molecular mechanisms of radiation induced brain damage, and (3) develop biological effect models for clinical use. The knowledge gained will quickly influence the treatment of brain tumor patients and expedite the clinical introduction heavy ion therapy for glioblastoma.