Neuroimaging has revealed that a significant percentage of patients treated for cancer develop cognitive deficits and impaired brain connectivity. How cancer treatment causes chemobrain is poorly understood, and no mechanism-based treatments currently exist.
Current Chemobrain Studies
Principal Investigators: Heijnen, Kavelaars
We have developed a mouse model of cisplatin-induced cognitive impairment. Utilizing this model, we showed that cognitive impairment is associated with structural abnormalities in white matter and a reduction in dendritic spine density and dendritic branching. We have also shown that co-administration of metformin prevents cisplatin-induced cognitive impairment and the related structural changes. We are now investigating the underlying mechanism.
Principal Investigators: Heijnen, Kavelaars ● Funding: GAP project 2014-2015
On the basis of our earlier work on neonatal brain damage, we have conducted studies showing that inhibition of a mitochondrial p53/JNK-mediated damage pathway protects against chemobrain. Preliminary data show that the small compound pifithrin-µ prevents cisplatin-induced mitochondrial p53 association and protects against cisplatin-induced cognitive impairment in our mouse model.
We are investigating the effects of cisplatin and protective treatment on brain mitochondrial morphology and function using electron microscopy and Seahorse Flux technology.
Principal Investigator: Kavelaars ● Funding: MD Anderson IRG
Chemobrain, as assessed by questionnaires as well as by formal neuro-psychological assessments, is frequently identified in patients treated for cancer. Neuroimaging using diffusion tension imaging (DTI) shows that chemobrain is associated with a widespread decrease in fractional anisotropy indicative of disrupted white-matter organization. Additionally, DTI and functional MRI (fMRI) followed by novel connectome analysis in humans has shown that chemotherapy reduces the connectivity in the brain, especially at highly connected brain regions known as “hubs,” areas where there is very high energy demand. It has been hypothesized that this reduction of connectivity results from local metabolic deficiencies that necessitate a reduction in energy use.
The goal of this project is to test this hypothesis in a mouse model. We aim at determining the effect of cisplatin on the functional and structural connectome of the mouse using fMRI and DTI performed by collaborators in the MD Anderson small animal imaging facility (Dr. Jim Bankson, Dr. Anthony Liu) followed by advanced connectome analysis by Dr. Shelly Kesler, Department of Neuro-Oncology. Underlying structural and biochemical changes in specific brain regions will be analyzed to identify the cellular and molecular mechanisms.
Principal Investigator: Heijnen ● Funding: MD Anderson
We have recently shown that ischemic brain damage in neonatal mice can be treated with nasal administration of mesenchymal stem cells. Upon nasal administration, these cells migrate to areas of brain damage. Locally, the mesenchymal stem cells stimulate repair mechanisms and/or inhibit ongoing damage.
Preliminary data indicate that the cognitive impairment caused by chemotherapy can also be resolved by nasal administration of mesenchymal stem cells. We are now investigating the (intra)cellular mechanisms underlying how mesenchymal stem cells interact with neurons, how and when nasally applied mesenchymal stem cells enter the brain, and whether mesenchymal stem cell treatment also repairs structural abnormalities in the brain.
Treatment of Neurotoxicity Induced by Radiotherapy for Glioblastoma via Nasal Administration of Mesenchymal Stem Cells
Principal Investigator: Heijnen ● Funding: MD Anderson, Texas Medical Center
This study is a subproject within the collaborative program “Preclinical rodent models to determine the safety and efficacy of mesenchymal stem cells for the treatment and prevention of radiation neurotoxicity in glioblastoma.”
No radiation therapy technique completely spares the normal tissues of the brain during brain tumor irradiation. Clinically, radiation-associated neurotoxicity most commonly manifests as diminished memory and impaired executive function and processing. Stem cell therapies offer great promise as a regenerative medicine approach. Mesenchymal stem cells (MSCs) have a robust capacity for self-renewal, home to areas of injury, and stimulate endogenous neural stem cells. In preclinical models, MSCs have demonstrated ability to improve outcomes after traumatic brain injury, stroke, hypoxic–ischemic brain injury, and spinal cord injury.
The hypothesis underlying this project is that transplantation of allogeneic MSCs into individuals with brain damage caused by chemotherapy and/or radiation will stimulate endogenous neurogenesis and repair damaged neurons and glia, reduce pro-inflammatory responses, and reduce microcirculatory dysfunction, thereby decreasing the adverse effects of radiation therapy on brain and cognition.
This is a collaborative project between the departments of Neuro-Oncology, Neurosurgery, Symptom Research, Radiation Oncology, and Stem Cell Transplantation at MD Anderson.