Malignant Gliomas and Glioblastoma
Malignant gliomas and glioblastoma in particular, are the most common and malignant of all primary brain tumors. These brain tumors infiltrate the brain and are lethal. All malignant gliomas undergo the same non-curative treatment, including surgery, chemotherapy and radiation.
Precision Medicine applied to brain tumors: Personalizing the use of chemotherapy
Given that the molecular features of malignant gliomas are highly variable across patients, these tumors have been classified into different groups based on which genes are active or expressed. These molecular patterns and their underlying mechanisms might provide a unique tumoral vulnerability to treatments.
The regulation of brain tumor gene expression
The lab is focused on exploring the mechanisms that brain tumors rely on to express genes that are important for cancer, and using these molecular features to personalize the use of chemotherapy for patients with malignant brain tumors. Topoisomerase II (TOP2) is an enzyme that de-coils DNA. TOP2 is highly elevated in a subset of gliomas starting at early stages of tumor development. Our research team is exploring the role this enzyme plays in tumor development, including regulation of transcription.
Personalizing TOP2 targeting with chemotherapy for brain tumors
There are multiple FDA-approved drugs such as etoposide that target TOP2, and we are investigating the mechanisms that determine the susceptibility of glioblastomas to these drugs. Our goal is to develop a test that will predict which patients might benefit from TOP2-targeting drugs, as some tumors are susceptible to these drugs whereas others are resistant.
Chemotherapy delivery into the brain: Thinking outside the box
Given by traditional routes, etoposide does not reach tumor cells on patients’ brains at sufficient levels. In preclinical studies, Dr. Sonabend and colleagues showed that direct delivery of etoposide into the tumors is highly effective at inhibiting tumor growth. We are investigating novel means of delivery of these treatments directly into the brain including intratumoral delivery through convection-enhanced delivery (CED) and the use of nanoparticles to improve their efficacy while avoiding unnecessary side effects of these therapies.
Glioma Genome-Immune System Interactions
Dr. Sonabend’s lab is also investigating how the immune system shapes the genome of malignant gliomas, and the possible implications of this process for brain tumor immunotherapy.
PDGFB+Pten-/- mouse transgenic gliomas were characterized at an early (21 days) and late (end stage) of development. Histology and Ki-67 lebeling index (top), and array Comparative Genomic Hybridization (bottom) shows that at end stage these tumors have the histological appearance of glioblastoma with vascular proliferation (V) and pseudo-palisading necrosis (N), and suffer highly recurrent deletions, yet at early stages these tumors have low proliferation index, and do not harbor frequent genomic alterations. The height of the bar indicates the frequency of a given genetic alteration on the genome-wide view (bottom). Figure from Sonabend et al., Cancer Research 2014.
Genes frequently deleted PDGFB+Pten-/- mouse end-stage transgenic gliomas are specifically found deleted in human proneural glioblastomas (top) and are localized on a few loci of the human genome (bottom). Figure from Sonabend et al., Cancer Research 2014.
Cross-species comparison of gene deletions shows that genes frequently deleted PDGFB+Pten-/- mouse end-stage transgenic gliomas on separate loci coincide on a single deletion within the genome of human glioblastomas. Figure from Sonabend et al., Cancer Research 2014.
Master Regulator transcription factors of Proneural glioma gene expression profile during tumor progression were identified through the MARINA analysis. Figure from Sonabend et al., Cancer Research 2014.
TOP2B ChIP-seq experiment shows this helicase is positioned on an important oncogene in gliomas.
The high-variability of susceptibility to chemotherapy seen across glioma cell lines provides a rationale for the personalized use of these drugs for human gliomas.
We use expression-based predictions and validate these on patient-derived glioma xenograft lines to develop biomarkers for personalizing the use of chemotherapy for brain tumors.
Characterization of TOP2 expression in the brain surrounding enhancing glioblastoma lesions obtained through intraoperative sampling using stereotaxic navigation techniques and RNA-seq. Expression data derived from Gill et al., PNAS 2014.
Convection-enhanced delivery of etoposide experiments in transgenic mouse glioma models shows that the delivery of doses similar to the concentrations achieved in clinical trials are not associated with efficacy. Yet, 20-fold higher doses are efficacious. Figure derived from Neurooncol 2014.
Convection-enhanced delivery (CED) of etoposide experiments in transgenic mouse glioma models shows that the delivery of doses similar to the concentrations achieved in clinical trials are not associated with efficacy. Yet, 170-fold higher doses are curative in a large proportion of mice. Figure derived from Neurooncol 2014.
Subcutaneous pump implantation connected to an intracerebral catheter allows for continuous and chronic convection-enhanced delivery and a sustained volume of distribution of gadolinium in a porcine model. Figure from Sonabend et al., Neuro Oncol 2011
Results of genome-wide CRISPR chemotherapy susceptibility screening experiment on glioma cells identified several genes whose deletion by CRISPR is selected following etoposide treatment compared to the baseline distribution following an initial puromycin treatment.