Glioblastoma is the most aggressive brain tumor in adults and children and is typically fatal despite multimodality therapy. The two year overall survival rate of less than 30% in newly diagnosed patients has not improved in over a decade. Treatment options for malignant gliomas are significantly limited by the presence of the blood-brain barrier (BBB). Specifically, the BBB inhibits effective therapy from reaching tumor cells due to the function and expression of endothelial cell junctional proteins, crosstalk of pericytes to glioma cells, astrocytes impairing drug entry and efflux of varied agents by multi-drug resistance proteins. Amongst glioblastoma tumor cells, BBB permeability is quite heterogeneous, with leaky vasculature in the bulk of the tumor and highly selective drug/molecule entry in peripheral vasculature. This diversity in BBB integrity aids glioma stem cells (GSCs) in evading treatment, proliferating and developing treatment resistance, despite multi-modality therapy. The failure of current therapies to eliminate specific GSC subpopulations has been considered a major contributing factor to tumor recurrence.
Specifically, these GSCs secrete high levels of growth factors in their microenvironment, contributing to vascular proliferation and heterogeneity of BBB leakiness. Interestingly, recent studies have shown that targeting GSC self-renewal signaling pathways (ex. BMX, mTOR, WNT, STAT3) can inhibit stem cell growth and invasion, while decreasing associated BBB integrity. Interestingly, these signaling cascades have been shown to promote BBB strength specifically by 1) regulating vascular development, 2) inducing endothelial cell migration/tubulogenesis/angiogenesis and 3) directing the communication of vascular cells to microenviromental cues of varied cell types. However, there are a paucity of malignant brain tumor studies that center around the use of targeted therapies to both GSCs and their supportive BBB cells. Our ultimate goal is to enhance therapies targeting malignant tumor cells and their supportive BBB, in an effort to improve treatment response and prolong overall survival.
What are the goals of this project?
The goals of this project are to identify expression profile of contrast vs. non-contrast enhancing pediatric malignant glioma tumor tissue (genomic and protein/signal transduction and to target signal transduction pathways involved in both glioma stem cell proliferation and restrictive BBB cells using in vitro and in vivo studies
What is the impact of this project?
The blood-brain barrier (BBB) is a semipermeable collection of cells responsible for inhibiting toxins to the CNS. The presence of the blood-brain barrier (BBB), which is mainly composed of endothelial cells, pericytes and astrocytes, is very important in the hindrance of effective chemotherapy delivery for malignant brain tumors, such as glioblastoma (GBM). To date, the majority of agents used to combat high grade glioma growth have been centered on agents that are known to cross into the central nervous system (CNS). However, there are a plethora of agents that are effective against malignant glioma proliferation and invasion, but are not being utilized because they fail to cross the BBB. As such, there is a strong interest to enhance delivery of certain CNS agents, so as to improve survival rates of patients with malignant brain tumors. Yet, few studies have been performed to evaluate the potential to transiently increase BBB permeability while also treating aggressive tumor cell growth and invasion. Our future studies will be focused on translating these results from the bench to the bedside. There are a multitude of therapies that have been found to kill malignant glioma cells in culture but do not cross the BBB and thus have not been found to be successful in clinical studies. The proposed studies targeting both cell populations, glioma and the BBB, is aimed at decreasing treatment resistance due to the presence of this physical CNS barrier.
Why the CBTN request is important to this project?
CBTN source provides a uniform database of optimized tissue with highly notated data regarding clinical specimens, location, and associated therapies. At the NIH, we do not have a large clinical sample database for translational studies. Thus, use of CBTN specimens and data will allow us to evaluate BBB restrictions related to treatment response with bioinformatic data mining, in culture and with rodent tumor models.
The Children's Brain Tumor Network will contribute to this project by providing cell lines and patient derived xenografts.
Sadhana Jackson, MD
Dr. Jackson’s research interests center on evaluating the blood-brain barrier (BBB) of malignant gliomas. Her clinical and translational research focuses on transiently disrupting the BBB by pharmacologic means, in an effort to improve cytotoxic therapy to the central nervous system. She uses b
High-grade glioma/astrocytoma (WHO grade III/IV)
High-grade Gliomas (HGG) in children nearly always result in a dismal prognosis. Although novel therapeutic approaches are currently in development, preclinical testing has been limited, due to a lack of pediatric specific HGG preclinical models. These models are needed to help test the effective
Brainstem glioma- Diffuse intrinsic pontine glioma
A presumptive diagnosis of DIPG based on classic imaging features, in the absence of a histologic diagnosis, has been routinely employed. Increasingly however, histologic confirmation is obtained for both entry into research studies and molecular characterization of the tumor.[