Brain tumor is the leading cause of solid tumor death in children and one of the top leading causes of cancer death in young male and female adults with ages of 20-39 . Glioblastoma (GBM) is the most common primary brain cancer in adults with an overall incidence of 20% of all primary brain tumors. Despite current standard of care, which includes surgery and chemo-radiation, the median survival is only 14.6 months. Due to the highly invasive nature of GBM cells, standard treatment with gross total resection of the tumor is insufficient to achieve a cure because of the high rate of recurrence by tumor cells outside the tumor resection margins. Moreover, there is an unmet need in the ability of clinicians to identify patients with lower survival times and high risk of recurrence. Developing novel prognostic tools for determining patient survival and for identifying cell subpopulations that have a significantly increased motility and aggressiveness, and drive recurrence is of utmost importance. Intriguing data based on a retrospective study of our GBM patients reveal that: 1) our novel Microfluidic Invasion Network Device (MIND) predicts survival in GBM patients based on the increased percentage of invasive cells in the heterogeneous population; 2) we are able to separate the invasive from non-invasive cell using MIND device, which will allow us to understand the underlying molecular differences of the more aggressive subpopulations; 3) the targetable transcription factor TEAD4 is selectively overexpressed and hyperactive in GBM and promotes confined GBM migration. In light of these findings, we propose to: i) establish our MIND platform as an adjunct tool to the clinical management of GBM patients prospectively, ii) uncover novel drivers of GBM cell invasion, and iii) utilize it as a high-throughput assay for screening potential therapeutic drugs. To achieve these goals, we will pursue the following specific aims: to determine the prognostic power of confined space migration in a prospective cohort of GBM patients using MIND (Aim 1); to characterize the molecular drivers of confined space migration of phenotypically aggressive brain cancer cells using MIND (Aim 2); to evaluate the in vivo translational efficacy of 42 chemotherapeutic agents tested in MIND (Aim 3). In vitro experiments will be conducted using prospectively collected patient-derived primary GBM cell lines from over 100 patients. Our proprietary and novel MIND platform will be used to study confined- space migration from these patients to identify poor prognosis and high recurrence prospectively with the future goal of achieving personalized treatments for patients. In vivo studies will be conducted using our established orthotopic human brain tumor initiating cell-derived GBM model in mice. The results obtained from this study will to lead to the development of a platform for precision medicine with the ability to test drugs in a high throughput fashion using freshly isolated human tissue.
In the United States, glioblastoma (GBM), the most common brain cancer, is responsible for over 13,000 deaths per year with an economic burden of $7.2 billion. Despite radical surgery and chemo-/radiotherapy, median survival for this lethal brain cancer is only 14.6 months. Given this dismal prognosis and paucity of effective treatment options, we aim to establish a novel device, Microfluidic Invasion Network Device (MIND), for clinical assessment of outcomes in GBM patients, genetic characterization of aggressive tumor behaviors and high-throughput screening of novel potential therapeutic drugs, with the potential to greatly impact the therapeutic management of patients with malignant brain tumors.
|Kim, Jayoung; Shamul, James G; Shah, Sagar R et al. (2018) Verteporfin-Loaded Poly(ethylene glycol)-Poly(beta-amino ester)-Poly(ethylene glycol) Triblock Micelles for Cancer Therapy. Biomacromolecules 19:3361-3370|