Role of N-Cadherin in the Therapeutic Resistance of Glioblastoma
Abstract
Our study is responsive to the Topic Area of brain cancer. Our proposed study is responsive to the Military Relevance Focus Area of addressing gaps in cancer treatment that may have a particularly profound impact on the health and well-being of military personnel, their beneficiaries, and family of active duty Service members and Veterans. Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in the adult. It is extremely aggressive, with a median overall survival of less than 2 years. Poor prognosis of patients with GBM is due to cells that survive initial therapies, grow back and lead to tumor recurrence. Prior studies revealed that resistant GBM cells have characteristics of glioma stem cells (GSCs), with stem-like characteristics such as relative quiescence, high self-renewal capacity, and high chemo- and radioresistance. Currently, there are no effective therapies to treat recurrent GBM; therefore, a molecular analysis of treatment-resistant GSCs is needed to develop new effective therapies for these patients. Scientific Objective and Rationale: This study will examine the role of N-cadherin-mediated cell-cell adhesion in GBM radioresistance and evaluate the potential of inhibiting this process as a novel therapeutic intervention. The rationale for this objective is that we found in our new models of GBM adaptation to irradiation that acquisition of radioresistance is accompanied by increased N-cadherin expression. We further show stable transfection of N-cadherin in GSCs confers radioresistance and decreased cell proliferation and knockdown of N-cadherin in resistant cells radiosensitizes them. Moreover, the expression level of N-cadherin is correlated with poor outcome in the patients with GBM. In this application, we will define the N-cadherin-mediated signaling that confers radioresistance, map the protein domains involved, examine their role in proliferation control, and determine whether therapeutic targeting of N-cadherin can reverse radioresistance. We will analyze the efficacy of two drugs (ADH1 and PPP) that can inhibit N-cadherin directly (ADH-1) or its activation by irradiation (PPP) in animal models of GBM. The role of N-cadherin in GSCs radioresistance has never been examined, making the proposed research novel and innovative. These studies will provide proof-of-principle preclinical data supporting a future clinical trial for the treatment of patients with GBM. Ultimate Applicability of the Research: The outcome of this study will directly benefit all the GBM afflicted patients who are military personnel, their beneficiaries, and family of active duty Service members and Veterans. It will help them by offering a new type of therapy for extremely aggressive disease. The proposed N-cadherin-targeted therapy using pharmacological agents offers a novel strategy for highly specific, yet less aggressive treatment of GBM with reduced treatment toxicity. The projected timeline to achieve the interim outcome of our new advances in cancer research is 2 years, and to attain a clinically relevant outcome about 4-7 years. Two candidate inhibitors (ADH1 and PPP) are clinically safe and are currently being tested in patients with other cancers in Phase II clinical trials; hence, our findings could be rapidly translated in patients with GBM. The results of this study will tremendously advance and streamline the treatment of GBM patients. Relevance to Active Duty Service Members, Veterans, and Other Military Beneficiaries: The outcome of this study will have a direct effect on the approach of treating GBM afflicted patients who are military personnel, their beneficiaries, and family of active duty Service members and Veterans. This new form of therapy for GBM patients is expected to be less toxic compared to regular chemoradiotherapy, thereby improving the quality of life in GBM patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810373
Entities
People
- Erwin G. Van Meir
Organizations
- Emory University
- United States Army