Over 44,500 people in the United States are diagnosed with a primary tumor in the brain or spine each year. Of this group, approximately 20,500 are diagnosed with primary malignant brain tumors. Brain tumors are also the second most common cancer of childhood comprising approximately 25% of all pediatric cancers. It is the leading cause of solid tumor cancer death in children. Mortality rates from brain tumors are extremely high, with a median survival of approximately 12 months. Notably, mortality rates have remained unchanged over the last two decades as malignant gliomas continue to present significant problems for successful clinical treatment with the current regimen of surgery, radiotherapy or chemotherapy. The highly aggressive nature of malignant gliomas - glioblastoma cells rapidly invade the surrounding brain parenchyma - stems from defects in genes that control cell motility. Invasive tumor cells remaining after surgical resection confound clinical management and significantly contribute to the lethality of this disease. Additionally, a chemotherapy and radiotherapy resistant subpopulation of glioma cells retain stem cell-like properties to re-seed the tumor. This leads to recurrence with even poorer prognosis. The glioma stem cell population may harbor defects in genes that control self-renewal, proliferation and differentiation. Effective targeting of these invasive cells and the stem cell population is critical for the improved management and positive clinical outcome in malignant gliomas. The objective of this proposal is to determine if apical-basal polarity signaling is an important molecular element in the invasive pathology and recurrence of gliomas. We have observed that altered apical- basal polarity signaling causes the rapid proliferation and abnormal migration of undifferentiated cells bearing markers of embryonic neural stem cells in the developing chick central nervous system. Based on this previous study, we hypothesize that aberrant function of apical-basal polarity signaling pathway may play a central role in the invasive progression and growth of glioblastoma.
The specific aims of this proposal are: (i) to validate our preliminary observation of a positive association between elevated apical-basal polarity signaling pathway components and clinical glioblastoma, and to investigate the function of this pathway in glioma pathology. This study is likely to elucidate the molecular function of apical-basal polarity signaling pathway in glioma invasion, growth and progression, and provide the proof-of-concept for targeting this pathway as a novel strategy for glioblastoma therapy. Our long-term goal is the rational targeting of this pathway in an improved therapeutic paradigm for gliomas.
Prospects for better efficacy of glioma treatment protocols hinge on the successful unraveling of molecular pathways that control the aberrant invasion and recurrence of glioma tumors. Our experiments are designed to identity a novel molecular element that aids glioma invasion and growth, and understand the molecular basis of its function. Successful completion of this study will establish the proof-of-concept for rational therapeutic targeting of a novel, pharmacologically tractable, drug discovery target to specifically counter glioma tumor spread and growth.
