| Gliomas present a significant clinical burden. In 2008, there were 22,000 new cases of brain and nervous system cancers in adults. The five-year survival rate is markedly poor with only 35% of diagnosed patients surviving. Nearly 20% of the tumors were glioblastoma exhibiting an invasive phenotype that has even poorer prognosis. This results in malignant glioma being the second leading cause of cancer death in middle aged adults. Primary malignant brain tumors are also the second leading cause of cancer death in adolescents. Surgical resection has poor outcomes, and chemotherapy and local therapy do not significantly affect survival. There is an urgent need to develop alternative, more effective therapy for glioma and enhance current treatments for better prognosis.;The primary reason for poor outcomes for glioma after therapy is their invasive nature which, when combined with the need to minimize amount of normal tissue damaged to preserve neural function, almost always leads to incomplete resection. While the standard chemotherapy with temozolomide has enhanced clinical options, this is a cytotoxic agent whose ability to be effective is hampered by invasive tumor fronts being surrounded by normal brain tissue, complicating dosing, delivery and effectiveness.;Therefore it would be useful if there were effective 'anti-invasive' agents that limit the migration of tumor away from the primary site. This ability would enhance the outcomes of surgical resection, and make chemotherapy and radiation more likely to succeed due to the proximity of tumor regions without risking damage to normal brain. Unfortunately, while there are several candidate cytotoxic agents such as temozolomide, BCNU, and doxorubicin, currently there are no effective anti-invasive agents for glioma in the clinic. If an effective anti-invasive agent were identified, we hypothesize that a combinatorial therapy, with an anti-invasive agent that limits the aggressive invasion of glioma and an effective cytotoxic agent delivered preferentially to tumors would significantly increase the success of treatment.;To test this hypothesis, we proposed to identify an anti-invasive, but not cytotoxic agent by using in vitro screening methods. Further, we encapsulated this compound in order to passively target brain tumor to test the efficacy of the compound in vivo. Lastly, we determined if use of an anti-invasive agent will enhance the efficacy of current chemotherapeutic compounds in vivo.;In all, this thesis encompasses work surrounding the invasion of glioma. Through determination of a compound that will halt invasion in a glioblastoma model without causing cytotoxicity (Chapter 2) we identified a compound, Imipramine Blue. Then, using liposomes and in vitro and in vivo invasion quantification methods we show that this compound halts invasion and can assist the efficacy of doxorubicin to enhance survival (Chapter 3). In Chapter 4, we co-encapsulated IB and doxorubicin in a single nanoparticle and showed again, enhanced survival but with a disadvantage in survival time. Last, in Chapter 5, we performed a series of experiments, and, along with information from collaborators, determined a plausible mechanism of action of Imipramine Blue through binding of NADPH Oxidase 4. This thesis offers a new method of treatment and validation of the hypothesis that halting invasion can, in fact, enhance common anti-tumor therapy. |
