Developing rodent models for testing brain tumor therapies
Human MG renewable tissue/cell resources are important because of the ongoing need for evaluating novel therapeutics in preclinical animal studies. My laboratory’s approach to therapeutic testing primarily involves the use of an intracranial MG xenograft model, so that therapy evaluations are conducted against human tumors growing in an appropriate microenvironment. This approach has motivated research in my laboratory for increasing the efficiency and maximizing the information yield of intracranial xenograft therapeutic testing, including the incorporation of methods for continuous monitoring of intracranial tumor growth and response to therapy in living animals. Towards this purpose, we utilize bioluminescence imaging and magnetic resonance imaging as part of our intracranial tumor therapy response testing, with each imaging method continuously being evaluated for its full range of application. My laboratory is also developing and characterizing transplantable/engraftable MG models using tumors from genetically engineered mice, and for which corresponding immunocompetent rodents can be used as hosts for establishing syngeneic/isogenic intracranial tumors.
Investigation of tumor adaptation to small molecule inhibitor therapy
Many cancers, including MG, are remarkably resistant to single agent therapies. Tumors adapt to the challenges posed by small molecule inhibitors by expanding subpopulations of cells that have inherent resistance to specific chemotherapeutics. Our lab investigates the adaptive responses of MG for the purpose of identifying secondary therapeutics that can be used, either concurrently with or following MG response to initial therapy, so as to improve the extent and duration of tumor response to treatment.
Use of small molecule inhibitors to influence cell cycling during cytotoxic therapy
Small molecule inhibitors of specific enzymatic activities can be used to advantage when combined with with conventional cytotoxic therapies (radiation and temozolomide) for enhancing cytotoxic therapy efficacy. Our research in this area suggests that the sequence of applying small molecule inhibitors with cytotoxic therapy is extremely important to maximizing benefit from combination therapy, and we are focused on understanding how small molecule inhibitors effect DNA repair processes important to tumor cell survival following treatment with radiation or temozolomide.
Convection Enhanced Delivery of Therapy for Treating MG
A major problem associated with the treatment of MG is the blood-brain-barrier, which limits access of peripherally (systemically) administered therapy for treating these brain tumors. Convection enhanced delivery involves controlled rate infusion of therapy directly into tumor, using cannula that are placed in the brain. My laboratory is investigating CED administration of therapy directly into brain tumors, for achieving more substantial anti-tumor effect than can be achieved by peripheral drug administration.
Histone Gene Mutations in Diffuse Intrinsic Pontine Glioma (DIPG)
DIPGs are MGs that occur in the brainstem of young children, and are nearly uniformly fatal. Recently, a frequently occurring mutation was discovered, that eliminates a methylation site of histone H3, and in so doing imposes substantially decreased H3 methylation throughout DIPG genomes. My lab is investigating basis as well as consequences of this mutation’s effect on histone H3 methylation.