Glioblastoma mutliforme (GBM) is the most common form of primary brain cancer. Despite aggressivetherapies including surgery, radiotherapy, and chemotherapy, recurrent disease is nearly always fatal.Oncolytic HSV vectors (e.g. G207) have shown some promise in the treatment of GBM however therehave been few complete responses, a disappointing outcome most likely related to inadequate vectorinfection and growth, particularly among tumor cells that migrate from the tumor mass and invadenormal brain tissue. Thus a central goal of Project 3 is to improve oncolytic vector delivery, replicationand spread while maintaining safety and tumor specificity. Because changes in the tumor microenvironmentgreatly influence virus growth, we propose further to arm these oncolytic vectors withgenes that improve vector distribution, overcome local anti-viral responses and enhance susceptibilityto apoptotic mechanisms. Specifically, we propose to: (i) to explore the growth, spread and anti-tumorpotential of a highly active HSV -1 strain KOS Oncolytic Vector (KOV) deleted for the non-essentialimmediate early (I.E.) genes ICPO, ICP22 and ICP47, (ii) to employ a recombinant KOV vectorexpressing a secreted matrix metalloproteinase protease (ADAMTS-8) with strong anti-angiogenicactivity in an effort to increase initial vector distribution and to facilitate vector spread during replication,(iii) examine the use of a recombinant KOV capable of expressing VH1, binl and a dominant negativeIKB (kBaM) as inhibitors of the interferon gamma (IFNy) and indoleamine 2,3-dioxygenase (IDO) antiviraland cytokine induction pathways and (iv) to evaluate the ability of recombinant KOV expressing(a) a novel dominant negative PKCe (DNP) that blocks its anti-apoptotic function, (b) caspase 8a tolaunch the apoptotic cascade and (c) an optimized recombinant soluble TRAIL (orsTRAIL) to inducetumor cell apoptosis. Ultimately, it is our intention to create a powerful oncolytic vector that exploitsthese combined growth-facilitating, anti-tumor functions that will set a new standard for this form ofglioma therapy. This new vector will be compared to G207 to demonstrate improved anti-tumorresponses. The highly engineered vector will also provide opportunities to better understand gliomacell biology, greatly improve the use of anti-cancer drugs in collaboration with Project 1 and assist theinduction of tumor-specific immunity in collaboration with Project 2. Together our replication competentgene vectors should be useful in the development of an effective multi-modal therapy, an importantoverall goal of our program project grant.
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