Principal Investigator/Program Director (Last, first, middle): Lesniak, Maciej, S RESEARCH & RELATED Other Project Information 1. * Are Human Subjects Involved? l Yes m No 1.a. If YES to Human Subjects Is the IRB review Pending? l Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 00005565 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? m Yes l No IACUC Approval Date: 03-16-2006 Animal Welfare Assurance Number A3523-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract 8857-LesniakAbstract.pdf Mime Type: application/pdf 7. * Project Narrative 1694-LesniakNarrative.pdf Mime Type: application/pdf 8. Bibliography & References Cited 9412-LesniakLitCited.pdf Mime Type: application/pdf 9. Facilities & Other Resources 3377-LesniakResources.pdf Mime Type: application/pdf 10. Equipment 5165-LesniakEquip.pdf Mime Type: application/pdf Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Lesniak, Maciej, S Abstract Glioblastoma multiforme (GBM) represents the most common primary malignant tumor of the adult central nervous system. The median survival after surgical intervention alone is approximately six months and the addition of radio-/chemotherapy can extend this time up to twelve months. Failed therapy is most often associated with local recurrence in the proximity of the original tumor. Consequently, efforts aimed at developing new therapies have focused on treatment strategies that target the tumor environment but spare normal and healthy surrounding brain cells. Oncolytic viruses (CRAds) that are replication competent in tumor but not in normal cells represent a novel approach for treating neoplastic diseases. To bypass the dependence on CAR for adenoviral entry and replication, we created a new generation of novel adenoviral vectors which selectively bind to receptors which are over-expressed by GBMs. First, we substituted the receptor binding domain of Ad5 with either (a) integrin binding sequence, RGD, (b) the receptor binding domain of serotype Ad3, or (c) a heparan sulfate binding proteoglycan (HSPG), pk7. Second, we tested a variety of tumor specific promoters (TSP) and identified survivin as the optimal TSP for transcriptional control of E1a. Survivin expression in gliomas is associated with poor prognosis, increased rates of recurrence, and resistance to chemo- and radiotherapy. Finally, in an effort to create a novel viral imaging modality that would provide a signal correlating with viral replication and progeny production, we developed an approach to incorporate an imageable substrate directly into the adenovirus capsid for subsequent imaging of viral replication and spread with PET. Based on the above considerations, we then created three conditionally replicative vectors: CRAd-S-RGD, CRAd-S-5/3, and CRAd- S-pk7. Our hypothesis is that such transcriptional/transductional modifications of Ad5 will show superior tumor selectivity and a high oncolytic efficacy against malignant glioma, with minimal toxicity to normal brain. Preliminary studies suggest that of the three vectors, CRAd-S-pk7 is the optimal virus for further preclinical development. In this application, we will focus on CRAd-S-pk7 and examine the mechanism by which this no |