Viable treatment options for refractory solid tumors, such as malignant gliomas, are extremely limited, and the clinical outcome (12 months median survival) for affected patients remains dismal. Alternative treatments based on exploiting the current understanding of the molecular biology of malignant tumors is an urgent necessity. One such molecular-based treatment makes use of conditionally replication- competent adenoviruses that replicate specifically within tumor cells without being able to replicate (or replicate very inefficiently) within normal tissue. Replication-selective adenoviruses (oncolytic adenoviruses) are curative in a number of orthotopic mouse xenograft models, and those viruses that conditionally replicate based on the retinoblastoma (Rb)/p16 pathway status of the tumor cell are the next generation of oncolytic adenoviruses that will be tested in clinical trials. This is due to their extremely large therapeutic window and apparent lack of toxicity in animal systems. The replication efficiency amplifies the original input dose of the oncolytic virus and helps the agent spread to adjacent tumor cells in a """"""""chain reaction"""""""" like modality, providing a direct antitumor effect. Since these viruses are only permissible for replication within human cells (tumors), it is only possible to study their biology in human tissue specimens and mouse xenograft models. Therefore, many gaps in our knowledge exist. Delta-24 (D-24)-RGD-4C, the oncolytic adenovirus that has been chosen to enter Phase I clinical trials, has been modified to alter the natural tropism. The introduction of the RGD-4C peptide motif in the viral fiber knob will allow this virus to target both tumor cells and tumor neovasculature. This enhanced targeting is expected to cause an anti-angiogenic effect that should be detectable by perfusion-based imaging techniques. All of these interactions between human tumor and oncolytic viral therapy are currently unknown, critically important, and represent a fundamental gap of knowledge in the field that needs to be filled in order to successfully modify and improve this mode of cancer therapy. The objective of this application is to answer these gaps in knowledge that were briefly stated above by using imaging techniques currently available and by evaluating human tumor specimens that will be made available during the course of the planned Phase I clinical trial. The central hypothesis is that the effect of a conditionally-replicating tropism-modified oncolytic adenovirus (D-24-RGD-4C) on human high-grade tumors will cause the following detectable changes: (1) active replication and patterned spread through the treated tumor; and (2) disruption of neovasculature through endothelial cell lysis that can be assessed by standard and available clinical perfusion imaging techniques. This proposal will determine the effects of the replicating oncolytic adenovirus in a resected tumor that had been previously injected with D-24-RGD- 4C 14 days prior in patients enrolled in the Phase I clinical trial. Also, this proposal will determine in vivo changes in imaging markers of tumoral perfusion and identify the underlying histopathology responsible for such changes. Viable treatment options for refractory solid tumors, such as malignant gliomas, are extremely limited, and the clinical outcome for affected patients remains dismal, in fact, few gains have been achieved in increasing patient survival beyond the median of 12 months. Replication-selective adenoviruses (oncolytic adenoviruses) are curative in a number of mouse models, and viruses that conditionally replicate in tumor cells based on the retinoblastoma (Rb)/p16 tumor suppressor pathway, are the next generation of oncolytic adenoviruses that will be tested in clinical trials. The objective of this application is to answer questions related to using imaging techniques currently available and to evaluate human tumor specimens that will be treated during the course of a planned Phase I clinical trial testing a replication-selective adenovirus named D-24- RGD in patients with malignant glioma. ? ? ?
