The mandate to realize surrogate endpoints in the context of human clinical trials with conditionally replicative adenovirus (CRAd) agents has thus suggested the utility of imaging analysis. In theory, this type of assay could provide critical information with respect to CRAd replication, amplification, and localization. These types of studies could thereby provide key insight into CRAd function in a human clinical context. To address this key issue we have developed a novel labeling system based upon structural incorporation of imaging reporter motifs into the adenovirus capsid. We hypothesize that this approach will provide the basis of deriving useful surrogate endpoint read-outs allowing valid imaging analysis of a human CRAd intervention for carcinoma of the ovary. In this regard, we have recently demonstrated our ability to incorporate complex heterologous fusion proteins at adenovirus minor capsid sites. Proof-of-principle studies with direct incorporation of fluorescent or SPECT/PET-linked imaging motifs validated that functional reporters could be incorporated within the adenovirus capsid and provide imaging signal. These demonstrated capacities provide the framework for understanding if such imaging detection systems can be employed in combination via capsid incorporation of dual modality reporter fusions which embody the capacity for SPECT/PET and fluorescent monitoring. Furthermore, the validation of this approach in relevant animal model systems will provide the rationale for clinical translation of this strategy as a means to derive useful surrogate endpoints of CRAd function in the context of human clinical employ. On the basis of these considerations, the Specific Aims of our proposal are:
Specific Aim #1 : To develop candidate ovarian cancer CRAd agents which embody capsid incorporated dual modality structural reporter fusions allowing dynamic fluorographic and SPECT/PET-based imaging analysis.
Specific Aim #2 : To employ the derived dual imaging modality CRAds in orthotopic murine models of carcinoma of the ovary to validate SPECT/PET and fluorographic imaging analysis of CRAd functionally.
Specific Aim #3 : To employ the optimal imaging modality for CRAd-based imaging analysis in the context of our next generation CRAd agent to be employed in a Phase I human clinical trial for carcinoma of the ovary to validate the analytical value of the structural reporter fusion method for CRAd monitoring. ? ? ?
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