Enhanced CRAd for Esophageal Adenocarcinoma

DESCRIPTION (provided by applicant): Esophageal adenocarcinoma is now the fastest growing cancer category in western men. Additionally, the prognosis of locally advanced disease has remained static despite current management advances. These facts clearly indicate the necessity of developing novel therapeutic approaches for esophageal adenocarcinoma. Even though conditionally replicative adenoviruses (CRAds) offer a novel and potent modality to approach solid tumors of the gastrointestinal tract, esophageal adenocarcinoma cells are extremely resistant to adenoviral infection due to minimal expression of the adenoviral primary receptor (coxsackie-adenovirus receptor, CAR). Furthermore, the lack of promoters with selectivity for esophageal adenocarcinoma has hindered the construction of CRAds that can selectively replicate in target tumor cells to achieve a useful therapeutic index for clinical utility. Lastly, absence of a non-invasive in vivo imaging method to detect CRAd replication and spread has hampered an understanding of CRAd biology in vivo. To achieve full therapeutic potential of CRAds for esophageal adenocarcinoma, we propose the construction of promoter-driven, infectivity-enhanced CRAds with imaging capabilities. To address the first issue, we have identified three promising promoters that exhibit favorable "tumor versus liver" and "tumor versus normal mucosa" differentials which are critical for utility in an adenoviral context. As well, we have developed methods to alter the tropism of adenoviruses, thereby achieving infectivity enhancement of tumor target ceils. The incorporation of an RGD4C motif in the HI loop of the fiber-knob region and Ad5/3 chimeric fiber modification has been shown to dramatically improve the infectious potency of adenovirus on esophageal adenocarcinoma cells. These findings offer solutions to the problem of esophageal adenocarcinoma cell resistance to adenoviral infection. In addition, we will configure optical and radiological imaging functions into our infectivity enhanced CRAds driven by optimal promoter. These features provide minimally invasive detection of CRAd replication and spread in a clinical setting, serving as a monitoring system with relevance to patient safety. Thus, it is obvious that infectivity-enhanced CRAds controlled by an optimal promoter element and possessing an imaging capability will be a therapeutic agent with great clinical utility for esophageal adenocarcinoma. The applicability of these modalities will be established from both toxicological and tumoricidal effect standpoints along with confirmation of CRAd functionality by optical and radiological imaging.