The investigator writes that the majority of malignant tumors are resistant to radio- or chemotherapy in advanced stages mainly due to loss of p53 function. New tumor gene therapy approaches must consider targeting every cell in the primary tumor and all metastases with a maximal cytotoxic index for cancer cells. First generation adenovirus (Ad) vectors are attractive for cancer therapy because of their potential to transduce all tumor sites after systemic application. These vectors are deleted in the E1 region, rendering them highly replication-defective. This proposal is based on the observation that E1-deleted Ad vectors replicate selectively in HPV associated cervical carcinoma cells because the HPV E6/E7 proteins which are responsible for the maintenance of the malignant phenotype effectively complement the deleted Ad E1 proteins. The goal is to develop oncolytic Ad vectors for cervical cancer that replicate in tumor-specifically and disseminate throughout the tumor, selectively killing all tumor cells by viral cytolysis or p53-independent apoptosis. The studies will be performed in immunodeficient mice with hepatic tumors derived from cervical carcinoma cell lines or in immunocompetent mice with HPV induced tumors.
The specific aims are: 1. To develop an expression system based on a unique Ad-AAV hybrid vector, which activates a tumor-specific promoter only upon viral DNA replication. 2. To test whether virus dissemination throughout the tumor can be obtained if virus release from infected tumor cells is supported by cytolysis or apoptosis induced after viral replication is completed. For this purpose the investigators will use the AD-AAV system and investigate virus spread and anti-tumor efficacy after a) E3-11.6K expression, and b) expression of a transdominant i-kB mutant to sensitize tumor cells to apoptosis induced by TNF treatment or TRAIL expression. 3. To investigate the effect of antiviral immune responses on oncolytic vector spread and, if required, to suppress these responses by expression of Ad E3 proteins and/or transient immuno-modulation. These studies will give valuable information about the influence of apoptosis and host immune responses on replication-competent Ad vectors developed for tumor gene therapy. This proposal may provide a means for treatments of cervical carcinoma and has potential application for other malignancies with deregulated pRb/p16 functions that allow for replication of E1-deleted Ad vectors.
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