Image Based Evaluation of Tumor Targeting and Efficacy of Gene Therapy

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DESCRIPTION (provided by applicant): Although gene therapy and cellular therapies have great promise, they suffer from a lack of methods for specifically locating expression or cell trafficking. Reporter genes can both locate and quantify expression. In a pre-clinical tumor model, we demonstrated that transfer of a somatostatin receptor type 2a (SSTR2) gene chimera can be quantified in vivo. The growth inhibitory signaling incited by the SSTR2 may be advantageous when targeting cancer for therapy, but may not be desirable for disorders such as diabetes or when evaluating a linked gene of interest, such as for cancer. We propose to create an imagable, signaling deficient SSTR2. This reporter will have broad applicability for a number of disease states and applications. Most gene transfer techniques use constitutive promoters that drive high levels of expression in a variety of tissues. When introducing a toxic gene, promoters may be used to target tumors, and not normal tissues. Telomerase activity is found in nearly all tumors, but is absent or minimal in almost all normal tissues. This distribution is mimicked by the human telomerase reverse transcriptase (hTERT) promoter. A disadvantage of tissue specific promoters, including hTERT, is that their ability to drive transcription is relatively weak. We propose to create an amplified hTERT promoter-reporter system for tumor specific imaging. To limit effects on normal cells due to promoter leakiness or on bystander cells that can drive hTERT expression, we propose to create such constructs with signaling deficient reporters. We have quantified in vivo expression of a human somatostatin receptor gene 111 chimera in tumors using the FDA approved radiopharmaceutical in octreotide. Clinically, non-invasive methods, including anatomic imaging to assess change in tumor size, are desirable to assess efficacy. Combining functional and anatomic imaging, we will test whether the reporter system can be used to monitor expression of a linked therapeutic as well as to predict efficacy. Specific aims 1. Test the hypothesis that a signaling deficient somatostatin receptor type 2 (SSTR2) can function as a reporter of gene transfer. 2. Test the hypothesis that an amplified hTERT promoter linked to a reporter, such as a signaling deficient SSTR2 drives expression in tumors and the expression can be imaged in vivo. 3. Test the hypothesis that a signaling deficient SSTR2 linked to a therapeutic gene can be used to monitor expression and efficacy of a linked therapeutic gene. This project potentially will provide new tools for monitoring cancer treatment; as well as, increase the range of diseases that can be addressed by functional and anatomic imaging techniques, non-invasively. PUBLIC HEALTH RELEVANCE: This project potentially will provide new tools for monitoring cancer treatment; as well as, increase the range of diseases that can be addressed by functional and anatomic imaging techniques, non-invasively.