Heat-Activated Gene Therapy

The research goal is to develop heat shock as a modality for optimizing and controlling gene therapy for treating prostate cancer. Heat activatible tissue permeabilizers will increase dissemination of adenoviral vectors throughout solid tumors. The optimal permeabilizer has been identified and its usable ranges of concentration and activating heat shocks have been narrowed sufficiently to begin testing in human Xenograft tumors. A quantitative relationship between time at temperature and induced expression from a truncated heat shock promoter have been established in exponentially growing and plateau phase prostate cancer cells, which is essential for planning and analyzing parallel experiments in solid tumors. This is a fundamental step for establishing controllable expression of transgenes under control of a heat shock promoter within solid tumors. Mammalian expression constructs for expressing diphtheria toxin A and shiga toxin A have been made and tested, and are currently being used to produce adenoviral expression vectors. Fluorescent chimeras of both proteins have also been made, which may prove useful for monitoring gene expression in tumors and normal tissues. The work presented herein represents considerable progress towards achieving the approved tasks, and establishes a solid foundation for developing a form of controllable gene therapy for treating prostate cancer.