1997 WHRG Grant Program

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Viral Vectors for Toxin Gene Therapy in Ovarian Cancer
Yaron Lidor, M.D.
School of Medicine, University of Maryland, Baltimore

Ovarian carcinoma is the fifth most common cause of cancer death in women in the United States. About 35 women die each day from this disease in the USA alone. Despite a frequent temporary remission achieved with surgical cytoreduction and multiple agent chemotherapy, long term survival for ovarian carcinoma has improved little in the past three decades. Due to the limited success of traditional therapeutic regimens on survival of patients with advanced disease, alternative methods of treatment, including gene therapy, are currently being explored. Extensive work from our group has shown that tissue-specific expression of the diphtheria toxin A-chain (DT-A) is selectively toxic to distinct cell types, including ovarian cancer cells. This proposal is part of a general plan to develop in vitro and in vivo systems for exploring the use of hCG-alpha and -beta promoters regulated by DT-A constructs in the treatment of refractory ovarian malignancies. Retroviral gene therapy vectors expressing the DT-A gene under regulatory control of the hCG-alpha and -beta promoters (LNXX-47R/-49R) and their frame- shifted control vector (LNXX-48) have been constructed in our laboratory. The scope of the proposed study is to optimize production of high titer retroviral supernatants from these vectors, using efficient packaging lines. In addition, construction of E1, E2 and E4 deleted adenovirus 47R, 49R and 48R vectors will be carried out. Last, we will replace the DT-A gene with the gene for Green Flourescent Protein in the retroviral and adenoviral -47R/-49R/-48R vectors, to construct expression vectors driven by the hCG-alpha and -beta promoters. In future studies, once high titer retroviral and/or adenoviral supernatants are avialable, efficiency of transduction and the specificity of DT-A expression in ovarian carcinoma cells versus normal cells of ovarian, liver, and mesenchymal origin will be explored. Specific killing of malignant ovarian cells by the hCG-DT-A constructs will then be analyzed, both in vitro by clonogenic and MTT assays and in vivo in the human heterograft model of ovarian cancer in nude mice. The proposed studies may provide the framework for implementation in the clinic of gene therapy for advanced ovarian carcinoma mediated by targeted expression of a toxin gene.