Gene Therapy - B. Jill Williams, Ph.D.

Key Member

B. Jill Williams, Ph.D.
Associate Professor
Dept. of Urology

See the Curriculum Vitae
Williams Lab

Development of novel therapeutics based on modulation of prostate tumor biology may be useful as alternatives to, or in combination with, traditional therapies such as surgery, radiation, and hormone ablation that have significant co-morbidities. This application is designed to address the development of a gene therapy based on modulation of expression of a gene, eIF4E, that is frequently dysregulated in prostate cancers. The translation initiation factor eIF4E is the least abundant member of the protein synthesis machinery, making it the "rate-limiting" step in protein synthesis. In prostate tumor cells, abnormally high eIF4E levels allow for more efficient translation of certain mRNAs with complex secondary structure in their 5' untranslated region. Many of these mRNA, including those for VEGF, FGF-2, c-myc, and cyclin D1 have been tested for their responsiveness to eIF4E levels. This has significance for prostate cancer, as many of these mRNAs are known regulators of prostate tumor progression. Other mRNA with long or complex 5' UTRs, such as cathepsin B, matrix metalloproteinase (MMP)-2 and MMP-9, are involved in tumor invasion and are aberrantly expressed in prostate cancers. It is possible that eIF4E will become a valuable multi-target therapeutic for many types of human cancers. In this application, we propose to evaluate antisense RNA- or interference RNA (RNAi)-based reduction of eIF4E as a potential gene therapy for use in treating human prostate cancer. We suggest that in prostate cancer there exists an eIF4E-mediated dysregulation of potent growth regulatory molecules that at least in part drive prostate tumor progression and metastasis. We propose reduction of eIF4E to near-physiological levels will result in reduced translation of these mRNA and will subsequently reduce prostate tumor growth, invasion, and metastasis. The aims of this application are to determine the most advantageous combination of vector system, dosage schedule, and delivery route for transgene delivery. Our long-term goal is to prepare eIF4E antisense gene therapy for Phase I clinical trial.

Hypothesis: Use of an antisense eIF4E RNA-based or RNAi-based gene therapy approach will decrease tumor growth, metastatic progression, and overall survival in an animal model of human prostate cancer.

Specific Aims:

1 To determine the effects of vector, delivery route, dosage, and delivery schedule on biodistribution and durability of transgene expression in an orthotopic tumor model of prostate cancer
    a) To test delivery vehicles: adenovirus, lentivirus, and a lentivirus with a prostate-specific (probasin) promoter
    b) To test delivery routes: intratumoral, intraperitoneal, or intravesical/transurethral
    c) To test number number and concentration of viral doses: 2 times at 2 dosage levels
    d) To determine the expression pattern of each virus/delivery in lungs, liver, spleen, kidneys, ureters, bladder, seminal vesicles, prostate, lymph nodes, brain and bone
    e) To determine the level of transgene expression in these tissues at 1 day, 7, and 21 days post injection

To use optimized delivery strategies of viral-mediated eIF4E antisense or interference RNA to examine its effect on tumor progression and animal survival in an orthotopic model of human prostate cancer.

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