Adenovirus vectors specific for cells expressing androgen receptor and methods of use thereof

Abstract

Replication-competent adenovirus vectors specific for cells which allow a probasin transcriptional response element (PB-TRE) to function, such as cells which express the androgen receptor (AR), and methods of use of such viruses are provided. These viruses comprise an adenoviral gene under control of a transcriptional regulatory portion of a PB-TRE, which is in turn dependent upon AR expression. The gene can be, for example, a gene required for viral replication or the adenovirus death protein gene (ADP). The viruses can also comprise at least one additional adenoviral gene under control of at least one additional prostate-specific transcriptional response element, such as that controlling prostate-specific antigen expression (PSA-TRE). Thus, virus replication can be restricted to target cells exhibiting prostate-specific gene expression, particularly prostate carcinoma cells. An adenovirus of the present invention can further comprise a heterologous gene such as a reporter under transcriptional control of a PB-TRE. The adenovirus vectors can be used to detect and monitor samples for the presence of prostate cells as well as to selectively kill malignant cells producing prostate-specific gene products.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims benefit of U.S. Provisional Patent Application Ser. No. 60 / 039,762, filed on Mar. 3, 1997.STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH[0002](Not applicable)TECHNICAL FIELD[0003]This invention relates to cell transfection using adenoviral vectors, especially replication-competent adenoviruses, and methods of their use. More specifically, it relates to cell-specific replication of adenovirus vectors in cells expressing the androgen receptor, particularly prostate carcinoma cells, through use of a probasin transcriptional regulatory element.BACKGROUND OF THE INVENTION[0004]There are three significant diseases of the prostate: benign prostate hyperplasia (BPH), prostate cancer, and prostatitis. The cost of treating these three diseases is immense. The annual treatment of prostate diseases in the U.S. required 4.4 million physician visits, 836,000 hospitalizations, and cost over $3 billion i...

AI Technical Summary

Problems solved by technology

The cost of treating these three diseases is immense.

BPH causes urinary obstruction resulting in urinary incontinence.

Unregulated dihydrotestosterone is believed to cause hyperplastic prostate growth.

Unfortunately, a side-effect of the TURP is the elimination of the ejaculatory ducts as well as the nerve bundles of the penis, resulting in impotence in 90% of patients.

A TURP is prefaced by an outpatient biopsy procedure to determine if the enlargement of the prostate is benign or cancerous, which also adds to the cost.

Further, prostate cancer can take up to 10 years to kill the patient after initial diagnosis.

There is also high morbidity.

Surgery is the mainstay of treatment but it too is largely ineffective and also removes the ejaculatory ducts, resulting in impotence.

Unfortunately, in 80% of cases, diagnosis of prostate cancer is established when the disease has already metastasized to the bones.

At this stage there is no effective cytotoxic chemotherapy for prostate cancer.

However, estrogens are no longer recommended because of serious, even lethal, cardiovascular complications.

However, hormonal therapy invariably fails with time with the development of hormone-resistant tumor cells.

Furthermore, since 20% of patients fail to respond to hormonal therapy, it is believed that hormone-resistant cells are present at the onset of therapy.

Clinical trials, however, have been disappointing when survival is used as an endpoint.

However, almost all advanced cancer prostate cells fail to respond to androgen deprivation.

None of these techniques for treating prostate diseases has been universally successful.

Treatment for advanced disease initially involving hormonal manipulations and palliative radiotherapy have demonstrated symptomatic relief, but not long-term disease-free survival.

The use of cytotoxic agents in the management of hormone-resistant advanced prostate cancer remains poorly defined.

A few single agents have become “standard therapy”, although demonstration of their efficacy, by contemporary standards, is lacking.

Combination chemotherapy is frequently employed, although its contribution to overall patient management is largely unsubstantiated, especially when critical assessment of efficacy parameters are used.

Newer approaches using chemohormonal therapy and hormonal priming therapies have failed.

High-dose chemotherapy with transplant regimens are not well-tolerated in an elderly population, to which most victims of prostate cancer belong.

However, no therapy to date has been demonstrated to improve overall survival in patients with advanced hormone refractory prostate cancer.

A major, indeed the overwhelming, obstacle to cancer therapy is the problem of selectivity; that is, the ability to inhibit the multiplication of tumor cells, while leaving unaffected the function of normal cells.

In contrast to conventional cancer therapies, which result in relatively non-specific and often serious toxicity or impotence, more specific treatment modalities attempt to inhibit or kill malignant cells selectively while leaving healthy cells intact.

Adenoviruses are among the most easily produced and purified, whereas retroviruses are unstable, difficult to produce and to purify, and may integrate into the host genome, raising the possibility of dangerous mutations.

Replication of adenovirus has been viewed as an undesirable result, largely due to the host immune response.

Thus, the ability to repeatedly administer cytokines, tumor suppressor genes, ribozymes, suicide genes, or genes which convert a prodrug to an active drug has been limited by the immunogenicity of both the gene transfer vehicle and the viral gene products of the transfer vehicle as well as the transient nature of gene expression.

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