The explosive increase in the apparent incidence of prostate cancer in the United States (which is due, in large measure, to wider efforts at early detection) has been accompanied by a dramatic stage migration, which can also be attributed to the increased use of prostate-specific antigen (PSA). Testing with PSA is used not only for the detection of prostate cancer but also as a measure of both response to therapy and progression after therapy. As a consequence, a lead-time bias in the identification of progressive disease has been introduced, which affects all treatment modalities, including surgery, radiation therapy, and systemic therapy, such as androgen deprivation. Consequently, a large group of patients have been identified who have early prostate cancer or in whom the only evidence of progressive disease is a rising PSA. This group of patients present a unique opportunity for the development of novel therapeutic approaches such a gene therapy that are likely to be more efficacious in patients with minimal tumor burden.
The rationale for the development of gene therapy in prostate cancer, potential situations in which it may be utilized, and its challenges and promises are carefully laid out in the article by Drs. Harrison and Glode.
The authors outline the various components required for successful therapy involving the introduction of genetic material into patients' cells. These include construction of the appropriate vector for delivery of the gene of interest, selection of an appropriate promoter to ensure that adequate expression of this gene occurs, and, most importantly, identification of the gene of interest.
Although numerous investigators are exploring nonviral means of gene transfer, it is fair to say that most approaches have taken advantage of the capacity of viruses to introduce genetic material into a cell. The authors correctly state that most viruses in current use are replication-deficient. However, it must be pointed out that a precedent now exists for mutant viruses that maintain the capacity for replication but retain specificity for targeted malignant cells. The first example of such a virus was recently reported. Bischoff et al showed that an E1B-deficient adenovirus can infect and lyse only cells that harbor a mutant p53 gene.
Although, technically, the use of this virus would not constitute gene therapy, since novel genetic material is not being introduced, the net effect, that of genetic selection of a target cell population, is the same. Contrary to the replication-deficient adenovirus used in gene transfer studies, the utility of the E1B-deficient virus would be that more than a limited number of cells could be infected and potentially destroyed.
The authors point out that one advantage of retroviral vectors is the possibility of selective targeting to the dividing tumor cell. However it is not entirely clear that overexpression (eg, of a wild-type tumor-suppressor gene) in normal tissue is necessarily deleterious. Nevertheless, the authors are correct in pointing out that one of the safety concerns in gene therapy is the possibility of inadvertently targeting normal as opposed to neoplastic cells. Extensive preclinical and phase I testing will be required to determine whether or not such an event would necessarily be detrimental.
The authors suggest that one of the unique aspects of prostate cancer is that, with the use of prostate-specific promoters, only prostatic tissue (both benign and malignant) could be targeted. Given that an innocent bystander effect involving normal prostatic tissue is not likely to have significant clinical repercussions and that patients may have already received definitive therapy for localized disease, targeting of both benign and malignant prostatic tissue would be acceptable.
Candidate Genes in Prostate Cancer
The authors have carefully listed features unique to gene therapy in prostate cancer, including unique clinical features of prostate cancer, as well as an overview of candidate genes. Regarding the utility of inserting wild-type tumor-suppressor genes, the authors appropriately note that consistent deletions of chromosomal material in patients with localized prostate cancer are not well identified. Nevertheless, some candidate genes do exist. In particular, p53 mutations have been found in anywhere from 20% to 75% of prostate cancer specimens, albeit at the lower end of the spectrum in patients with localized disease.
Furthermore, novel techniques, including comparative genomic hybridization, show great promise for identifying regions of the chromosome with frequent amplifications or deletions. More recently, the area distal to the BRCA-1 (breast-ovarian cancer susceptibility) gene has been shown to be deleted in 70% of patients with localized prostate carcinoma.
Other Potential Targets
In addition to the insertion of wild-type tumor-suppressor genes, efforts to inactivate specific genes or gene products, in particular, oncogenes, must be considered a form of gene therapy. In this regard, the utility of antisense or ribozyme technology to destroy or inactivate specific genetic sequences must be considered. In prostate cancer, potential targets include oncogenes, such as ERB-B2 and EGFR, although their exact role in the pathogenesis of prostate cancer is not well understood. Humanized antibodies to these oncogene products exist as well, and are the basis for ongoing trials.
Also discussed in the article are direct toxins targeted at specific cells. These approaches frequently capitalize on a bystander effect. In this regard, the E1B-deficient adenovirus noted above should be included as an agent capable of infecting and affecting more than a single cell.
The authors also describe, in general terms, the potential efficacy of targeting local growth factors, such as basic fibroblastic growth factor. Although there is no question that proangiogenic molecules, such as fibroblast growth factor (FGF) and perhaps vascular endothelial growth factor (VEGF), are involved in the progression of prostate cancer, it is not at all clear that the technology currently exists to target the gene sequences controlling the generation of these molecules. Other approaches, including the use of suramin (which is known to bind FGF), may have a similar effect. Other antiangiogenic molecules under development may be easier, less expensive, and perhaps as efficacious or more efficacious than gene therapy.
The authors discuss the utility of promoting the expression of various cytokines as a means of soliciting or enhancing an immunologic response. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is felt to be especially promising, and is the basis for one therapeutic gene trial in prostate cancer, referenced by the authors.
Preclinical animal data available on GM-CSF should be tempered by in vitro data suggesting that it appears to stimulate, rather than inhibit, several prostate cancer cell lines. Clearly, bench-top observations made in cell lines and tissue culture cannot be directly extrapolated to the clinical setting. Nevertheless, these data must be taken into account as therapeutic trials are designed.
It should also be pointed out that there are other ways of obtaining an immune response without the expense and difficulty of transfecting cells with a particular gene of interest. Numerous vaccine trials utilizing purified antigens, prostate cancer cells, and/or immune effector cells are currently underway and merit evaluation as well.
Guarding Against Unrealistic Expectations
The authors have carefully delineated the advantages and unique aspects of prostate carcinoma that may allow for the successful administration of gene therapy, but they appropriately warn about harboring unrealistic expectations about the early phases of these trials. They point out that perhaps the most appropriate setting in which to study immune therapy is in patients with minimal or microscopic disease. On the one hand, they argue that the long latency of prostate cancer offers a large window of opportunity for the use of gene therapy. However, if patients with minimal disease are to be treated, then trials will, by necessity, be large and will require lengthy maturation time before any determination can be made regarding an impact on end points.
Certainly, in this relatively early phase of gene therapy, it is prudent to test gene therapy in localized disease prior to undertaking systemic therapy. The authors hold that the anatomic considerations of prostate cancer make it an ideal tumor to treat. However, accessibility of tissue should not be confused with ease of administration. Although local therapy, such as brachytherapy and cryotherapy, have been successfully used in the context of real-time imaging of the prostate with either ultrasound or CT, the fact remains that these modalities can target a reasonable volume of tissue. By contrast, injections of nonreplicating virus into the prostate cannot be hoped to have significantly more activity than in the immediate microenvironment. Furthermore, if nonreplicating viruses are used, repeated injections may be required, which is not necessarily a pleasant prospect for patients.
The authors correctly conclude that gene therapy approaches are less likely to work in patients with overtly metastatic disease. It is not entirely clear that the reasonably restricted metastatic pattern involving the lymph nodes and lungs would be of a particular benefit in designing gene therapy, until the mechanism of these tropisms (eg, the overexpression of specific adhesion molecules) are better understood.
The authors' final note of caution regarding the overselling of expectations about these early clinical trials cannot be overstated. Particularly for gene therapy trials that exploit immunologic manipulations, it is likely that large randomized phase III adjuvant trials with lengthy follow-up will be required before any conclusions can be made about the utility of such an approach. Although the concept of gene therapy may be topical and splashy, this approach is clearly in its infancy, and it is unlikely that anything other than safety data will be derived from the early activated phase I trials.
Since it is indeed true that prostate cancer patients frequently perceive that they have few, if any, alternatives, every effort should be made to guard against promoting unrealistic expectations about these trials. On the other hand, the explosion in understanding of the molecular basis for the development and progression of prostate carcinoma makes the prospect of molecular medicine or gene therapy both a realistic and important goal to pursue.