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EDITORIAL Apoptosis: Translating Theory to Therapy for Prostate Cancer John T. Isaacs Lance Armstrong’s recent success as an athlete and as a cancer survivor has documented vividly that, by the appropriate focusing of mind, energy, and resources, goals can be achieved that only a few years ago appeared unrealistic. In Armstrong’s case, testicular cancer that had metastasized throughout his body was eliminated by effective chemotherapy. This is not an isolated case; presently, more than 80% of men with metastatic testicular cancer are curable with aggressive therapy (1). These results clearly validate that metastatic cancer does not have to be a death sentence, if effective systemic therapy is available. In stark contrast to these inspirational results, this year 34 000 men will die in the United States of metastatic prostate cancer despite the use of androgen ablation therapy (2). Metastatic prostate cancers are lethal because they are heterogeneously composed of both androgen-dependent and androgen-independent malignant cells (3–6). In androgen-dependent prostate cancer cells, a critical level of androgen is required to bind and thus activate a sufficient number of androgen receptors (ARs) as repressors of the constitutive transcription of specific “deathsignaling” genes (7). If this repression is not maintained, for example after androgen ablation therapy, the expression of these death-signaling genes triggers the biochemical cascade involved in apoptotic death of these dependent cells (8,9). In contrast, androgen ablation does not induce the apoptotic death of androgen-independent cells (10). It is the continuing survival and proliferation of these androgen-independent prostate cancer cells that eventually kills, no matter how complete the androgen ablation within the prostate cancer patient (11). Presently, there are a series of excellent strategies for development of effective therapy based on a growing understanding of how these devastating prostate cancer cells acquire androgen independence. There are multiple mechanisms for such acquisition. One mechanism is that molecular changes (e.g., mutation, loss of heterozygosity, and hypermethylation) occur in these cells, and these changes prevent the transcription of deathsignaling genes after androgen ablation. In this issue of Journal, Chang et al. (12) present data to support such a mechanism. These authors identified a gene, termed “GC79,” that apparently functions as such a deathsignaling gene. GC79 encodes a complex multitype zinc-finger protein with specific domains that suggest that it functions as a transcription factor. Chang et al. document that the expression of GC79 is repressed in normal rat prostate but that its prostatic expression is greatly enhanced after androgen ablation. These authors further demonstrate that constitutive expression of this GC79 gene is repressed in an androgen-regulated manner in an androgen-responsive prostate cancer subline but that it is not expressed regardless of the level of androgen in an androgenindependent prostate cancer subline. Although the authors do not provide a mechanistic explanation for this constitutive loss of GC79 expression, these results highlight that lack of increased transcription of death-signaling genes can be one mechanism for the inability to trigger the apoptotic pathway in androgenindependent prostate cancer cells after androgen ablation. The androgen-independent prostate cancer subline used in the study by Chang et al. (12) (i.e., LNCaP) is not universally resistant to induction of apoptosis but is resistant to apoptosis induced by androgen ablation. These cells can be induced to undergo apoptosis by a variety of agents that initiate the apoptotic cascade distal to the point regulated by AR in androgendependent prostate cancer cells (13–16). Unfortunately, however, by initiating the apoptotic cascade downstream, there is essentially no therapeutic index for the cytotoxic response induced by these agents between prostate cancer and proliferating normal gut, skin, and blood cells (17). This lack of cancer specificity leads to host toxicity, which limits both the dose and total length of treatment with such nontargeted cytotoxic agents. There are methods for selectively targeting the apoptotic death of androgen-independent prostate cancer cells induced by these agents, however, without inducing such death in normal host cells. Several of these agents are under preclinical development [e.g., prostate-specific antigen-activated prodrugs (18) and targeted antiangiogenic agents (19)], and several are in early clinical trials [targeted gene therapy based on prostate-specific promoters to drive expression of lytic virus (20) and targeted gene therapy to selectively activate the immune system (21)]. Other mechanisms are also possible for the acquisition of androgen independence by prostate cancer cells. For example, mutation in the AR steroid-binding domain can allow other nonandrogenic steroids (e.g., glucocorticoids, progestins, and estrogens) as well as antiandrogens to bind and activate the mutant AR, even when the level of systemic androgen is fully suppressed (22). Resistance to androgen ablation also can involve “cross-talk” between the AR and other signaling pathways that are induced by peptide growth factors. This “cross-talk” allows ligand (i.e., androgen)-independent AR activation and/or repression of transcription of specific genes by costimulation of pathways involving protein kinase A or various MAP kinases (mitogen-activated protein kinases), activated by specific peptide growth factor receptors (23–25). Therapies targeted either at inhibiting the MAP kinases or at decreasing the AR expression (26) within prostate cancer cells could be effective treatment for Affiliations of author: Division of Experimental Therapeutics, The Johns Hopkins Oncology Center, and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD. Correspondence to: John T. Isaacs, Ph.D., Division of Experimental Therapeutics, The Johns Hopkins Oncology Center, Bunting-Blaustein Bldg., 1M44, 1650 Orleans St., Baltimore, MD 21231-1001. See “Notes” following “References.” © Oxford University Press Journal of the National Cancer Institute, Vol. 92, No. 17, September 6, 2000 EDITORIAL 1367 androgen-independent prostate cancer cells and are under preclinical development. A fourth mechanism is that androgen ablation can result in the transcription of death-signaling genes but apoptosis is not induced because the cells have undergone molecular changes that result in constitutive expression of genes that inhibit downstream steps in the apoptotic cascade. There are a series of such downstream apoptosis-suppressing genes that are expressed by prostate cancer cells. These genes include inhibitors of apoptosis (IAP) (27), survivin (28), and bcl-2 (29). The use of either antisense (30) or gene (31) therapy to inhibit the expression of these antiapoptosis genes to restore androgen dependence of these malignant cells is being explored in preclinical studies. A fifth mechanism can involve molecular changes within prostate cancer cells, converting a normally redundant, androgen-independent signal transduction pathway into one that is uniquely required for survival. For example, androgenindependent prostate cancer cells acquire the ability to synthesize and secrete various neurotrophin ligands and to express their cognate trk receptors (32). This results in an autocrine survival pathway that is initiated by the binding of these neurotrophins to their cell surface cognate trk receptors inducing their dimerization, trans-autophosphorylation, and downstream initiation of a variety of kinase-dependent cell survival-signaling cascades (32). Unlike normal cells, including those of the prostate, where survival is regulated by a redundant series of signal transduction pathways, malignant prostatic cells are uniquely “addicted” to this neurotrophin/trk signaling for their survival (33,34). Small molecules that inhibit the tyrosine kinase of the trk receptors induce apoptosis of androgen-independent prostate cancer cells (33,34). These trk inhibitors are presently entering clinical trials in patients for whom androgen ablation therapy has failed. In summary, there are a series of novel, rational approaches to induce the apoptotic elimination of androgen-independent prostate cancer cells that are in various stages of preclinical testing and clinical testing. Based on these leads, the cure of metastatic prostate cancer is a realistic goal. Translating the theory of apoptosis to curative therapy will only happen, however, if appropriate human and material resources are allocated and maintained for a realistic time period. (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) REFERENCES (22) (1) Einhorn LH, Donohue JP. Advanced testicular cancer: update for urologists. J Urol 1998;160:1964–9. (2) Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin 2000;50:7–33. (3) Isaacs JT, Coffey DS. Adaptation versus selection as the mechanism responsible for the relapse of prostatic cancer to androgen ablation therapy as studied in the Dunning R-3327-H adenocarcinoma. Cancer Res 1981;41: 5070–5. (4) Isaacs JT, Wake N, Coffey DS, Sandberg AA. Genetic instability coupled to clonal selection as a mechanism for tumor progression in the Dunning R-3327 rat prostatic adenocarcinoma system. Cancer Res 1982;42: 2353–71. (5) Gingrich JR, Barrios RJ, Kattan MW, Nahm HS, Finegold MJ, Greenberg NM. Androgen-independent prostate cancer progression in the TRAMP model. Cancer Res 1997;57:4687–91. (6) Craft N, Chhor C, Tran C, Belldegrun A, Dekernion J, Witte ON, et al. Evidence for clonal outgrowth of androgen-independent prostate cancer cells from androgen-dependent tumors through a two-step process. Cancer Res 1999;59:5030–6. (7) Denmeade SR, Lin XS, Isaacs JT. 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Sustained in vivo regression of Dunning H rat prostate cancers treated with combinations of androgen ablation and Trk tyrosine kinase inhibitors, CEP751 (KT-6587) or CEP-701 (KT-5555). Cancer Res 1999;59:2395–401. NOTES Editor’s note: Dr. Isaacs is conducting research sponsored by Cephalon, Inc. (West Chester, PA), and TAP Pharmaceuticals (Deerfield, IL). He is a paid consultant for both companies. The Johns Hopkins University in accordance with its conflict-of-interest policies is managing the terms of this agreement. Supported by Public Health Service grant 2P50CA5823607 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Journal of the National Cancer Institute, Vol. 92, No. 17, September 6, 2000 EDITORIAL 1369