Download Apoptosis: Translating Theory to Therapy for Prostate Cancer

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)
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(20)
(21)
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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
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