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The
Malignant Milieu - “No Man is an Island” (August 2004)
...and no malignant
cell arises alone (apology to poet John Dunne, 1684). Although
historically the major focus in prostate cancer biogenesis has been on
the endocrine effect of testosterone, histologically identifiable
“cancer” is spawned in a sea of endocrine, paracrine, and autocrine
influences, and is in active reciprocal cross talk with its host
speaking the language of growth factors and cytokines. A hook into this
all encompassing subject is provided by two studies that illustrate the
clinical usefulness of synthetic somatostatin analogs that bind their
receptors, which are abundant in prostate cells, benign and malignant.
Somatostatin (SST), itself a naturally secreted neuropeptide, functions
as a regulator and inhibitor of many cellular processes. “Somatostatin
inhibits cell secretion and prevents cell proliferation by inducing cell
cycle arrest and apoptosis. These effects are thought to be directly
mediated by SST receptors on tumor cells and indirectly on non-tumor
cell targets, which inhibit the secretion of tumors and growth factors
involved in promoting tumor growth (Hansson). By binding its receptors
in the hypothalamus SST downregulates the secretion of growth hormone,
another proliferative influence on malignant cells.
After biochemical
failure from first line androgen deprivation, chemotherapy is commonly
the next therapeutic choice. However, a group of Greek researchers
reported (Urology, Jan, 2004) a head to head comparison of chemotherapy
(estramustine/Etoposide) with a somatostatin analog in 40 HRPC patients
in whom AD was continued.
Somatulane, given
intramuscularly every 14 days, was combined with a decreasing dose of
dexamethasone tapered to 1 mg/day. The inhibition of pituitary derived
growth hormone by the SST analogs effectively suppresses the liver’s
production of the important prostate cancer stimulating action of
insulin-like growth factor-1 (IGF-1).
The outcome of the two
treatments was equivalent and both produced a > 50% decrease in PSA of
44-45%; a similar time to progression in the PSA responders in both arms
of about 8 months; objective responses in 29-30% of men; and a median
overall survival in both arms from protocol entry of 18 months. A
clearer test of the somatostatin analog’s individual contribution would
have a trial schema which added Decadron to the chemotherapy arm, since
the corticosteroid alone in a HRPC setting has produced PSA decreased of
> 50% in up to 50% of subjects for a disease control of 4-6 months. But
the lessor hematologic toxicity, alopecia, and nausea and vomiting in
the Somatulane arm makes it appealing.
Further support for
prostate cancer suppression by somatotropin analogs comes from a Tulane
study (The Prostate 56:pp.183-191,2003) in which the analog, Vapreotide,
given alone at the time of relapse from AD suppression produced clinical
improvement in 8 of 13 patients with 6 showing a 71% fall in PSA.
Supporting basic science studies revealed that “52 out of 80 surgical
specimens of prostate cancer (65%) displayed specific binding sites for
Vapreotide.”
There are five
different types of somatostatin receptors on prostate cells, and
research is ongoing in an effort to develop somatostatin analogs of
greater affinity and specificity to improve the anti-cancer performance
of SST analogs.
The second part of this
discussion links SST with an analysis of prostatic neuroendocrine cells
(NE), which exert a paracrine stimulation of nearby prostate cancer
cells, and in the metastatic setting stimulate osteoblasts. Somatostatin
analogs function to blunt these adverse relationships. An excellent
review of this topic is “Somatostatin receptors: from basic science to
clinical approach...”, by Mosca (Digestive and Liver Disease 36(Suppl 1)
2004).
NE cells are found in
PIN and in all stages of PC. At diagnosis preexisting focal NE cells are
present in 30-50% of prostate cancer specimens. NE cells are
non-proliferating, and androgen receptor negative, and do not secrete
PSA. As pointed up by Dr. Larry True in a January 2004 Journal of
Urology editorial, the NE cells are vigorous exporters of a wide variety
of growth factors and cytokines, the most relevant for this article
being the VEGF (angiogenesis promotion), transforming growth
factor-alpha (promoter of tumor proliferation), bombesin (an inducer of
tumor invasiveness), and survivin (an anti-apoptotic protein). These
“factors stimulate the growth and progression of histologically
conventional cancers.” ( Dr. True) It’s important to note that “in an
androgen depleted environment, malignant epithelial prostate cells are
induced toward NE differentiation, and “hormone-refractory” PCs show
increased NE differentiation over time with disease progression. ...
Tumors displaying NE phenotype tend to be more aggressive and resistant
to hormone-therapy.” (Mosca) Chromogranin A (CgA) is a major secretory
product of NE cells and studies have shown significant increases in the
serum values for CgA 24 months after castration, and to a lessor extent
after Casodex therapy. This transition to NE phenotype is especially
prominent in bone mestatases where NE cell paracrine factors promote
osteoblastic lesions.
The goal for the
therapeutic use of SSTs is the development of analogs of high affinity
and specificity to effectively inhibit the adverse effects of NE cell
derived stimulation of prostate cancer growth. Mosca concludes: “The
concept that paracrine factors secreted by NE cells could exert effects
on surrounding non-NE cells of PC provide a rationale for the use of
somatostatin analogs to counteract these effects.”
[An excellent review of
this topic is “Neuroendocrine Differentiation in Prostatic Carcinoma”,
Jens Hansson, Lund University, Scand J Urol Nephrol 37 (Suppl 212):
28-36, 2003]
Bottom Line:
Malignant cells are supported and promoted by cross-talk with their
host, and effective therapy requires an interruption of this subversive
conversation.
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