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Endothelin A: "Its biology - an
emerging target of PCa intervention." (October 2002)
The remarkable biologic fact about normal cells is that
without sufficient survival stimuli from their surroundings - usually in
the form of "growth factors" - cells execute their death program and die,
that is, undergo apoptosis. Much current biotechnology is focused on
exploiting this mechanism in abnormal cells (i.e. cancer cells) by
attempting to interrupt signaling via the cellular receptors for these
growth factors. "Atrasentan", under development by Abbott (see "Protocol"
next section) is a promising drug directed at blocking the Endothelin A
receptors on prostate cancer cells. There is good science to support this
approach.
Multiple studies illustrate the basis for optimism that an Endothelin A
receptor antagonist (Atrasentan) will limit the progression of metastatic
prostate cancer.
Carducci (Journal of Clinical Oncology 20:(8);2171-2180,2002) explained
that there is a family of Endothelin growth factors, ET-1,-2,and -3. ET-1
is of principle interest because it strongly stimulates the cellular ET(A)
receptors on prostate cells thereby promoting cell proliferation,
angiogenesis, bone remodeling, and preventing apoptosis. ET-1 was first
discovered as a secretion of endothelial cells circulating in plasma where
it functioned as a potent vasoconstrictor. However, more importantly, ET-1
is also produced by prostate epithelial cells (normal and neoplastic) and
stimulates both the cells producing it and also their neighbors. Plasma
ET-1 levels increase in metastatic PC. Interestingly, the cellular
expression of the ET-(A) receptor increases in an environment of low
testosterone, thereby suggesting usefulness of the ET(A) blocker
Atrasentan in association with androgen deprivation therapy.
In an editorial in "The Prostate", Vol.49:91-92,2001, Nelson emphasizes
the action of Atrasentan in combating bone metastases. Atrasentan reduces
the markers of bone metabolism by silencing the signaling via the ET(A)
receptor. Since osteoclasts exhibit ET(A) receptors, Atrasentan, by
blocking the receptor, can inhibit the osteoclasts' role in destroying
bone and thereby reduce the development or slow the progression of bone
metastases. In a study comparing Atrasentan treated patients to those
receiving a placebo the Atrasentan treated patients maintained their
baseline values (elevated at baseline, as expected) for alkaline and acid
phosphatase and N-telopeptides (markers of bone osteolysis) whereas the
placebo group showed a dramatic increase in these biomarkers of bone
metabolism. A clinical benefit of Atrasentan was less pain from metastatic
disease in bone. The editorial conclusion was that Atrasentan limited the
progression of metastatic disease in bone.
In the ASCO Abstract #12 (2001) Nelson presented the data showing the
inhibition of skeletal metastasis in hormone refractory prostate cancer
patients, and in #694 Carducci presented the data from a study of 244
evaluable men with hormone refractory PC showing the increase in median
time to both PSA progression and clinical disease progression.
In ASCO Abstract #708 ( May '02) Carducci updated (to June '01) the Phase
II data to show a median survival of 583 days for Atrasentan treated
patients versus 478 days for placebo patients, and a 196 day versus 129
day median time to clinical progression favoring the patients treated with
10 mg oral Atrasentan. However, as any pharmaceutical company knows... the
"proof of the pudding is in the eating", and therefore we await of results
of the Phase III studies underway (see below).
Bottom Line: The Endothelin A receptor antagonist Atrasenten shows promise
in Phase II studies in limiting the progression of metastatic PC.
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