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Capoxigem® (apricoxib, TG01)
Capoxigem is a once-daily oral, potent and selective inhibitor
of COX-2 for the treatment of cancer. Tragara licensed Capoxigem
from Sankyo Pharmaceuticals in January 2007. Tragara is currently
evaluating Capoxigem in several phase II studies, testing
for efficacy improvement in NSCLC (two studies) and pancreatic
cancer when used in combination with standard-of-care chemotherapy
or targeted therapy.
The roles of COX-2 and PGE2 in carcinogenesis have been described
pre-clinically, but little success in identifying the clinical
utility of a COX-2 inhibitor in oncology has been made until
recently. Pharmacia Corporation embarked on a battery of phase
II and III studies in the early 2000’s adding celecoxib
to a variety of standard treatment regimens for several tumor
types. Overall, these studies showed little benefit in adding
celecoxib to regimens without selecting for patients who might
benefit from celecoxib, or conversely, selecting out patients
who had a low probability of benefit. Upon Pfizer, Inc.’s
acquisition of Pharmacia, oncology work with celecoxib from
the company perspective was terminated. Analyses of several
of these studies demonstrated that patients with active COX-2
systems in their tumors (defined as either (i) increased COX-2
expression in tumors measured using IHC or (ii) patients who,
in response to treatment with a COX-2 inhibitor, had major
decreases in their urinary metabolite of PGE2 known as PGEM)
had longer survival versus patients who did not. Tragara initiated
strategic development of its proprietary COX-2 inhibitor,
Capoxigem, based on these patient selection results.
Mechanistic Rationale for Inhibiting COX-2 in Cancer
Treatment
The COX pathway has been implicated in carcinogenesis since
the 1970s when increased concentrations of prostaglandins
were detected in neoplastic tissues, especially colon cancer.
COX-2 is consistently overexpressed in a large percentage
and variety of human tumors. The presence of elevated COX-2
in tumor tissue represents a poor prognostic factor in a number
of cancers, including NSCLC and pancreatic cancer. Multiple
lines of evidence using genetic manipulation that either increased
or decreased COX-2 expression in cell lines and xenograft
models have confirmed the growth or inhibition of tumors in
the presence of up- or down-regulated COX-2, respectively.
COX-2 inhibitors, including Capoxigem, have been shown to
inhibit proliferation, induce apoptosis, stimulate the immune
system and down-regulate angiogenesis. PGE2, formed from arachidonic
acid by COX-2, impacts a number of pathways known to be involved
in carcinogenesis including cell cycle regulation, apoptosis,
metastasis and angiogenesis. PGE2 is thought to mediate some
of its tumor promoting activities via induction of epithelial-mesenchymal
transition (EMT). EMT is a developmental program that has
evolved to provide the plasticity of cellular fate required
for embryonic development. In solid tumors, epithelial tumor
cells that undergo EMT acquire anchorage-independent growth
capability and invasive characteristics that support growth
and survival of the primary tumor and metastatic spread to
secondary sites. Capoxigem reverses EMT in vitro and in vivo,
resulting in a multipronged effect on tumor promotion.
There is also a strong rationale for using COX-2 inhibitors
in combination therapies. COX-2 inhibitors have been shown
to prevent (i) chemotherapy-induced upregulation of COX-2
and thus PGE2 expression, and (ii) chemoresistance through
down-regulation of anti-apoptosis pathways including NF-?B
and Akt, and up-regulation of death receptors. , Use in combination
with targeted agents such as inhibitors of the EGFR family
is supported by the following: (i) EGFR activation upregulates
COX-2 expression, (ii) up-regulation of COX-2 can increase
expression of EGFR ligands , and (iii) COX-2 induces EMT,
which is associated with resistance to EGFR inhibitors. COX-2
upregulation of prostaglandins induces tumor neovascularization
and activates EGFR-mediated VEGF expression. Thus, use in
combination with anti-vascular agents may prove useful.
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