Stem Cells, Vol. 17, No. 4, 237-240,
July 1999
© 1999 AlphaMed Press
New Drugs on the Horizon: Matrix Metalloproteinase Inhibitors
Mace L. Rothenberg,
Amy R. Nelson,
Kenneth R. Hande
Vanderbilt University Medical Center, Division of Medical Oncology, Department of Medicine, and the Nashville Veterans Affairs Medical Center, Nashville, Tennessee, USA
Dr. Mace L. Rothenberg, Vanderbilt University Medical Center, Division of Medical Oncology, Department of Medicine, 1956 The Vanderbilt Clinic, Nashville, Tennessee 37232-5536, USA.
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INTRODUCTION
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Matrix metalloproteinases (MMPs) are a family of enzymes involved
in a number of normal cellular processes, such as regulation of
endometrial growth and menstruation, and abnormal processes, such as
tumor growth, invasion, and metastasis [1]. There are now 18 distinct enzymes that fall
into three functional classifications based on their substrate target:
collagenases which degrade fibrillar collagen;
gelatinases which degrade denatured and basement membrane
collagens, and stromelysins which degrade proteoglycans and
glycoproteins. The MMPs can also be separated into five categories
based on structural and functional similarities [2, 3].
There are several observations that associate MMPs with tumor
progression and metastasis:
- The number of different types of MMPs that can be detected in
a tumor tends to increase with the progression of the cancer.
- The relative level of individual MMPs tends to increase with
increasing tumor stage.
- Transfection of selected MMPs into cancer cells can increase
the generation of distant metastases in vivo.
- Inactivation of these same enzymes reduces the production of
tumor metastases.
MMPs are considered to be key enzymes involved in angiogenesis,
since degradation of basement membrane and stromal tissue is an
essential process for migration of endothelial cells needed to form
new blood vessels. They are also critical for the entry and exit of
tumor cells into existing blood vessels that are necessary for
metastasis. For these reasons, the MMPs represent an attractive
therapeutic target.
Matrix metalloproteinases may be produced by the tumor cells
themselves or by surrounding stromal cells when stimulated by nearby
tumor cells [4]. These
enzymes are tightly regulated through gene expression and secretion in
an inactive, pro-enzyme form that must be cleaved to become
active. The function of MMPs is further controlled by local
concentrations of specific inhibitors known as tissue inhibitors of
metalloproteinases (TIMPs).
Over the past five years, matrix metalloproteinase inhibitors
(MMPIs) have undergone rapid clinical development. Since MMPIs target
enzymes that are more essential to tumor invasion and metastasis than
to growth of the primary tumor, standard phase II clinical trial
endpoints such as objective tumor response rate are not likely to
accurately reflect the true clinical impact of the MMPIs. Indeed, in
preclinical studies, tumor growth delay and reduction in metastasis
formation, rather than tumor shrinkage, have been the main
findings. This pattern has carried over into human trials, as well,
where very few objective responses have been reported with
single-agent trials of MMPIs. This presents a formidable challenge in
their clinical development and evaluation. One approach has been to
proceed from phase I directly to phase III trials, where overall
survival and time to tumor progression for patients treated with MMPIs
or MMPI-containing chemotherapy regimens could be compared directly to
that achieved with patients treated with placebo or placebo-containing
chemotherapy regimens. Another approach has been to look at surrogate
endpoints, such as tumor marker levels or change in the rate of rise
of tumor markers pre- and post-treatment with an MMPI. Another
challenge has been to define criteria for identification of the doses
that should be used for phase II and III trials of each MMPI. Dose
escalation to the maximum tolerated dose may not be appropriate for
agents which may induce optimal inhibition of target MMPs, such as
MMP-2 and MMP-9, and relative sparing of MMP-1. There are now three
MMPIs undergoing phase III
evaluation.
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Batimastat
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Batimastat (BB-94), a hydroxamic acid derivative that mimics the
peptide structure of natural substrates, was the first matrix
metalloproteinase inhibitor to enter clinical testing. Reports of the
initial phase I trials began to appear in 1994 [5]. Because of poor solubility, batimastat
could not be administered orally and was limited to direct injection
into the pleural space or the abdomen to control fluid
accumulation. Preliminary reports estimated that up to 47% of patients
experienced a slowing in the reaccumulation of fluid and a reduction
in the need for thoracentesis or paracentesis following treatment with
batimastat [5]. Phase III
trials were initiated, but closed soon afterward due to slow accrual,
local tissue reaction (peritonitis) and the development of an orally
bioavailable analog of
batimastat.
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Marimastat
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Marimastat (BB-2516) is another hydroxamic acid analog that is
structurally similar to batimastat. Unlike batimastat, however,
marimastat is extensively absorbed following oral administration and
has a long plasma half-life of 8-10 hours [6, 7]. The most common toxicity has been a
syndrome of musculoskeletal pain and stiffness, often starting in the
small joints of the hands and progressing to the arms and shoulders,
mainly at tendon-insertion points. This toxicity occurs after three to
five months in approximately 30% of patients treated with doses of 10
mg bid [8]. A one- to
three-week drug "holiday" is sufficient for resolution of
this toxicity, and most patients are able to continue treatment at a
lower dosage.
The data from early clinical trials of marimastat are difficult to
interpret for several reasons: A) most trials have been reported in
abstract form only; B) most trials were conducted as combination phase
I/II studies and the results reported primarily in terms of activity
across all or a selected range of doses; C) clinical activity has been
reported primarily in terms of change in the rate of rise of tumor
markers pre- and post-treatment, an endpoint with unclear clinical
implications, and D) mechanisms underlying the principle toxicity of
marimastat—joint pain and stiffness—and measures to
prevent or to minimize this toxicity are poorly
understood.
Phase I/II trials performed with marimastat have demonstrated a
significant impact in reducing the rate of rise in the tumor markers
of a variety of malignancies, such as CEA (colorectal cancer), CA 19-9
(pancreatic cancer), CA-125 (ovarian cancer) and PSA (prostate cancer)
[8-12]. Marimastat appears to reduce the rate of
rise of these markers in a dose-dependent fashion. Patients
experiencing such a reduction tended to survive for longer periods of
time than those who did not [8, 13]. Accrual to a phase III trial comparing
marimastat to gemcitabine in patients with advanced pancreatic cancer
has been completed, as has a second phase III trial in which the
combination of marimastat plus gemcitabine was compared to gemcitabine
in the same group of patients. The results of these trials should
become available within the next one to two years. Phase III trials
have also been completed in patients with extensive-stage small cell
lung cancer and glioblastoma multiforme. Phase III trials are ongoing
in patients with non-small cell lung cancer and gastric cancer. A
phase I study of marimastat plus carboplatin has been performed in
patients with ovarian cancer who had previously responded to a
platinum-based regimen [14]. Marimastat, in doses of 5-20 mg bid, was
administered concurrently with six cycles of carboplatin (AUC=6). The
spectrum and severity of toxicities were no different than what would
be expected from each drug administered as a single agent. Marimastat
had to be interrupted in 9 of 20 patients due to musculoskeletal
toxicities. Seven were able to restart marimastat after the
break. Eight of 25 assessable patients attained objective responses,
including three patients with complete responses. Based on these data,
a randomized, double-blind, placebo-controlled study has been
initiated in women with platinum-sensitive, relapsed ovarian
cancer.
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AG3340
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AG3340 is a hydroxamic acid derivative that was synthesized based
on knowledge obtained from the x-ray crystallographic structure of
selected MMPs. As a result, it is more selective for certain MMPs
(e.g., MMP-2, 3, 9 and 13) that are felt to be involved in tumor
invasion and metastasis and less potent against MMP-1, which is
believed to be associated with the primary toxicity of this class of
agents, arthralgia. A phase I trial of AG3340 given twice daily on a
continuous basis until tumor progression has recently been completed
[15]. Although no
dose-limiting toxicities were noted in the first four weeks of
treatment at doses from 10-100 mg bid, delayed-onset joint-related
complaints involving the shoulders, knees and hands occurred in a
dose- and time-dependent manner, necessitating treatment interruption
for two to four weeks. Plasma exposure of AG3340 at the lower dose
levels is similar to the optimal plasma profile obtained in mice which
resulted in nearly continuous inhibition of targeted MMPs and only
transient inhibition of MMP-1.
In an attempt to develop a strategy for integrating MMPIs into the
treatment of hormone-refractory prostate cancer, Wilding and
colleagues have performed a phase I trial in which AG3340 was combined
with mitoxantrone and prednisone [16]. AG3340 was administered twice a day at
doses of 5 and 25 mg. No significant pharmacological interactions were
noted with this combination and no additional or unexpected toxicities
were observed with this combination. This strategy has now been taken
directly into phase III in which men with hormone-refractory prostate
cancer are treated with mitoxantrone plus prednisone plus placebo or
AG3340. A similar design is being used in patients with Stage IV
non-small cell lung cancer, in which patients are randomized to
carboplatin plus paclitaxel plus placebo or AG3340. Primary endpoints
in both trials include overall survival and time to tumor
progression.
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BAY 12-9566
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BAY 12-9566 is a butanoic acid analog and is, therefore,
structurally distinct from other MMPIs. BAY 12-9566 has a very long
terminal plasma half-life (90-100 hours), but also has an extremely
high plasma protein binding fraction (>99.99%). Four phase I trials
have been conducted, all using a daily dosing schedule [17]. Initial schedules called for
treatment on a daily basis for four out of every five weeks. When this
appeared to be quite tolerable, the schedule was changed to continuous
administration until disease progression. Doses from 100 mg qd to 800
mg bid have been evaluated. The primary toxicities observed have been
mild to moderate thrombocytopenia, liver enzyme and bilirubin
elevations (especially in patients with compromised hematopoietic or
liver reserve) and nausea [18-20]. Interestingly, no drug-related arthralgias
have been reported, suggesting that the unique structure of BAY
12-9566 may confer a certain degree of enzyme specificity that the
hydroxamic acid derivatives do not. Although no objective responses
have been observed in phase I trials of BAY 12-9566, the median time
to tumor progression has been four months, which is relatively long
for a phase I trial. An attempt to measure the effect of BAY 12-9566
on surrogate endpoints in one phase I trial failed to discern a change
in plasma vascular endothelial growth factor, basic fibroblast growth
factor, or urinary pyridinoline or deoxypridinoline crosslink levels
[21].
Phase I trials evaluating the tolerability and pharmacokinetic
interaction between BAY 12-9566 and doxorubicin and 5-FU plus
leucovorin are under way. Phase III trials have also been initiated in
four diseases. In patients with small cell lung cancer, Stage IIIA and
IIIB non-small cell lung cancer, and ovarian cancer, patients are
randomized to placebo or BAY 12-9566 after attaining best response to
standard front-line therapy. In patients with advanced pancreatic
cancer, patients are being randomized to front-line therapy consisting
of either BAY 12-9566 or
gemcitabine.
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CGS27023A
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CGS27023A is the latest entry into the matrix metalloproteinase
inhibitor field. A single phase I trial has been reported with this
compound [22]. Doses
from 150 mg bid to 600 mg tid were explored. Two main toxicities were
observed: a widespread, self-limiting maculopapular rash at doses of
300 mg bid or higher, and mild to moderate arthralgias and myalgias
which did not appear to be
dose-related.
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Summary
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The implication of matrix metalloproteinases in processes critical
to tumor invasion, angiogenesis, and metastasis and the great
therapeutic potential of agents capable of inhibiting tumor
progression through this novel mechanism have prompted the aggressive
and rapid clinical development of a new class of agents known as
matrix metalloproteinase inhibitors. There are currently four MMPIs in
clinical development (three of which are in phase III) and several
others poised to enter clinical development within the year. The
agents are all orally administered, making them suitable for chronic
administration which appears to be necessary for optimal effect. Some
are relatively non-specific inhibitors of MMPs (such as marimastat),
while others are more selective (AG3340 and BAY 12-9566). It is not
yet known which strategy will yield superior clinical results, but it
is becoming apparent that this selectivity (or lack of it) may be
responsible for the pattern of clinical toxicity that has been
observed in early clinical trials.
Three main strategies have been pursued in phase III trials: A)
comparing the activity of single-agent MMPI to the best known standard
therapy (e.g., marimastat versus gemcitabine in pancreatic cancer); B)
combining the MMPI with cytotoxic chemotherapy and comparing it to
cytotoxic chemotherapy alone (e.g., paclitaxel plus carboplatin plus
AG3340 or placebo in non-small cell lung cancer), or C) comparing MMPI
to placebo in patients who have completed cytotoxic chemotherapy and
have achieved their best clinical response (e.g., BAY 12-9566 versus
placebo in patients with small cell lung cancer who have completed
planned induction therapy). Appropriately, the primary endpoint for
all of these phase III trials is survival, with disease- or
progression-free survival as an important secondary endpoint. The
results from these trials are eagerly awaited and will determine
whether inhibition of matrix metalloproteinases can translate into
clinically meaningful effects.
Reprinted from The Oncologist
1998;3:271-274.
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Introduction
Batimastat