NEW ORLEANSAntiangiogenesis drugs under development may find
their greatest utility in early-stage cancer and in combination with
other agents, Michael S. Gordon, MD, said at a symposium sponsored by
Agouron Pharmaceuticals (La Jolla, Calif). The symposium, Novel
Mechanisms in the Future of Cancer Treatment, was held in
conjunction with the American Society of Clinical Oncologys
36th Annual Meeting.
Dr. Gordon, of the University of Arizona College of Medicine, pointed
out that the focus with antiangiogenesis agents is really not
an issue of larger vessels present in tumors. We are focusing on
tumor microvessels that are rapidly proliferating and emerging to
feed and nourish new tumors.
The processes being targeted by such agents are found in wound
healing, embryogenesis, tumor cell invasion, and the development of
overt metastases, he said. Those processes are tightly regulated by
pro- and antiangiogenic factors.
One proposed target for angiogenesis inhibitors is that of prolonging
tumor dormancy. During dormancy, before the appearance of a
macroscopic tumor, angiogenesis and apoptosis are in balance, and
angiogenesis is insufficient for tumor progression.
A further goal would be to take a tumor in a growing proliferative
phase and induce dormancyleading not to cytoreduction but to
stabilization of the tumor and prolonged survival.
Dr. Gordon said that angiogenesis involves three steps:
Dissolution of the basement membrane (allowing extravasation
of tumor cells and sprouting of microvessels from existing small vasculature).
Endothelial cell proliferation and migration (critical to the
formation of new microvessels and microtubules).
Re-establishment of the basement membrane and vascular
In the initial phase, the capillary basement membrane is degraded by
matrix metalloproteinases (MMPs), a family of enzymes also
responsible for the remodeling of bone and soft tissue. The MMPs most
directly involved in angiogenesis are MMP-2 and MMP-9 (gelatinase A
and B, respectively).
This critical role of MMPs in the invasion of tumor cells suggests
that inhibitory agents may impede the development of micrometastases,
Dr. Gordon said.
He pointed out that preclinical single-agent models do not show
significant antitumor responses but, rather, suggest a synergistic
interaction between MMP inhibitors and chemotherapy or radiation
therapy. The outlook for single-agent antiangiogenesis therapy
as a significant cancer therapy is waning, he said.
The effect of MMPs and other agents being developed to influence
vascular endothelial growth factor (VEGF) activity may be limited to
those microvessels with rapidly proliferating cells. They may
not have any effect on tumors that have an established vascular
supply, Dr. Gordon said.
The viable strategy may be, therefore, to reduce tumor load with
standard chemotherapy agents or radiation therapy and inhibit
regrowth of the vascular endothelial component through
antiangio-genesis agents. The ideal result would be disappearance of
the tumor and the recapturing of tumor dormancy, he said.
Therapies combining angiogenic agents with chemotherapy or radiation
therapyor combining several angiogenic agentshold promise
for results superior to those obtainable with any of the components alone.
Agouron Pharmaceuticals investigational MMP inhibitor
prinomastat (AG3340) is currently being evaluated in several phase II
trials, primarily in patients with early-stage disease, and in one
phase III study of stage IIIB non-small-cell lung cancer (NSCLC).
Two phase III trials in advanced NSCLC and hormone-refractory
prostate cancer were recently discontinued because preliminary
results did not meet primary efficacy objectives.
Phase II trials are also in progress in newly diagnosed glioblastoma
multi-forme, locally advanced esophageal cancer, and metastatic
The agent is administered orally twice daily. Results from
preclinical research in animal models are promising, according to
Agouron, indicating that prinomastat inhibits angiogenesis and
reduces the growth of primary tumors and the number and size of metastases.