HOUSTONRemember the enthusiastic reports in the popular press
that antiangiogenic therapy would provide a quick cancer cure by
starving tumors of their blood supply? Lee Ellis, MD, quoted H. L.
Mencken in describing the aftermath of those reports: All
complex problems have simple answers that are invariably wrong.
Speaking at a clinical investigators workshop, Dr. Ellis noted,
however, that newer work, particularly that directed at vascular
endothelial growth factor (VEGF), has opened several promising new
veins of research. The workshop was sponsored by Pharmacia Oncology
and the University of Texas M. D. Anderson Cancer Center, where Dr.
Ellis is Associate Professor of Surgery and Cancer Biology.
Understanding biology is the basis of developing effective
therapies, Dr. Ellis said. The tumor and normal host
tissues can both contribute to angiogenesis. Research into the
process of neovascularization suggests four potential antiangiogenic
strategies directed either at angiogenic factors or at endothelial
cell survival factors:
- Decrease the activity of angiogenic factors.
- Decrease the activity of endothelial cell survival factors.
- Increase the activity of naturally occurring antiangiogenic agents
by endogenous or exogenous means.
- Indirectly down-regulate the activity of angiogenic/survival factors.
VEGF emerged as a target because it is associated with progression
and poor prognosis in several tumor types, including colon, breast,
prostate, central nervous system, gastric, hepatocellular, ovarian,
and melanoma. Dr. Ellis described two anti-VEGF approaches:
antibodies to VEGFR2, and tyrosine kinase inhibitors to VEGFR2.
The monoclonal antibody DC101 has been associated with decreased
angiogenesis, a lower proliferative index of tumor cells, an increase
in apoptosis, and a decrease in tumor blood vessel counts. Similar
effects have been seen with the tyrosine kinase inhibitors SU5416 and SU6668.
This raised the question of whether endothelial cell apoptosis
precedes tumor cell apoptosis. Research into this question showed
that a wave of endothelial cell apoptosis precedes a wave of tumor
cell apoptosis [following anti-VEGF treatment], Dr. Ellis
stated. VEGF is a survival factor for tumor endothelium, and
anti-VEGF treatment induces tumor endothelial cell apoptosis [in
Anti-VEGF treatment has been associated with increased survival in
mice with metastatic colorectal cancer, but not with cures. This may
be the result of redundancy in survival factors for tumor
endothelium and in angiogenic factors in tumors and host
cells, Dr. Ellis noted.
Low-dose Metronomic Therapy
Conventional chemotherapeutic agents are also being studied as
antiangiogenic therapy in the form of low-dose metronomic
therapy. The principle is that continuous low-dose chemotherapy
will damage vasculature and not allow time for endothelial cell
repair, Dr. Ellis explained, referring to work done by
laboratories headed by Judah Folkman, MD, of Harvard Medical School,
Cambridge, Massachusetts, and Robert S. Kerbel, PhD, of Sunnybrook
Health Science Center, Toronto, Canada.
Dr. Ellis described one promising recent study reported by Dr. Kerbel
and colleagues in the April 15, 2000, issue of the Journal of
Clinical Investigation. That study combined low-dose vincristine
(Oncovin) with an anti-VEGFR2 antibody, on the premise that
vincristine would damage the endothelium and the antibody would
block the survival of the endo-thelial cells. Dr. Ellis said that
tumor regression sustained to 210 days had been observed in animal
models with this combination.
Clinical use is likely to require more carefully tailored agents,
however. Tumor endothelium is phenotypically distinct,
Dr. Ellis said, and each tumor has its own angiogenic zip
code, using a term coined by Erkki Ruoslahti, MD, PhD,
President and CEO of the Burnham Institute in LaJolla, California.
For example, Dr. Ellis continued, VEGF expression
is higher in the primary tumor than in liver metastases, and tumors
with low VEGF may not respond as well to anti-VEGF treatment.
He added that optimal antiangiogenic therapy would require knowledge
of the angiogenic profile of individual tumors.
An additional concern is the potential for side effects from
anti-angiogenesis drugs. Dr. Ellis pointed out that the heart and the
central nervous system both use angiogenesis as part of their normal
repair mechanisms and could be adversely affected by broad blocking
or inhibition of this process.