Folkman and O’Reilly also tried to translate laboratory gains into
clinical advances. When word got out about their successes with mice,
expectations soared, and newspaper stories predicted a cure for cancer
within years. But clinical trials of endostatin and angiostatin, begun
in 1999 and 2000, respectively, did not live up to the hype.
Though both drugs proved nontoxic to humans, their
tumors didn’t show the dramatic regression seen in mice. One reason
may have been the nature of the trials, says O’Reilly, now assistant
professor of radiation oncology at Houston’s M.D. Anderson Cancer
Center. “The mouse tumors increased in size before the inhibitors
could overcome the angiogenic stimulators,” he says. “Used
alone in patients with advanced cancer, the drugs may not have been able
to get over that initial delay.” Patients died before tumors had
a chance to shrink.
The age of antiangiogenic cancer treatments now seems
to be in full swing. New Avastin trials involving patients with advanced
breast, kidney, lung and colorectal cancer continue to produce dramatic
results. In a Phase III lung cancer trial, though median survival rates
have increased by only two months, some patients are alive after two years,
living with a disease that kills most victims within 10 months. About
50 other antiangiogenic drugs are in trials or under development.
For now, Avastin and some other angiogenesis inhibitors
are more effective when used in conjunction with lower-than-normal doses
of chemotherapy. Rakesh K. Jain, director of the Edwin L. Steele Laboratory
of Tumor Biology at the Massachusetts General Hospital and professor of
tumor biology at Harvard Medical School, believes Avastin may convert
a tumor’s chaotic vascular tree into more normal blood vessels and
reduce fluid pressure inside the tumor, thus providing a more efficient
conduit for the chemotherapy.
Meanwhile, a report presented at an American Society
of Clinical Oncology meeting in spring 2005 detailed a Chinese study in
which 493 people with non-small-cell lung cancer received chemotherapy
plus a Chinese formulation of endostatin called Endostar. “Although
it wasn’t clear how advanced the lung cancer was, the reported doubling
of survival rates is very impressive,” says O’Reilly. “We
need to expand on that trial and see if the data are as robust as they
seem.”
Combinations of drugs, including those pegged for
diseases other than cancer, are also proving able to thwart angiogenesis. “Many
molecules do the job quite efficiently,” says Kieran. “It’s
almost a game now, to discover that yet another drug we’ve used
for years has an antiangiogenic effect.”
In a Phase I trial begun in June 2001, Kieran combined
the arthritis drug Celebrex with thalidomide, the notorious anti-nausea
treatment that caused birth defects during the 1950s. Though he worried
that most of the participants, 20 children with terminal cancer, might
die before the end of the planned six-month trial, he instead faced a
very different problem—forcing unwilling patients to stop taking
the drugs after two years because of concerns about long-term toxicity.
Tumor growth stabilized in 40% of the patients; one
in six saw tumors shrink by at least half. Many patients regrew their
hair and regained lost weight, and five were still alive three years later.
A Phase II trial under way at 15 medical institutions will test which
tumor types respond best to this therapy.
Yet as excited as most cancer experts now are about
the potential of antiangiogenic treatments, they are also realistic. Most
tumors can make at least four stimulators of angiogenesis, and Avastin,
the best drug available, targets just one—VEGF. Moreover, tumors
that start out making only VEGF can eventually begin to overproduce other
angiogenic growth factors as they progress to late-stage disease. (Broad-spectrum
angiogenesis inhibitors are in development, but have not yet received
FDA approval.)
“Tumors develop a lot of bypass mechanisms to survive, and my concern
is that eventually they may grow through Avastin,” as they have
done with other drugs, says LoRusso. “There are too many different
kinds of cancer with too many different pathways and alternative mechanisms
they can turn on to think that one drug will be a magic bullet,” she
adds.
Moreover, Avastin’s extreme expense could discourage some physicians
and their patients from using it. A year’s treatment for colon cancer
costs about $50,000, according to Genentech, and the higher doses recommended
for patients with lung or breast cancer come with proportionately steeper
price tags. Even with insurance coverage, patients may face copayments
of $10,000 to $20,000 annually. |
