In cancer fight, antiangiogenesis drugs still in play
Researchers at a recent cancer symposium reported encouraging
results with several approaches designed to prevent tumors from growing
or induce them to destroy themselves.
The Dec. 7, 2002 symposium, sponsored by the University of California
at San Francisco, singled out anti-angiogenesis drugs as promising
and was highlighted by a public appearance by Judah Folkman, MD,
the pioneer in such research. Other presentations focused on telomerase
inhibitors and viruses designed to stimulate apoptosis in tumors.
The "old way" of treating cancer—chemotherapy, surgery,
radiation, or all three—selects patients by broadly defined
disease, notes Margaret Tempero, MD, deputy director of the UCSF
Comprehensive Cancer Center and chief of medical oncology in the
Department of Medicine. The "new way" will focus on molecular profiles,
such as the overexpression of HER2 in some breast cancers.
Although "we can’t count on miracle drugs," there should be continued
improvement in treatment with new biologic agents, ever-earlier
detection, and narrowly targeted therapies, she says. "Incurable
cancers will become a chronic disease" that can be kept in check.
Dr. Folkman, the Julia Dyckman Andrus professor of pediatric surgery
and cell biology at Harvard Medical School, and Gabriele Bergers,
PhD, assistant professor in the UCSF Department of Neurosurgery,
summarized developments in anti-angiogenesis research, which targets
new blood vessels that solid tumors need to grow.
The positive regulators of angiogenesis include growth factors
such as VEGF, FGF, PDGF, and EGF. Several drugs work against VEGF,
including Genentech’s Avastin, AstraZeneca’s Iressa, and Sugen’s
SU 11248 and SU 5416. Drugs that block EGF include Iressa, another
Genentech drug Tarceva, and ImClone’s Erbitux.
Since tumors appear to add growth factors as they enlarge, "you
need to add these indirect anti-angiogenic drugs together" in later-stage
cancers, Dr. Folkman says. For example, in women with advanced breast
cancer, "the tumors are making up to six angiogenic factors," he
says. So if a patient is treated with an angiogenesis inhibitor
that targets only one angiogenic factor, it would be important to
select patients whose tumor makes that factor.
Direct inhibitors of angiogenesis are also under study, including
COX-2 inhibitors such as Celebrex, which is already marketed for
arthritis. The COX-2 inhibitors "increase serum levels of endostatin,"
which has a protective effect against solid tumors, Dr. Folkman
says. Five angiogenesis inhibitors are being studied, he says, "and
they’re not as likely to develop resistance" as the indirect inhibitors.
Although anti-angiogenesis so far has not yielded stunning results,
Dr. Folkman is hopeful. "Certain improvements in medical practices
are just beginning to emerge," he says. He describes two instances
in which experimental anti-angiogenesis therapy helped patients
A few months ago at the Dana Farber Cancer Institute, a 47-year-old
woman with von Hippel-Lindau disease, which causes hemangioblastomas
in the eye and brain, was treated with an anti-VEGF drug, SU 5146.
The patient had already lost one eye to the tumor and had since
become legally blind in the other eye. But treatment with the drug
caused her eyesight to return within four weeks and the tumor vessels
to stop leaking. Von Hippel-Lindau tumors produce only VEGF, which
makes them simpler to treat than many cancers.
In another case, researchers at Massachusetts General Hospital
reported disappearance of tumors in eight patients treated with
interferon alpha for cancer of the jawbone that produces FGF. The
eight patients had previously failed surgery and radiation therapy.
The many types of angiogenesis inhibitors will give physicians
an array of choices and could be added to other types of cancer
therapies, says Dr. Folkman. "There are many ways we can go."
Dr. Bergers presented data showing that two distinctive vascular
cell types—endothelial and perivascular cells—are functionally
important and targetable with inhibitors of receptor tyrosine kinase
signaling. Many angiogenic inhibitors are more efficacious in early-stage
cancers, she notes. For example, 95 percent of early-stage mouse
pancreatic tumors could be blocked by the anti-angiogenic drug SU5416,
an inhibitor of VEGF receptor signaling. However, combinatorial
efficacy against otherwise intractable late-stage islet carcinomas
is observed when VEGF receptors on endothelial cells and PDGF receptors
on perivascular cells are targeted together in tumors, resulting
in stabilization and regression of end-stage disease. This supports
the notion that cocktails can improve efficacy, says Dr. Bergers.
The drugs can block the switch from a small to a large tumor,
but "they don’t regress end-stage disease," she says, agreeing with
Dr. Folkman that patients with advanced cancer may require a number
of anti-angiogenesis drugs.
In other presentations:
David B. Karpf, MD, executive medical director
of oncology at Geron Corp. and voluntary clinical associate professor
of medicine at Stanford University, detailed research into telomeres,
the "molecular clock" that counts cell division. As telomeres
shorten in cells, apoptosis—or programmed cell death—occurs.
Virtually all cancer cells express telomerase, which maintains
the telomeres, rendering the cells immortal and possibly contributing
to their resistance to radiation and chemotherapy.
"If you can target telomerase in cancer cells, you could induce
apoptosis," Dr. Karpf says. Such a drug would also conceivably
be quite safe because most normal cells don’t produce telomerase
(it’s only expressed constitutively in the developing embryo).
At Geron, Dr. Karpf is leading the development of a direct
enzymatic inhibitor of telomerase, GRN 163, as an anticancer
agent. Early studies show it has activity against at least 19
cancer cell lines and demonstrates a lack of cytotoxicity in
normal cells. He presented in vivo data demonstrating anti-tumor
efficacy in mice bearing tumors due to glioblastoma, prostate
cancer, lymphoma, myeloma, and cervical cancer. In rats with
glioblastoma tumors in their brains that were treated with a
short infusion of GRN 163, five of seven animals were alive
after day 116 and showed no evidence of tumors, whereas four
of four control animals were dead by day 43.
Frank McCormick, PhD, director of UCSF’s Comprehensive
Cancer Center and Cancer Research Institute, described early clinical
trials with a cytolytic virus that infects and kills cancer cells
directly, an altered adenovirus called Onyx 015. "We can make
viruses that depend on defects in the cancer cells and don’t harm
normal cells," he says.
Onyx 015 interrupts a pathway that is defective in tumors.
About 60 percent of all tumors suppress p53, which leads to
apoptosis. The adenovirus "provokes p53 and forces the cell
into suicide," he says. A second protein then binds to p53 and
degrades it. "The virus will kill the [cancer] cell and replicate
in similar cells, but it shouldn’t grow in normal cells," because
the same pathway is not present, Dr. McCormick explains.
In phase II trials involving direct injection into head and
neck tumors, Onyx 015, combined with cisplatin, resulted in
23 percent of patients having a complete response and 60 percent
seeing their tumor shrink by at least half. The cytolytic virus
is also being tested against metastatic colon cancer, pancreatic
cancer, and oral leukoplakia.
"Onyx 015 has been safe and well tolerated," Dr. McCormick
adds. Side effects are flu-like symptoms and high temperature.
Heat shock is needed to drive the virus from cell nuclei, where
it can get stuck, into the cytoplasm. "We raise the patient’s
temperature about two degrees or we give drugs that provoke
heat shock," he says.
The symposium, titled "War on Cancer: Where Are We Now?" was
offered by UCSF’s Department of Biochemistry and Biophysics
and its Hillblom Center for the Biology of Aging.
Karen Southwick is a writer in San Francisco.