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In cancer fight, antiangiogenesis drugs still in play

February 2003
Karen Southwick

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 dramatically.

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.