National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
April 21, 2009 • Volume 6 / Number 8

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Studies Suggest Unintended Consequences of Angiogenesis Inhibition

During tumor angiogenesis, cancerous tumor cells release molecules that send signals to surrounding normal host tissue. This signaling activates certain genes in the host tissue that, in turn, make proteins to encourage the growth of new blood vessels. During tumor angiogenesis, cancerous tumor cells release molecules that send signals to surrounding normal host tissue. This signaling activates certain genes in the host tissue that, in turn, make proteins to encourage the growth of new blood vessels. (Artwork by Jeanne Kelly® 2002)

Angiogenesis inhibitors, drugs thought to work by attacking a tumor’s vasculature, are following a familiar pattern. Having proven that alone or in combination with chemotherapy they can modestly improve progression-free and/or overall survival in patients with several forms of advanced cancer, their investigational use is expanding. Several are now being tested as adjuvant (after surgery) and neoadjuvant (before surgery) therapy in clinical trials involving patients with earlier stage disease.

The first efficacy results from a phase III trial using adjuvant bevacizumab (Avastin), an angiogenesis inhibitor that targets the growth factor VEGF, are expected some time this year. The trial, the National Surgical Adjuvant Breast and Bowel Project’s C-08 trial, enrolled patients with stage II and III colorectal cancer.

While the oncology community anxiously awaits the results, animal model studies published last month have further intensified interest in the trial. Angiogenesis inhibition did indeed shrink tumors in the animal models. But after the initial response, the tumors often returned with increased aggression, were far more likely to metastasize, and in some cases decreased survival.

The fact that tumors are developing resistance to treatment isn’t unexpected, researchers agree. But the findings may require closer scrutiny of how anti-angiogenic agents are tested in patients, argued Dr. Robert Kerbel, a leading angiogenesis researcher at the University of Toronto whose lab conducted one of the animal model studies, because they suggest that rather than eliciting garden-variety resistance to treatment, these agents are radically altering the tumor’s biology.

“If our mouse findings are relevant,” he said, “you can see where one might predict that the outcome of [these] trials might not turn out as well as originally hoped or expected.”

Like Water on an Oil Fire

Other lab and animal model studies have hinted that angiogenesis inhibition could have such untoward effects. But these recent studies appear to provide the most direct evidence.

In the study from Dr. Kerbel’s group, led by Dr. John Ebos and published last month in Cancer Cell, several of the experiments were “crude representations” of neoadjuvant or adjuvant therapy, Dr. Kerbel explained. For example, when sunitinib (Sutent), which inhibits several proteins essential to angiogenesis, was given for a short time before or after the intravenous injection of metastatic breast cancer cells, it accelerated metastasis compared with untreated mice and decreased overall survival.

A second study published in the same issue of Cancer Cell tested several anti-angiogenic approaches in mouse models of glioblastoma and pancreatic cancer. In the pancreatic cancer model, treatment for 1 week with an investigational angiogenesis inhibitor initially shrank tumors. But as treatment continued, the tumors grew, developing “wide fronts of invasion,” stretching out into the surrounding tissue, wrote Dr. Marta Pàez-Ribes, of the Catalan Institute of Oncology in Spain, and her colleagues. The untreated tumors, on the other hand, remained localized and were less invasive.

One intriguing aspect of these studies, explained Dr. Gabriele Bergers of the University of California, San Francisco and a co-author on the Pàez-Ribes paper, is that the tumors are adapting even as the endothelial cells on the vasculature that feeds the tumors are still sensitive to the agents being used to target them.

“The tumors find other ways to reinitiate neovascularization or to grow by becoming more invasive,” she said. “This mechanism is very different and distinct from classical tumor cell resistance, in which tumor cells, for example, do not take up drugs anymore, or else expel them. The evasive adaptation allows the addition of other inhibitors that potentially block these evasive pathways. That is encouraging.”

It’s clear that angiogenesis inhibition elicits a strong response from the tumor and its microenvironment, Dr. Kerbel stressed. It actually increases, for example, levels of VEGF and PIGF-1, another growth factor important to angiogenesis.

“We’ve looked at G-CSF, SDF-1, SCF, and osteopontin, among others,” Dr. Kerbel said. “We looked across the board and saw a lot of these other growth factors and cytokines and chemokines all increasing. But we don’t know why it’s happening.” All of these factors are known, he added, to promote tumor growth.

Although he warns that it’s difficult to extrapolate findings from animal models to humans, Dr. Axel Grothey of the Mayo Clinic, who specializes in gastrointestinal cancers, said these data offer some important lessons.

“It makes us realize how much we still don’t know about tumor biology,” he said.

Implications for Practice?

The ongoing clinical trials of adjuvant and neoadjuvant therapy using anti-angiogenic agents will hopefully shed some light on the issues raised by the animal model work, said Dr. Helen Chen of NCI’s Cancer Therapy Evaluation Program. However, she stressed, it’s important not to have tunnel vision with regard to this subject, noting that some preclinical studies of radiation therapy have showed similar effects on cytokine release and tumor cell behavior.

“This is a phenomenon of the body or the tumor responding to any stress,” she explained. “The nature and magnitude of response as well as the net outcome, however, may vary depending on the specific agents and tumors under study.”

Based on the body of data on anti-angiogenic agents, said NSABP C-08’s lead investigator, Dr. Carmen J. Allegra, of the University of Florida Shands Cancer Center, the new studies don’t have immediate clinical relevance. But, he continued, “they certainly give me reason to rethink how we apply these agents,” particularly “in a potentially curative setting, where it’s possible that the only disease [patients] have is what we see.”

While differences in how the drugs were used complicates the comparison, evidence that the animal model results may not have clinical relevance, at least in the advanced-disease setting, come from the BRiTE study, led by Dr. Grothey. This observational, nonrandomized study of 1,900 patients demonstrated a more than 2-year overall survival associated with the use of bevacizumab. However, in the more than 1,400 patients whose disease progressed while taking bevacizumab as part of first-line therapy, those who remained on bevacizumab even after disease progression had a 52 percent improvement in overall survival compared with patients taken off bevacizumab after their disease progressed. The median survival difference between the groups was nearly 1 year.

Although patients develop resistance to angiogenesis inhibitors, Dr. Grothey said, in patients he has treated he has not seen the type of hyper ‘adaptive response’ reported in the Cancer Cell papers. Even so, he stressed, those studies highlight the importance of not using these drugs off-label outside the confines of a clinical trial.

In the meantime, Dr. Chen added, lab and animal model studies can help investigators choose and prioritize the most potentially efficacious—and safe—therapies to test in combination with anti-angiogenic agents.

“The real challenge,” she said, “is to understand what additional, compensatory pathways are involved and how to hit them in a rational way.”

Carmen Phillips

Update: On April 21, Genentech, which manufactures bevacizumab, announced that the NSABP C-08 trial had failed to meet its preliminary endpoint of improved disease-free survival. The announcement was based on a planned final analysis of the study data, according to a company news release. The complete results of the final analysis have been submitted for presentation at the upcoming American Society of Clinical Oncology annual meeting, which begins on May 29.

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