The Complexities of Inhibiting Angiogenesis Emerge

Donald M. McDonald, MD, PhD

During the past 40 years, the concept of thwarting a tumor by attacking its blood supply has become a central thrust of cancer research, a strategy that reached a milestone with the approval of bevacizumab in 2004.

Now, scientists are delving more deeply into the complexities of antiangiogenic approaches, paying particular attention to the processes that can be unleashed in the aftermath and exploring dual inhibition strategies.

Donald M. McDonald, MD, PhD, a professor in the Department of Anatomy and an investigator in the Cardiovascular Research Institute at the University of California, San Francisco Comprehensive Cancer Center, said inhibitors that block vascular endothelial growth factor (VEGF) can result in complex effects on tumor cells that promote the spread of cancer (see Table).

“There are competing actions here in response to treatment that cancel each other out,” McDonald said during his presentation. “There are multiple worlds of angiogenesis and angiogenic inhibitors.”

McDonald said blocking VEGF does inhibit angiogenesis, often causing tumor vessels to regress within a few days. It also prunes or reduces tumor blood vessels, resulting in vessel normalization. The vessels left behind are different, however.

Vascular pruning can foster intratumoral hypoxia, which in turn activates hypoxia inducible factor 1 alfa (HIF-1a) and pathways involving hepatocyte growth factor (HGF) and its receptor c-Met, as well as epithelial-mesenchymal transition (EMT)—processes that researchers have linked to invasive and metastatic tumors.

“It’s important to realize that these inhibitors can make tumors smaller, so it’s not the growth that is the problem,” McDonald said in an interview. “It’s what they do in addition, which is invasion and spreading. So tumor size is not a very useful measure of tumor aggressiveness.

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It’s important to realize that these inhibitors can make tumors smaller, so it’s not the growth that is the problem. It’s what they do in addition, which is invasion and spreading. So tumor size is not a very useful measure of tumor aggressiveness. ”

—Donald M. McDonald, MD, PhD

“The underlying mechanism is that the angiogenesis inhibitors, by pruning the blood vessels in tumors, cause intratumoral hypoxia by cutting off the blood supply in some regions,” he explained. “These changes activate systems that can promote invasion to metastasis from the tumor.”

He added this caveat: “The important thing at this stage, though, is that these observations are from preclinical models, and it’s still unclear as to how they are generalized and applied to human cancer.”

A Look at Approved Angiogenesis Inhibitors

The Angiogenesis Foundation in Cambridge, Massachusetts, counts more than a dozen anticancer therapies with antiangiogenic properties that the FDA has approved for use in oncology, with bevacizumab the only drug indicated for breast cancer.

McDonald defines the therapies more narrowly, focusing on 3 approved drugs:

• Bevacizumab (Avastin), a humanized monoclonal antibody approved for the treatment of 5 cancer types, including the controversial breast cancer indication that remains on the label pending a final ruling by the FDA commissioner
• Sorafenib (Nexavar), a tyrosine kinase inhibitor (TKI) approved for renal cell carcinoma (RCC) and unresectable hepatocellular carcinoma
• Sunitinib (Sutent), also a TKI approved for RCC, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors

Table. Changes in Tumor Blood Vessels

Tumor cell effects

Favorable

Unfavorable

Angiogenesisinhibition

Growth stops

Growth continuesHypoxia increases

Vessel pruning

Tumor cells die

Hypoxia > select forEMT > invasion

Vesselnormalization

Better drug delivery

Better blood flowFaster growth

Inhibiting angiogenesis to attack tumors remains a viable strategy, even though the approach has not been as widely successful as researchers believed after the concept was introduced in the early 1970s, McDonald said.

“The sky was the limit at the beginning, with the assumption that angiogenesis inhibitors could stop the growth of tumors and potentially maintain them in a dormant state or an ungrowing state,” McDonald said. “And that has been found not to be universally true.

“They provide clear benefit in several types of cancer; that’s the question proven in very broad trials,” he said.

McDonald added, however, that angiogenesis inhibitors “still have limitations in some types of cancer, breast cancer being an example, and how to overcome those limitations is really the next step.”

Dual Inhibition Strategies Explored

McDonald has focused his research on the role of the c-Met pathway in promoting the movement of tumor cells to lymph nodes.

“Upregulation of c-Met in tumor cells can contribute to lymph node metastasis by promoting a more aggressive tumor cell phenotype and growth of lymphatics around or within tumors,” McDonald said.

While these developments are damaging, they do present a potential strategy for attack. “Pharmacological inhibitors of c-Met can decrease tumor invasiveness and lymph node metastasis.”

McDonald said several agents that block c-Met are under investigation for use in a dual inhibitor approach, either as combination therapy or as a single agent that functions in 2 pathways. These include:

• PF-04217903, an investigational agent that inhibits c-Met that Pfizer has made available to researchers
• Crizotinib, an oral inhibitor of c-Met as well as ALK (also developed by Pfizer) that the FDA recently approved for the treatment for non—small cell lung cancer
• Cabozantinib, formerly known as XL184, a TKI that targets both c-Met and 3 forms of VEGF receptors that Exelixis is investigating for multiple tumor types, including breast cancer

“The combination of the angiogenic inhibitors with agents that block tumor invasiveness is, I think, the next generation,” McDonald said.