Why targeted cancer therapies have not hit the ‘bull’s-eye’

Editor’s Note:  This story, originally published in 2005, has been updated.

Melissa Marino, Ph.D.
Published: July, 2005

Mace Rothenberg, M.D.
Photo by Anne Rayner
An informal search of medical news Web sites on any given day will typically return dozens of reports on the discovery of a new cancer-related gene, yet between 2000 and 2005 only five new agents were approved for the treatment of cancer.

With so many new molecular and genetic targets being identified, why is the pace of cancer drug development so slow?

Leading researchers believe current design and analysis of clinical trials may contribute.

In a 2003 review in Nature Reviews Cancer, Vanderbilt cancer researchers Mace Rothenberg, M.D., David Carbone, M.D., Ph.D., and David Johnson, M.D., identified factors that may be prematurely sending some potentially useful cancer drugs to an early grave.

From a large volume of pre-clinical studies, compounds that inhibited angiogenesis, the formation of new blood vessels, appeared to be the “dawn of a new era” in cancer therapy, describes Rothenberg, professor of Medicine and Ingram Professor of Cancer Research.

Laboratory studies suggested that angiogenesis inhibitors alone could be used to cure cancer. Because blood vessel formation was one of the decisive factors in tumor growth, researchers thought that inhibiting this process would kill tumors by robbing them of their blood supply. Also, angiogenesis inhibitors were thought to be much less toxic than standard chemotherapeutics.

When the first angiogenesis inhibitor trials began, an ensuing hysteria—in the form of enrollment “lotteries” and patients traveling cross-country to participate—followed. The frenzied expectation surrounding these drugs soon diminished as the evidence began coming in from the clinical trials. When used alone, the first generation of angiogenesis inhibitors were not clinically effective.

These “failures” forced scientists to rethink their strategy. The tide shifted to testing angiogenesis inhibitors as an adjunct to conventional cytotoxic therapies and to developing better angiogenesis inhibitors. This strategy proved much more effective, leading to the approval of the first angiogenesis inhibitor, Avastin, in 2004.

“Animal/preclinical models have been very useful in helping us explore the biology of cancer, but we have very few useful models that have been developed that recapitulate the complexity of human cancers in the clinical setting,” Rothenberg explains.

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