Honing in on Tumors with Angiogenesis Inhibitors
Researchers at the University of California, San Francisco (UCSF) and Harvard University (Cambridge, MA) report that four angiogenesis inhibitors have been shown for the first time to be effective at treating spontaneous tumors at distinct stages of progression. The study, published in the April 30 issue of Science, provides evidence that angiogenesis inhibitors can act against tumors in a mouse model believed to be a good model for tumor development in humans. It also provides the first indication that angiogenesis inhibitors vary in their efficacy depending on the stage of cancer targeted. The model could provide a platform for exploring the potential of these and other angiogenesis inhibitors, or combinations of inhibitors, for not just treatment of cancer, but also for prevention, the researchers said.
The model used in this study is a transgenic mouse that expresses a viral oncogene in pancreatic islet cells. In this mouse, new, spontaneous pancreatic tumors continuously emerge, providing a spectrum of disease progression, which enabled the researchers to target different stages cancer cells. (Three to four weeks elapse before cells expressing an oncogene develop the capability to form solid tumors with invasive, or malignant, properties.)
The researchers examined the efficacy of four compounds, AGM-1470, BB-94, angiostatin, and endostatin, and a combination of angiostatin and endostatin. The goal of the first stage of the trial was to prevent the angiogenic switch in cells prior to the initial formation of solid tumors; in the second, to intervene in the rapid expansion of small tumors; and in the third, to cause regression of large, end-stage cancers.
In the precancerous lesions, BB-94, endostatin, angiostatin, and the combination of angiostatin and endostatin prevented activation of the angiogenic switch in over half of the lesions that otherwise would have turned on the switch. In the second stage, the intervention trial, all four drugs were efficacious, impairing tumor growth from 60% to 88%. (The combination drug was not tested.) In the regression trial, AGM-1470 and the combination of endostatin and angiostatin each produced significant tumor regression in mice with substantial tumors, in contrast to endostatin or angiostatin alone, or BB-94. The former drugs reduced tumor volume by around 60% (compared to tumor volume at the starting point of the trial) and by around 72% (compared to untreated mice at end-stage disease).
"We've shown that these drugs have beneficial effects when used to treat mice developing organ-specific cancer in which tumors arise from premalignant lesions in their natural tissue microenvironment, representing an important extension of the evidence for efficacy of angiogenesis inhibition in cancer," said the senior author of the study, Douglas Hanahan, a professor of biochemistry at UCSF.
None of the agents completely prevented the angiogenic switch in the precancerous stage, or blocked the growth of small tumors, or completely resolved lethal tumor burden. The fact that the treated mice still had cancer is not surprising, the researchers said, for two reasons. First, the time course of the trials was limited by design and by limited availability of the experimental drugs. Second, there was a relentless emergence and progression of new spontaneous pancreatic tumors due to the characteristics of the model, wherein tumor development is set in motion by an oncogene in virtually all of the 500,000 pancreatic islet ß cells.
The ultimate question, of course, the researchers emphasized, is whether the drugs will have similar effects in humans, and the answer is presently unknown.
The study was conducted as part of the ongoing collaboration of the Hanahan laboratory at UCSF and that of Judah Folkman, at Children's Hospital Medical Center and Harvard Medical School.
For more information: Douglas Hanahan, Professor of Biochemistry, Box 0534, UCSF, San Francisco, CA 94143-0534. Tel: 415-476-9209 or 415-476-4661. Fax: 415-731-3612.