Blood markers can help choose best dose for antiangiogenic drugs

Scientists at Sunnybrook have new information that may help to improve the use of anti-cancer drugs designed to block the growth of new blood vessels in tumors, a process called angiogenesis that is critical to tumor growth.

While these antiangiogenic drugs are effective, at present there are no reliable methods for determining whether they are working, if the right dose is used, or if a patient will benefit (or not) from treatment.

A team led by Dr. Robert Kerbel - a senior scientist in Molecular and Cellular Biology at Sunnybrook and Canada Research Chair - has just published a paper in the October issue of the Proceedings of the National Academy of Sciences which may help to answer these questions. “In the clinic, patients receiving these antiangiogenic drugs have a number of blood plasma proteins that rise and fall after treatment, so it is speculated that they could be used as surrogate biomarkers to tell us about drug activity and efficacy - our studies in mice show that this is correct”, says Dr. Kerbel. In the study, Kerbel's team found that drug-induced molecular changes observed in mice occurred at the same doses that had the best anti-tumor effect, suggesting that monitoring these changes in patients could predict the optimal dose of drug.

Surprisingly, the team also uncovered some unexpected insight into the nature of these observations. “The current hypothesis to explain these drug-induced molecular changes is that they are tumor dependent, possibly because blocking blood flow would starve tumors of oxygen, which in turn would cause tumors to produce more proteins to recruit new vessels”, says John Ebos, a doctoral student in Medical Biophysics at the University of Toronto and lead author of the study. “However, our study shows that the same molecular changes occur in normal mice, that have no tumors, and come from multiple organs - suggesting that these changes come mainly from the body not the disease”.

The study also found that, in addition to the molecular changes observed in the clinic, there were many other proteins that were also elevated after treatment. Ironically, many of these have been shown to have angiogenesis promoting properties and Kerbel's team is now investigating the possible implications of these findings. “The fact that these molecular changes occur independent of the tumor and involve many proteins that are unrelated to the drug activity, could explain why they have not been useful so far as predictors of patient benefit. They could also contribute to some of the observed drug associated toxicities seen with these drugs, play a role in drug resistance, and even may explain some recent observations where tumors rapidly regrow in some patients when therapy is stopped, using antiangiogenic drugs” says Dr. Kerbel, who is also a professor in the Departments of Medical Biophysics and Laboratory Medicine/Pathobiology at University of Toronto. “We are testing these hypotheses now”.

In the study, the research team used a class of drugs designed to block the activation of receptors (known as “receptor tyrosine kinase inhibitors”, or RTKIs) activated by an important regulator of angiogenesis called vascular endothelial growth factor (VEGF). The drug they used is called sunitinib which is used for the treatment of kidney cancer, and is now being evaluated for its effects on many other types of cancer. Dr. Kerbel's results have led to collaborations between his team and several medical oncologists leading clinical trials at Sunnybrook's Odette Cancer Centre involving late stage kidney cancer and early stage breast cancer therapy with the aim to determine if these preclinical findings are observed in patients, and if so, how the results might be exploited in the future to improve the benefits of antiangiogenic drugs for cancer treatment. This is a major goal of the Toronto Angiogenesis Research Centre established at Sunnybrook with the support of an infrastructure grant from the Canadian Foundation for Innovation (CFI).