Robert S. Kerbel, PhD [ View bio ] (University of Toronto)
As of 2013 a total of six different VEGF- pathway targeting antiangiogenic drugs, including an antibody (bevacizumab), a fusion protein trap (aflibercept) and four oral tyrosine kinase inhibitors (sunitinib, sorafenib, pazopanib and axitinib) have been approved for the treatment of 10 different types of cancer. This represents a major development and achievement in medical oncology. Nevertheless there are concerns regarding the mostly limited survival benefits brought about by such drugs or drug-based therapies in the metastatic treatment setting (which is similar to many other targeted therapies), in addition to the failures thus far observed in the adjuvant treatment setting, and the repeated failures of many different TKIs to enhance the efficacy of different standard chemotherapy regimens in multiple indications – in contrast to bevacizumab or aflibercept.
Numerous strategies are currently underway to improve the overall clinical benefits of antiangiogenic drugs. These include the discovery and validation of predictive markers, understanding the basis of innate and acquired resistance, modifying dose or schedule, and identification of new targets for angiogenesis inhibition that complement VEGF pathway inhibition. Another strategy is based on improvement of preclinical mouse tumor therapy models to more reliably predict clinical activity. Models being developed include patient derived xenografts (PDXs) and genetically engineered mouse models (GEMMs). A third approach - one which we have been undertaking - consists of the development of postsurgical models of both early (microscopic) and late stage overt metastatic disease using established human tumor cell lines. Using this approach, we recently reported that neither sunitinib, pazopanib or an antibody that targets VEGF receptor 2 (called DC101) weekly had any therapeutic impact when used as monotherapy to treat advanced visceral metastatic breast cancer (using a variant of the triple negative breast cancer cell line known as MDA MB 231 called LM2.4). In contrast, these drugs were active when treating established primary orthotopic tumors - as has been shown repeatedly by other investigators using this kind of primary tumor therapy model. The combination of sunitinib with standard paclitaxel chemotherapy did not improve outcomes in the metastatic setting either, whereas the combination of DC101 and paclitaxel chemotherapy, did induce a modest survival benefit. These preclinical results using the metastatic model approach largely reflected negative outcomes of multiple prior phase III clinical trials of sunitinib given alone, or in combination with chemotherapy, for the treatment of metastatic breast cancer patients. They also reflected the modest, but nevertheless significant benefit previously reported using bevacizumab with weekly paclitaxel chemotherapy for the first line treatment of metastatic breast cancer. A question we are now studying in detail is the reason why metastases respond so weakly, if at all, to the antiangiogenic therapies, in contrast to the same tumor grown as a localized primary tumor mass, with the research emphasis being on the possible contribution of either major qualitative changes in the nature of the tumor neovasculature or the impact of what is known as vessel co-option.
A second approach we have been studying for over a decade to improve the impact of antiangiogenic drugs is by combining them with what is known as low-dose continuous metronomic chemotherapy. A number of studies, not only from our lab but also by others, have shown potent antitumor effects can be achieved pre-clinically with minimal associated toxicity, when using this type of combination strategy, even when treating postsurgical advanced metastatic disease. Of particular interest as well in this regard is that such effects can also be achieved not only by using antibodies, but also oral TKIs in combination with various metronomic chemotherapy regimens. Such a treatment strategy may be particularly useful in the maintenance setting after upfront induction using standard chemotherapy regimens, using metronomic chemotherapy either alone or in combination with an agent such as bevacizumab. A number of phase III clinical trials evaluating metronomic chemotherapy alone or in combination with an antiangiogenic agent such as bevacizumab have now been completed, and the results should be reported in the near future.
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