Issues regarding improving the impact of antiangiogenic drugs for the treatment of breast cancer

Abstract

One of the major recent clinical advances in cancer treatment is the use of antiangiogenic drugs such as bevacizumab, sorafenib, and sunitinib. Bevacizumab, the monoclonal anti-VEGF antibody, has been approved for the first line treatment of metastatic breast cancer (MBC) when combined with taxane. However, the clinical benefits are modest; despite a doubling of response rates and significant prolongation of progression free survival times, no increase in overall survival is attained. This review summarizes some of the possibilities to account for this discrepant result. These include rapid development of acquired drug resistance due to the redundancy of proangiogenic growth factors, acceleration of tumor growth after antiangiogenic drug treatments are stopped, and increases in tumor cell malignant aggressiveness driven by mechanisms such as increased tumor hypoxia. Some possible strategies to improve the benefits of antiangiogenic drug therapy are discussed such as prolonging the treatment beyond tumor progression, combination with other therapeutic modalities, e.g. long term ('maintenance') low-dose metronomic chemotherapy or additional targeted/biologic drugs, e.g. trastuzumab.

Fig. 1

Diagrammatic representation of one proposed mechanism to explain how an antiangiogenic drug may enhance the efficacy of maximum tolerated dose (MTD) chemotherapy. An injection of chemotherapy, e.g. MTD paclitaxel leads to a local tumor response by direct cell kill, and possibly a local (tumor) antiangiogenic effect, as a result of death of dividing endothelial cells in the tumor-associated angiogenic neovasculature (1). However, a systemic host response (2) is also induced comprised in part of a rapid mobilization of various bone marrow-derived cell populations, including circulating endothelial progenitor cells (CEPs), which subsequently migrate to and invade the chemotherapy-treated tumors. These bone marrow colonizing cells accelerate the recovery of the drug treated tumors thus reducing the duration and extent of tumor responses induced by the chemotherapy. However, this systemic CEP response can be blunted by co-treatment with an antiangiogenic drug, e.g. anti-VEGF or anti-VEGFR-2 antibodies, thus optimizing the effect of the chemotherapy treatment. The chemotherapy-induced mobilization of bone marrow-derived cells, including CEPs, is caused, in part, by a rapid induction of growth factors such as SDF-1.

Fig. 2

Schematic representation of one of the ways resistance can develop, in principle, to a targeted antiangiogenic drug in tumors which initially respond to the drug, e.g. anti-VEGF or anti-VEGFR-2 antibody, as exemplified by the results of Casanovas et al. Angiogenesis in untreated tumors (A) is driven mainly, for example, by VEGF; upon treatment with an agent such as an anti-VEGFR-2 antibody (B), some regression of newly formed immature tumor neovasculature (small red circles) occurs, and further angiogenesis is blunted along with reduced perfusion/flow in some remaining vessels, many of which are more mature, pericyte covered vessels (larger red circles with a yellow border to symbolize pericyte coverage) leading to a tumor ‘response’, e.g. a reduction in tumor mass or no new growth (“stable disease”); however, these effects on the tumor vasculature lead to an overall increase in the levels of tumor hypoxia which in turn leads to induction of expression of new hypoxia regulated proangiogenic growth factors, such as bFGF (C); the induction of bFGF induces angiogenesis despite ongoing anti-VEGFR-2 therapy, leading to tumor ‘relapse’, i.e., resumption of angiogenesis and robust expansion of tumor mass (D). Initiation of bFGF(R) directed antiangiogenic therapy at this point could lead to angiogenesis inhibition once again and a tumor response (E). Taken and adapted from Kerbel RS; Therapeutic implications of intrinsic or induced angiogenic growth factor redundancy in tumors revealed.