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

Abstract

Summary 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.

Vascular Normalization by Loss of Siah2 Results in Increased Chemotherapeutic Efficacy

“…8 PyMT-WT tumor-bearing wild-type (WT) mice and 8 PyMT-Siah2 À/À tumor-bearing Siah2 À/À mice with tumor volumes of 525 mm 3 were injected with 5 mg/kg doxorubicin 3 hours before sacrifice. Doxorubicin concentration in tumors was measured fluorimetrically using an adaptation of the method described previously (27).…”

“…Mice were tail vein injected twice weekly for 4 weeks with the indicated doses when tumors reached 65 mm 3 . Animal weight and tumor dimensions were assessed as described above.…”

“…Animal weight and tumor dimensions were assessed as described above. Animals were culled when tumors reached 525 mm 3 .…”

“…Early work showed that VEGF-specific antibodies reduced tumor growth and angiogenesis in 3 cancer models (2). Bevacizumab (Avastin), a neutralizing humanized monoclonal antibody against VEGF, and VEGF receptor (VEGFR) inhibitors including sunitinib (Sutent) and sorafenib (Nexavar), are approved treatments for several cancers (3). VEGF and VEGFR inhibition transforms the morphology of tumor blood vessel from tortuous and leaky to pericyte covered and elongated (1).…”

Noteworthy clinical case studies in cancer gene therapy: Tumor-targeted Rexin-G advances as an efficacious anti-cancer agent

“…Worse yet, is the finding that failure to staunch the growth of metastatic pancreatic cancer can often lead to the development of even more dangerous and aggressive forms of the disease, which is concomitant with the development of chemotherapy-resistance (29,30). Likewise, with so-called targeted biologics directed against simplistic receptor-mediated mechanisms: not only is there little or no therapeutic benefit to the pancreatic cancer patient (31)(32)(33), but there is the substantial evidence to suggest that there are combined toxicities (34,35), and even rebound in disease progression (36,37), which sheds new light on the issues of comparative safety.…”