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Anti-Plgf, A Potent And Safe Antiangiogenic Strategy In Combination With Anthracyclines For Breast Cancer
Investigator Initiated Research
Background: Breast cancer is the fifth most common cause of cancer death and the leading cause of cancer mortality in women. The chance of developing invasive breast cancer at some time in a woman's life is about 1 over 8. Doxorubicin is an anthracycline agent widely used in chemotherapy in the clinical treatment of a broad range of malignancies including breast cancer. However, its clinical use is limited by a cumulative dose-related cardiotoxicity leading to dilated cardiomyopathy and heart failure in cancer patients. More recently, clinical trials showed that antiangiogenic agents prolong the survival of patients with breast cancer but do not provide a long-term cure and, importantly, enhance the doxorubicin-associated cardiotoxicity.
Rationale and hypothesis: Anti-angiogenic approaches focus on the inhibition of VEGF/VEGFR-2 signaling. Unfortunately, the same signaling regulates tumor angiogenesis but is also essential for vessel formation during embryogenesis and blood vessel homeostasis in physiological conditions. In contrast, plancental growth factor (PlGF), a homologue of VEGF, is redundant for vascular development and maintenance, but is important during aberrant angiogenesis, such as in cancer. Thus, PlGF inhibitors, unlike VEGF inhibitors, might represent a novel strategy to struggle breast cancer and metastasis, without aggravating anthracycline-induced cardiomyopathy.
Recent achievements and aim of the proposal: We have recently shown that a neutralizing anti-PlGF monoclonal antibody, which blocks the binding of PlGF to its receptor VEGFR-1, efficiently inhibits growth and metastasis of several tumors without affecting healthy vessels. Purpose of this project is to validate the therapeutic potential and safety profile of anti-PlGF when administered alone or in combination with cardiotoxic anthracyclines in the treatment of breast cancer.
Study design: The efficacy of anti-PlGF in inhibiting tumor growth and metastasis will be evaluated and compared to anti-VEGF(R) antibodies in several orthotopic breast cancer models. We will also assess whether anti-PlGF enhances the effect of doxorubicin treatment on tumor progression and metastatic cancer cell spreading. Finally, we will evaluate the cardiotoxicity of anti-PlGF in comparison to the effects of anti-VEGF(R) antibodies when administered with doxorubicin.
Breast cancer is the leading cause of cancer mortality in women and the most common cancer among women worldwide and its incidence has increased alarmingly over the past decades. Cancer tissue, like all of the functioning parts of the body, must receive a regular supply of blood to survive and grow. The growth of vessels (known as angiogenesis) into the tumor is regulated by a cohort of angiogenic molecules that generate the vascular network that allows the cancer to grow. Antiangiogenesis therapy is therefore considered as a promising new cancer treatment. Vascular endothelial growth factor (VEGF) is one of the major players in angiogenesis. Bevacizumab, an antibody that prevents VEGF from binding to its receptor on the cell membrane via which VEGF gives instructions to the cell, became the first antiangiogenesis drug to be approved for treating cancer. While it appears to help people live longer, bevacizumab is not expected to be a cure. Furthermore, VEGF is widely expressed and plays a role in a number of physiologic pathways ongoing in healthy organs like the heart. Consequently, the combination of VEGF antibodies with the cardiotoxic chemetherapeutic drug doxorubicin (widely used in the clinical treatment of breast cancer) results life-threatening. In contrast, another angiogenic growth factor, placental growth factor (PlGF) acts primarily in diseased or inflamed tissue but is not needed for physiologic pathways in healthy tissue, and thus might represent an alternative, safer target for antiangiogenesis therapy. Several independent laboratories have discovered that PlGF indeed plays a role in cancer angiogenesis and growth. We have developed an antibody against PlGF that has demonstrated therapeutic activity in cancer growth and metastasis inhibition. We propose in this grant to assess the therapeutic potential of anti-PlGF in different breast tumor models. We will analyze tumor growth, angiogenesis and metastasis, and will study the effect of blocking PlGF alone or in combination with doxorubicin, in comparison with blocking VEGF. In addition we will investigate the safety of anti-PlGF treatment and evaluate whether or not it induces life threatening cardiotoxic effects as VEGF inhibitors when administered in combination with doxorubicin.