Inhibition of TF Signaling as a Novel Breast Cancer Therapy

Institution: Scripps Research Institute
Investigator(s): Wolfram Ruf, M.D. -
Award Cycle: 2008 (Cycle 14) Grant #: 14IB-0031 Award: $284,250
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

Initial Award Abstract (2008)

Activation of the blood clotting cascade and the resulting increased risk for thrombosis are well known to cancer patients. The cause of increased clotting tendency is expression of a cell surface receptor, termed tissue factor (TF), by cancer cells. Once TF comes in contact with blood, it triggers blood coagulation. Previous studies have focused on blocking the coagulation pathway in breast cancer patients. However, anticoagulant therapy increases the risk of bleeding which limits aggressive adjuvant therapy in long-term cancer care.

It has become evident from basic research that TF can change the basic biology of cells through direct cell signaling, which is independent of its ability to trigger blood clotting. We have identified an antibody with the unique property to block direct TF signaling without altering TF-induced coagulation. This antibody also attenuates the growth of highly aggressive breast cancer tumors in mouse models. These properties suggest a novel concept to block direct signaling of TF for breast cancer therapy without any adverse effects on normal blood clotting.

This research aims to evaluate the synergistic effects of anti-TF antibody when applied with existing anti-angiogenic, anti-growth factor and chemotherapy in a mouse model of aggressive human breast cancer. We have established an aggressive breast tumor cell line that will be “tagged” to allow tumor imaging. This new cell line will be injected into the mammary gland of immunodeficient mice together with either: (1) antibodies targeting the tumor vasculature (anti-VEGF or anti-VEGFR2), (2) our own anti-TF antibody to block signaling functions, or (3) a combination of both antibody types. In addition, we will also address the potential utility of anti-TF therapy in a chemotherapy regimen or anti-EGF (epidermal growth factor receptor) treatment (Cetuximab). We will follow the effect of the treatment with imaging techniques as well as with standard tumor measurement methods. A more in depth analysis will be performed by histology of the tumor samples collected from these experiments.

These experiments will test the novel concept that inhibiting direct TF signaling can enhance breast cancer therapy when applied in combination with established treatment options. Establishing potential treatment synergies is a crucial next step to address the viability of such therapies in clinical breast cancer care.

Final Report (2009)

Increased thrombosis (blood clotting) is often seen in cancer patients. Tissue factor (TF), the initiator of blood clotting, is expressed on the surface of many cell types including tumor cells. In addition to initiating the coagulation cascade, TF also initiates internal cell signaling via the activation of the protease-activated receptor 2 (PAR2). Thus, TF-PAR2signaling has been implicated in tumor growth, tumor angiogenesis and metastasis.

Using mouse models and human breast cancer cell lines (xenograft models), we showed that blocking TF signaling with a specific antibody in an aggressive breast cancer model reduces tumor growth. In this grant we further addressed the potency of this antibody to attenuate the growth of established tumors and its synergistic activity with other anti-angiogenic therapies. We showed that systemic administration of anti-TF antibody given alone suppresses the growth of xenograft tumors and that anti-TF produces a synergistic effect with anti-angiogenic therapy targeting VEGFR2. We have developed monoclonal antibodies that monitor the phosphorylation status of the TF cytoplasmic domain and found that phosphorylation of TF is correlated with relapse of newly diagnosed breast cancer. Our experiments indicate that detection of TF phosphorylation in treated xenograft tumors and the identification of biomarkers remain a challenge to monitor efficacy of anti-TF therapy.

An eventual goal of this line of research is to develop reagents or knowledge of TF-specific signaling in breast tumor cells that would allow for selective inhibition of tumor cell growth or induction of angiogenesis, while still allowing for the blood coagulation TF functions to be retained.