Abstract B78: Rebastinib, a small molecule TIE2 kinase inhibitor, prevents primary tumor growth and lung metastasis in the PyMT breast cancer model

Abstract

Abstract Rebastinib is an inhibitor of tyrosine kinases TIE2 and ABL1. A clinical trial in chronic myeloid leukemia (CML) to inhibit BCR-ABL was previously performed but efficacy was modest and development in CML is not continuing. Rebastinib is approximately 50 times more potent as an inhibitor of TIE2 than BCR-ABL. Biomarker analysis of patients from the CML trial of rebastinib revealed that a majority displayed significant increases in circulating angiopoietin 2 (ANG2) levels. Increases in ANG2, a TIE2 ligand, have been previously reported to correlate with inhibition of the TIE2 pathway. The hypoxic tumor environment engendered by radiation therapy, cytotoxic chemotherapy, or anti-angiogenic treatments (such as anti-VEGF therapies) leads to rebound tumor vascularization by the recruitment of pro-vasculogenic TIE2 expressing monocytes (TEMs) from the bone marrow to these hypoxic tumor sites. TEMs are believed to play an important role in the revascularization of tumors after these treatments, leading to progression of residual tumor. Thus, inhibition of TEM recruitment and activity could lead to better patient outcomes. The polyoma middle-T antigen (PyMT) syngeneic mouse breast cancer model utilizes the mouse mammary tumor virus (MMTV) promoter, a breast specific promoter, to express PyMT in mouse breast tissue. In this model, primary breast cancers spontaneously occur, proliferate, and metastasize (mainly to the lungs) and lead to the death of the mice. Unlike xenografts, the PyMT model utilizes fully immunocompetent mice and metastasis in this model is known to be modulated by TEMs. Rebastinib has been evaluated in a PyMT mouse where primary tumors were allowed to reach 800 mg in size before starting treatment. Rebastinib therapy resulted in a significant decrease in the growth rate of the primary breast tumor (75%), a 71% reduction in lung metastases, a decrease in the levels of tumoral TIE2 staining by immunohistochemical analysis (IHC) and caused the remaining tumor to become necrotic. Combining rebastinib with paclitaxel resulted in a synergistic response with 90% inhibition of tumor growth and a 93% reduction of lung metastases. This presentation will focus on the biochemical, cellular and in vivo activity of rebastinib as a novel small molecule inhibitor of TIE2 kinase and its potential for prevention of primary tumor rebound and metastasis in combination with first line interventional therapy. A clinical trial exploring this activity is planned for 2013. Citation Format: Bryan D. Smith, Molly M. Hood, Michael D. Kaufman, Mark Berger, Daniel L. Flynn, Scott C. Wise. Rebastinib, a small molecule TIE2 kinase inhibitor, prevents primary tumor growth and lung metastasis in the PyMT breast cancer model. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B78.