Abstract P4-15-12: Rebastinib in combination with eribulin ablates TIE2-expressing macrophages, reduces metastasis, and increases survival in the PyMT metastatic breast cancer model
Authors: Smith BD , Leary CB , Kaufman MD , Hood MM , Lu W-P , Turner BA , Vogeti S , Wise SC , Berger MS , Flynn DL 
Published: August 2014

Abstract
In cancer models, TIE2 kinase plays an important role in angiogenesis, vasculogenesis, and tumor metastasis. TIE2 expression is largely restricted to vascular endothelial cells, tissue macrophages, and bone marrow derived TIE2-expressing monocytes (TEMs), which are proangiogenic, provasculogenic and enhance invasiveness. The hypoxic tumor environment engendered by damaging the vasculature with chemotherapy, radiation, or anti-angiogenic treatments leads to rebound tumor vascularization by an angiogenic switch from the VEGF pathway to the angiopoietin/TIE2 pathway. This leads to recruitment of provasculogenic TEMs from the bone marrow, leading to the growth of residual tumor cells and disease progression. Significantly, a subset of TIE2-expressing macrophages are located within specialized vascular structures known as tumor microenvironment for metastases (TMEMs). Recent observations have linked TIE2-expressing macrophages within TMEM structures to intravasation of cancer cells into circulation and subsequent dissemination to metastatic sites. We hypothesized that TIE2 inhibition should decrease migration and association of TEMs with blood vessels in the tumor stroma, therefore blocking their proangiogenic activity and leading to reduced tumor growth. TIE2 inhibition may also alter TMEM function, leading directly to a blockade of metastasis.
Rebastinib is a picomolar inhibitor of TIE2 kinase, and exhibits an extraordinarily long off-rate from TIE2, measured to be over 24 hours in a cell-based assay. Herein, we examine the efficacy of rebastinib in the polyoma middle-T antigen (PyMT) syngeneic mouse breast cancer model. In this model, PyMT breast cancer cells are implanted in the mammary fat pad, and primary tumor growth leads to metastasis, which is known to be modulated by TEMs and TMEM vascular structures. We examined dosing rebastinib in combination with eribulin, an inhibitor of microtubule dynamics that recently was FDA-approved for treatment-refractory metastatic breast cancer. Rebastinib treatment in this model significantly ablated TEMs in the primary tumor stroma and caused a significant decrease in lung metastases. Furthermore, the combination of rebastinib and eribulin led to a significant further decrease in lung metastases compared to treatment with eribulin alone (Table 1). Rebastinib also enhanced the activity of eribulin in reducing primary tumor growth and regrowth of tumor post-resection.
TIE2 inhibition represents a novel treatment approach for metastatic breast cancer and other cancers that rely on TEMs and TMEMs for growth and metastasis. As such, rebastinib has been selected for further clinical development in combination with eribulin for treatment-refractory metastatic breast cancer, with a Phase 1b trial being planned for late 2013.
Rebastinib reduces lung metastases in the PyMT breast cancer modelTreatmentLung Metastases (% of Control)Vehicle100%Eribulin 1 mg/kg three times/week71%Rebastinib 10 mg/kg twice/week + Eribulin 1 mg/kg23%Eribulin 0.3 mg/kg three times/week71%Rebastinib 10 mg/kg twice/week + Eribulin 0.3 mg/kg51%Eribulin 0.1 mg/kg three times/week72%Rebastinib 10 mg/kg twice/week + Eribulin 0.1 mg/kg43%
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-15-12.