Reciprocal Dormancy-Promoting Nanomedicine Altering EGFR and TSP-1 for the Management of Glioblastoma - ICMS2015 Abstract Submission Form Tumor Microenvironment Conference

Eilam Yeini ¹ Shiran Ferber ¹ Galia Tiram ¹ Orit Amsalem ² Nava Almog ³ Jack Henkin ⁴ Eylon Yavin ² Marcelo Calderon ⁵ Rainer Haag ⁵ Ronit Satchi-Fainaro ¹

¹Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University
²School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem
³Center of Cancer Systems Biology, School of Medicine, Tufts University
⁴Cemistry of Life Processes Institute, Northwestern University
⁵Institut fur Chemie und Biochemie, Freie Universitat Berlin

Glioblastoma is one of the most aggressive human cancers. Due to glioblastoma’s invasive nature, recurrence occurs in 95% of cases. Tumor progression is dependent on recruitment of blood vessels, as well as an established interaction with the surrounding microenvironment. Failure of a tumor to complete these stages results in a non-angiogenic and non-progressing dormant tumor. Residual tumor cells constitute fundamental clinical manifestation of tumor dormancy that is responsible for the majority of deaths. Therefore, novel agents targeting relevant pathways are needed.

We have previously generated two glioblastoma dormancy models in mice. While the dormant avascular and fast-growing angiogenic tumor-forming cells share a similar growth rate in-vitro, we found profound differences in tumor growth patterns in-vivo. Furthermore, the cells differ in their angiogenic potential and in gene expression involved in angiogenesis regulation. Two of the major dissimilarities were thrombospondin-1 (TSP-1), a key angiogenesis inhibitor, and epidermal growth factor receptor (EGFR), a modulator of tumorigenicity. The dormant tumor-generating cells express higher levels of TSP-1 and lower levels of EGFR compared to the fast-growing tumor-generating cells.

Here, we induced upregulation of TSP-1, using a TSP-1-peptidomimetic (TSP-1-PM), and downregulation of EGFR, using a dendritic nanocarrier entrapping siRNA (PG-NH₂-siEGFR). Treatment with combination therapy of TSP-1-PM and PG-NH₂-siEGFR to mice bearing established fast-growing tumors exhibited anti-angiogenic and anti-tumorigenic activity. It remarkably decreased tumor volume by 99.5% compared with the control 25 days post treatment initiation, to a volume of 1 mm³. Immunohistochemistry analysis revealed reduced vasculature, increased αSMA and decreased VEGF expression in treated tumors. We concluded that combination of TSP-1-PM with EGFR-siRNA represents a promising treatment for advanced glioblastoma promoting a dormant phenotype and in some cases total tumor eradication.