Abstract 198: The T3R domain of thrombospondin-1 delays tumor growth and improves tumor response to chemotherapy by remodeling the tumor vasculature

Abstract

Abstract The disorganized and inefficient nature of the tumor vasculature affects the delivery and activity of antineoplastic treatments. Certain antiangiogenic agents induce a transient normalization of tumor vessels, hence representing a promising strategy to improve the delivery and efficacy of cytotoxic therapy. Our previous studies demonstrated the antiangiogenic activity of the type III repeats (T3R) domain of thrombospondin-1 (TSP-1), a major endogenous inhibitor of angiogenesis. Aim of this study was to investigate the role of the T3R domain in tumor growth and tumor response to chemotherapy. Ectopic tumor cell expression of T3R delayed in vivo growth in two tumor models, the human ovarian carcinoma A2780-1A9 and endometrial adenocarcinoma HEC-1B. This was associated with vascular remodeling, decreased cell proliferation and increased apoptosis. T3R was active in preventing tumor growth also when expressed by the host cells (rather than the tumor cells), following pretreatment of mice with adeno-associated virus (rAAV)-T3R before tumor cell implantation. Expression of T3R also resulted in improved tumor response to paclitaxel (PTX 10 mg/kg Q4x3, i.v.) and cisplatin (DDP 4 mg/kg Q4x3, i.v.). Through the pharmacokinetic study, conducted by HPLC and MALDI imaging mass spectrometry analysis, a higher concentration and a more homogeneous drug distribution were observed in tumors expressing T3R 4h after a single administration of PTX (60 mg/kg, i.v.). This was associated with a marked reorganization of the tumor vasculature that presented decreased vessel area and vessel diameter and increased number of CD31-positive vessels. These findings indicate the ability of T3R to reduce tumor growth and improve tumor response to chemotherapy through the remodeling of tumor vasculature. This sets the basis for the development of new therapeutic strategies based on T3R to be used in combination therapies. Supported by AIRC. DP is recipient of the AIRC fellowship “Lina e Giovanni Giasini” Citation Format: Denise Pinessi, Andrea Resovi, Lavinia Morosi, Patrizia Borsotti, Alexander Berndt, Raffaella Giavazzi, Massimo Zucchetti, Giulia Taraboletti. The T3R domain of thrombospondin-1 delays tumor growth and improves tumor response to chemotherapy by remodeling the tumor vasculature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 198.