Abstract 1042: Fc3TSR improves intratumoral treatment delivery by normalizing tumor vasculature and reducing interstitial fluid pressure in an orthotopic, syngeneic mouse model of epithelial ovarian cancer

Abstract

A hallmark of solid tumors is the need for vascularization to supply oxygen and nutrients. Aggressive pro-angiogenic signals induced by tumors lead to malformation of vessels characterized by reduced pericyte coverage and low perfusion. As a result of this vascular dysfunction, tumors have elevated hypoxia and high interstitial fluid pressure (IFP), yielding an aggressive phenotype, and reducing efficacy and trafficking of intravenous therapies to the tumor core. Anti-angiogenic therapies aim to reduce angiogenic stimuli and normalize tumor vessels. The three type-1-repeat (3TSR) region of thrombospondin-1 contains the majority of its anti-angiogenic properties in a small bioactive peptide. These functions are mediated through the membrane protein, CD36. We have previously shown that administration of native 3TSR leads to improved tumor perfusion, and enhancing delivery of chemotherapy drugs and oncolytic viruses. We have developed a novel compound, Fc3TSR, that has two 3TSR peptides linked with a Fc to increase in vitro and in vivo efficacy. In an orthotopic, mouse model of ovarian cancer, we examined the effect of Fc3TSR treatment on tumor IFP using a 1.2Fr pressure catheter guided into the tumor core of anesthetized mice. Compared to untreated controls, mice treated with Fc3TSR had significantly lower IFP, even after considering differences in heart rate among animals. Immunofluorescence on fixed sentinel lymph nodes revealed enhanced presence of immune cells, a positive predictor of lymphatic patency. To determine impact on chemotherapy delivery, mice were injected with 40mCi paclitaxel and tumor uptake of the isotope was measured. At 12, 24 and 48h post injection, Fc3TSR treated tumors had significantly increased uptake of paclitaxel compared to untreated or 3TSR treated mice. In vitro cell viability assays and western blot analysis of cleaved-caspase-3 revealed that Fc3TSR enhances direct apoptosis in human ovarian cell lines (OVCAR-2 and 36M2) compared to untreated cells or those treated with native 3TSR at equimolar concentrations. In a human subcutaneous xenograft model using 36M2 cells in SCID mice, Fc3TSR significantly reduced tumor volume as a single agent compared to PBS controls.Fc3TSR causes direct ovarian tumor cell apoptosis in vitro and significant anti-tumor effects in vivo. In vivo, Fc3TSR causes potent vascular normalization, decreases tumor hypoxia and IFP in the tumor core. As such, Fc3TSR has the potential to remodel multiple aspects of the tumor microenvironment which would otherwise obstruct treatment delivery and efficacy in solid tumors. The multi-modal aspects of Fc3TSR makes this therapeutic approach attractive for the treatment of advanced ovarian cancer and other malignancies that typically overcome single-agent therapy. Citation Format: Kathy Matuszewska, Madison Pereira, Leslie Ogilvie, Duncan Petrik, Allison Gartung, Dipak Panigrahy, Kin-Ming Lo, Jack Lawler, Jeremy Simpson, Jim Petrik. Fc3TSR improves intratumoral treatment delivery by normalizing tumor vasculature and reducing interstitial fluid pressure in an orthotopic, syngeneic mouse model of epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1042.