Enhancing Cancer Therapy Delivery and Efficacy using Thrombospondin-1 Type 1 Repeats in Advanced Solid Tumors

Matuszewska, Kathy
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University of Guelph

The standard of care for Epithelial Ovarian Cancer has remained unchanged for over 30 years, reflecting the need for innovative treatments targeting advanced disease. A hallmark of solid tumors is the need for vascularization to supply oxygen and nutrients. Aggressive pro-angiogenic signals within the tumor microenvironment lead to formation of abnormal vessels characterized by reduced pericyte coverage and low perfusion. As a result of this vascular dysfunction, tumors have elevated hypoxia and interstitial fluid pressure (IFP), yielding an aggressive phenotype and reducing delivery 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 peptide. These functions are mediated through the membrane protein, CD36. This thesis demonstrates that administration of 3TSR leads to vascular changes that prevent vascular shutdown caused by oncolytic Newcastle Disease Virus (NDV). Vascular normalization results in improved tumor perfusion, enhancing efficacy of oncolytic virotherapy through improved intratumoral immune cell delivery. We have also developed a novel compound, Fc3TSR, that has two 3TSR peptides linked with a non-immunostimulatory Fc to increase in vitro and in vivo efficacy. Fc3TSR induces CD36 receptor clustering and potentiates enhanced downstream signal transduction in murine ovarian cancer cells compared to native 3TSR. In an orthotopic, syngeneic mouse model of ovarian cancer, Fc3TSR lowers IFP in the tumor core and enhances immune infiltration to sentinel lymph nodes. This novel construct also proves efficacious in other models, including a murine model of advanced pancreatic ductal adenocarcinoma (PDAC). This work utilizes advanced models to characterize the effects of Fc3TSR in remodeling multiple aspects of the tumor microenvironment that 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. In the future, the hope is that Fc3TSR may be used clinically in combination with other cancer therapies to improve intravenous delivery, avoid side-effects as a result of hyper-dosing and enhance survival of patients with advanced disease.

Epithelial Ovarian Cancer, Angiogenesis, Vascular Normalization, Immunotherapy, Oncolytic Viruses, Pancreatic Ductal Adenocarcinoma, Thrombospondin-1, Fusion Peptides, Murine Models
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Matuszewska K, Ten Kortenaar S, Pereira M, Santry LA, Petrik D, Lo KM, Bridle BW, Wootton SK, Lawler J, Petrik J. Addition of an Fc-IgG induces receptor clustering and increases the in vitro efficacy and in vivo anti-tumor properties of the thrombospondin-1 type I repeats (3TSR) in a mouse model of advanced stage ovarian cancer. Gynecol Oncol. 2022 Jan;164(1):154-169. doi: 10.1016/j.ygyno.2021.11.006. Epub 2021 Nov 16. PMID: 34799137.
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PMCID: PMC8635771.