Abstract
Recent data in our laboratory indicate that engagement of host-derived microenvironmental elements impact tumor response to single high dose radiation therapy (SDRT). In these studies we showed that microvascular endothelial damage plays a critical role in tumor response as regulator of direct lethal damage of SDRT. Using a genetic model of Acid Sphingomyelinase (ASMase)-deficient mice we showed that activation of this enzyme by SDRT-induced damage in the endothelium is mandatory for tumor cure. ASMase activation triggers ceramide-mediated apoptosis, and therein microvascular dysfunction, which increased the vulnerability of tumor cells to lethal damage by radiation. Angiogenic factors repressed this activity while a monoclonal antibody targeting VEGF, de-repressed ASMase activity and radiosensitized tumor endothelium when delivered immediately prior to SDRT. In this study, we tested the effect of SDRT in combination with the short-acting anti-angiogenic agent, Pazopanib (anti-VEGFR-1/2/3, PDGF-α/β and c-kit), in two xenograft models of human sarcoma. Pre-treatment with a single dose of Pazopanib increased SDRT-induced ASMase activity and endothelial dysfunction in vitro and in vivo, enhancing SDRT tumor cure, and exhibiting critical dependence on timing relative to SDRT exposure, suggesting a mechanism of action identical to that demonstrated for anti-VEGF/VEGFR2 antibodies. These results demonstrate the ability of Pazopanib to shift the response towards tumor cure and could therefore have a significant impact on clinical trial development in combination with SDRT for sarcoma cancer patients.
Highlights
As one of the potent and efficient cancer therapies, radiation is widely used to treat a variety of cancer types
The molecular mechanism of combination of anti-vascular endothelial growth factor (VEGF) reagent and single high dose radiation therapy (SDRT) on tumor response via amplification of ceramide-driven endothelial apoptosis was investigated in two human sarcoma animal models
Our findings revealed that pre-treatment with Pazopanib prior to SDRT enhances tumor endothelial dysfunction and tumor growth delay in these tumors
Summary
As one of the potent and efficient cancer therapies, radiation is widely used to treat a variety of cancer types. The goal of radiation therapy (RT) is to maximize damage to cancer cells while keeping collateral damage to a minimum [1, 2] Studies in this field revealed that IR-induced DNA damage repair is more efficient in normal cells than in tumor cells, which display dysregulated repair [2]. We recently reported that SDRT induces a rapid wave of endothelial cell apoptosis via ceramide generation in both normal gastrointestinal tract and tumors [5,6,7]. In vivo these agents cause a synergistic increase in radiationinduced tumor endothelial apoptosis and enhanced tumor response to SDRT [14] These studies define that an ASMase/ceramide pathway-dependent endothelial response plays a crucial role in tumor cure by SDRT and is modulated by angiogenic factors
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