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Hepatocellular carcinoma (HCC) related mortality ranks second worldwide and stands one step behind lung cancer. Due to the asymptomatic nature of the cancer, early diagnosis is a major problem. Currently only liver transplantation is curative for early stage hepatocellular cancer. There are other multidisciplinary treatment options like radiation and chemotherapy available for advanced patients. However, chemotherapy resistance is a common problem in the treatment of liver cancer. Newer therapeutics are needed for better management of advanced HCC. Angiogenesis and lymphangiogenesis are processes that are vital for tumorigenesis and metastasis. HCC is known to be a hypervascular tumor and many pro-angiogenic proteins are found significantly overexpressed in HCC. We explored the therapeutic potential of the anti-angiogenic and anti-lymphangiogenic, biomimetic peptide SP2043 developed by our group in HCC. Hepatocellular carcinoma cell lines HuH-7, Hep3b and HepG2 showed significant disruption of cell adhesion and migration following treatment. Furthermore, SP2043 was found to impair microvascular endothelial cell (MEC) tube formation induced by HepG2 tumor conditioned media and to significantly inhibit HepG2 tumor xenograft growth compared to untreated controls. The peptide drug was also found to improve the survival of autochthonous Myc induced HCC in a transgenic mouse model from two weeks to four weeks. We discovered the peptide to be a multi-modal anti-angiogenic drug that also inhibits IGF1R and MET signaling pathways in HCC cell lines. We also found that SP2043 treatment reduced the microvascular density in both subcutaneous and autochthonous liver tumors with reduced tumor cell proliferation and increased apoptosis. This study shows the therapeutic potential of SP2043 in the treatment of hepatocellular carcinoma. Note: This abstract was not presented at the meeting. Citation Format: Mustafa A. Barbhuiya, Adam C. Mirando, Brian W. Simons, Ghali Lemtiri-Chlieh, Jordan J. Green, Aleksander S. Popel, Niranjan B. Pandey, Phuoc T. Tran. Therapeutic potential of anti-angiogenic multimodal biomimetic peptide in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3201. doi:10.1158/1538-7445.AM2017-3201

In mammalian systems, several aminoacyl-tRNA synthetases are known to have distinct non-canonical functionality. For the first time, we demonstrate that human threonyl-tRNA synthetase (TARS) induces angiogenesis through endothelial cell signaling, and this induction can be blocked by the borrelidin derivative compound BC194. Upon stimulation with vascular endothelial growth factor (VEGF) or tumor necrosis factor-alpha (TNF-α), human endothelial cells secrete TARS into the extracellular space. Extracellular TARS induces and BC194 inhibits angiogenesis in both in vitro tube formation assays and in vivo chick chorioallantoic membrane assays. Furthermore, the anti-angiogenic effects of BC194 are specific to its inhibition of TARS angiogenic activity rather than an indirect stress response. Additional evidence supports a stimulatory role for TARS in endothelial cell migration as a mechanism for its angiogenic activity. Taken together, these findings reveal a previously undefined function for TARS as an angiogenesis inducer stimulated by hypoxic and inflammatory signals. Detecting or intervening in the non-canonical extracellular TARS signaling pathway may thus provide a novel means of diagnosing or treating angiogenesis and inflammatory responses involved in cancer. Citation Format: Tamara Williams, Adam Mirando, Christopher Francklyn, Karen M. Lounsbury. A novel function for threonyl-tRNA synthetase as a stimulator of angiogenesis and endothelial cell migration. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3897. doi:10.1158/1538-7445.AM2013-3897