Abstract 5557: BoxA and ethyl pyruvate offer novel therapeutic approaches for human malignant mesothelioma.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Human malignant mesothelioma (MM) is an aggressive and highly lethal cancer that has been linked to asbestos and erionite exposure. MM causes about 3,000 deaths per year in the US and more than 100,000 deaths per year worldwide. We previously found that the damage-associated molecular pattern (DAMP) high-mobility group box-1 protein (HMGB1) plays a critical role in the early carcinogenic events in MM development by inducing tumor necrosis factor-alpha (TNF-α) secretion, potentiating survival of fiber-exposed primary human mesothelial cells (HM) and enabling HM malignant transformation. We recently showed that HMGB1 is upregulated in MM tumor tissues and cell lines and its levels to be significantly higher in the blood of MM patients compared to healthy individuals. Moreover, MM cells are “addicted” to HMGB1 and HMGB1 promotes proliferation, viability, motility and invasiveness of MM cells. Here we show that the use of the HMGB1 antagonists BoxA or ethyl pyruvate (EP) inhibit the motility, survival and progression of MM cells in vitro and reduce the growth of MM xenografts in SCID mice. BoxA is a fragment of HMGB1 protein that corresponds to the one of the two highly conserved DNA binding domains, and behaves as a competitive inhibitor. EP is the ethyl ester of pyruvic acid, is known to suppress oxygen radical formation, and suppresses HMGB1 secretion. Both BoxA and EP have been shown to down-regulate the activation of the proinflammatory transcription factor, NF-κB, as well as the expression of several proinflammatory proteins, such as TNF-α, IL-6, and HMGB1 itself. Taken together, our results provide a preclinical proof-of-principle that inhibition of HMGB1 activity using either BoxA or EP is sufficient to elicit therapeutic activity, offering novel therapeutic approaches for MM treatment. Citation Format: Sandro L. Jube, Zeyana Rivera, Maura Casalgrandi, Marco Bianchi, Harvey I. Pass, Giovanni Gaudino, Michele Carbone, Haining Yang. BoxA and ethyl pyruvate offer novel therapeutic approaches for human malignant mesothelioma. [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 5557. doi:10.1158/1538-7445.AM2013-5557