Abstract 2600: HMGB1, a potential new target for mesothelioma therapy

Abstract Malignant mesothelioma (MM) is a very aggressive cancer that causes 2000-3000 deaths annually in the U.S. and is resistant to current therapies. Diagnosis frequently occurs at a late stage of disease progression and median survival from time of diagnosis is about 1 year. Therefore, novel therapeutic strategies are urgently needed. We found previously that High-Mobility Group Box 1 protein (HMGB1), a known pro-inflammatory cytokine, induces tumor necrosis factor-alpha (TNF-α) secretion, potentiates survival of asbestos-exposed primary human mesothelial cells (HM) and enables HM malignant transformation, which leads to the initiation of MM. We show here that HMGB1 is also critical in the maintenance and progression of established MM. We found that HMGB1 is highly expressed in MM tissues and its levels in MM patients’ sera are significantly higher than in those of healthy individuals (P < 0.0001). MM tumor cells over-express HMGB1 in both the nucleus and cytoplasm. Instead, normal HM only express nuclear HMGB1 at significantly lower level than MM cells. The main receptor of HMGB1, receptor for advanced glycation end products (RAGE), is also upregulated in MM cells compared to HM. MM cells release biologically active HMGB1 into extra-cellular space, and the interaction with its receptors induces cell proliferation and chemo-attractant activity on MM cells. Moreover, the interference with HMGB1 activity by using specific HMGB1 inhibitors, such as BoxA and HMGB1 neutralizing monoclonal antibodies, leads to MM cell death. HMGB1 inhibitors impair MM cells migration, invasion, wound healing and also colony formation in soft agar. Our results strongly suggest that HMGB1 can be a novel target for mesothelioma therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2600. doi:10.1158/1538-7445.AM2011-2600