Abstract 2514: CSPG4 as a target of antibody-based immunotherapy for malignant mesothelioma

Abstract

Abstract Malignant mesothelioma (MM) is an aggressive tumor, resistant to conventional therapies, with median survival of 1 year from diagnosis. The lack of effective therapies available prompted us to implement antibody-based immunotherapy against novel targets and to investigate possible synergies with chemotherapy on MM. CSPG4 is involved in the onset and progression of melanoma and other tumors, as well as in neo-angiogenesis. CSPG4-specific monoclonal antibodies (mAb) have shown anti-tumor effects in both preclinical and clinical trials of melanoma. We hypothesized that targeting CSPG4 with a CSPG4-specific mAb would have therapeutic efficacy against MM. We found that chondroitin sulphate proteoglycan 4 (CSPG4) was aberrantly expressed in 6 out of 8 MM cell lines and in 24 out of 40 MM biopsies, with minimal expression in surrounding non-malignant cells. The expression of CSPG4 in MM was higher upon engagement of extracellular matrix components (ECM) and was associated with increased MM cell viability and motility. Silencing of CSPG4 expression by siRNAs supported this functional significance of CSPG4 in MM. Consistently, the CSPG4-specific mAb TP41.2 inhibited MM cell attachment to the ECM, resulting in decreased phosphorylation of FAK and AKT, decreased expression of cyclin D1 and apoptosis. Moreover, TP41.2 significantly reduced MM cell motility, migration and invasiveness, and inhibited MM growth in soft agar. TP41.2 prevented the outgrowth of human MM tumors in SCID mice and inhibited the growth of established MM xenografts, resulting in significantly extended survival of tumor-bearing mice. These results represent a novel approach for CSPG4 mAb-based immunotherapy of MM. Combinatorial strategies with chemotherapeutic agents and with mAbs targeting c-Met related receptor are ongoing, aimed at translating CSPG4-specific mAb into clinical setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2514. doi:1538-7445.AM2012-2514