Abstract 1235: A long pentraxin-3-derived small molecule FGF trap for the treatment of multiple myeloma

Abstract

Abstract Despite advances in systemic and supportive therapies, multiple myeloma (MM) remains incurable because of chemotherapeutic resistance. Fibroblast growth factor-2 (FGF2) plays a pivotal role in MM acting as an autocrine/paracrine mitogen on plasma cells, bone marrow-derived endothelial cells and fibroblasts. In keeping with the pivotal role of the FGF system in MM, the recurrent chromosomal translocation t(4;14) identified in MM patients is associated with upregulation of FGF receptor-3 (FGFR3). Agents able to hamper FGF signaling are therefore of interest as a novel approach for the treatment of MM. The soluble pattern recognition receptor long pentraxin-3 (PTX3) owns an unique N-terminal amino acid domain containing the pentapeptide ARPCA able to bind FGFs with high affinity and selectivity and to prevent their binding to FGFRs and their activation. Molecular modeling based on ARPCA structure and small molecule library fishing have allowed the identification of a novel orally active 480 Da FGF trap named NSC12. NSC12 has been shown to hamper tumor growth and vascularization in FGF-driven human lung and prostate tumor models. Here, the therapeutic potential of NSC12 for MM treatment was tested on four human MM cell lines harboring (KMS-11 and OPM-2 cells) or not (U-266 and RPMI8226 cells) the t(4:14) translocation. NSC12 blocked the proliferation of all human MM cell lines with an IC50 ≅ 3 μM. Western blot and immunofluorescent analyses showed that NSC12 inhibited the activation of FGFR3 signaling, hampered nuclear translocation of NF-kB and strongly downregulated the anti-apoptotic protein mcl-1, leading to an apoptotic response. In addition, co-treatment with the proteasome inhibitor Bortezomib strongly increased KMS-11 cell death. In vivo, oral delivery of NSC12 significantly blocked the growth of KMS-11 (286.9 ± 22.4 vs 459.8 ± 27.4 mm3, p<0.001) and RPMI8226 (141.5 ± 17.7 vs 245.9 ± 46.4 mm3, p<0.001) xenografts injected subcutaneously in immune-compromised NOD/SCID mice. Analysis of KMS-11 xenografts from NSC12-treated mice showed a significant reduction of CD31-positive tumor vascularization and a strong increase of TUNEL-positive apoptotic cells compared to xenografts from vehicle-treated mice. Altogether, these data suggest that NSC12 affects MM tumor growth through a direct cytotoxic activity on MM cells and by inhibiting FGF-mediated paracrine/autocrine crosstalk in tumor stroma/microenvironment. Thus, NSC12 may represent a novel “two compartment” inhibitor in MM by hampering FGF-dependent angiogenic/oncogenic signaling. Finally, combinations of NSC12 with conventional therapies, such as Bortezomib, may enhance cytotoxicity and overcome drug resistance, thereby improving MM patient outcome. Citation Format: Arianna Giacomini, Roberto Ronca, Marco Presta. A long pentraxin-3-derived small molecule FGF trap for the treatment of multiple myeloma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1235.