Abstract B128: Efficacy of RP4010, a calcium release-activated calcium (CRAC) inhibitor, in preclinical models of DLBCL

Abstract

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive, rapidly growing type of lymphoma that comprises 30-40% of NHL cases. Chemotherapy remains the most widely used treatment for DLBCL, thereby necessitating the need to develop targeted and safer drugs. Calcium signaling via CRAC channels mediates several physiologic processes including cell proliferation and apoptosis. RP4010 is a potent inhibitor of CRAC channel activity (IC50=60 nM) with demonstrated efficacy across a range of cancer cell lines in vitro. The objective of this study was to evaluate the effect of RP4010 as a single agent or in combination with known agents in preclinical models of DLBCL. Methods: Growth inhibition and apoptosis was estimated following incubation with RP4010 for 48-72 h using representative DLBCL cell lines. Besides single-agent activity, the effect of combining RP4010 with emerging and marketed therapies for DLBCL such as Ibrutinib and GA-101 was evaluated. Translation of in vitro activity to in vivo efficacy was assessed in mouse xenograft models representative of DLBCL. The effect of RP4010 (30 mg/kg/BID) as a single agent or in combination with Ibrutinib (30 mg/kg/QD) was tested in a DOHH2 human non-Hodgkin lymphoma cancer model using CB17/SCID mice. In a follow-up study, RP4010 at 30 mg/kg/BID was tested in combination with Rituximab (2.5 mg/kg BIW x 2W) or Rituximab + Bendamustine (10 mg/kg; QD x 2, 12 days off i.v.). Results: Channel blockade resulted in reduction in cell viability (EC50 = 0.3 -18 μM) with a corresponding dose-dependent induction of apoptosis. Adding RP4010 to Ibrutinib or GA-101 resulted in a synergistic effect on OCI-LY-1 and OCI-LY-10 cell proliferation. Single-agent RP4010 and the combination of RP4010 + Ibrutinib or RP4010 + Rituximab + Bendamustine were well tolerated throughout the study period with no appreciable change in body weight. IN DOHH-2 mouse xenografts, RP4010 demonstrated significant (p<0.001) antitumor activity both as a single agent and in combination with Ibrutinib with tumor growth inhibitions of 68 and 86%, respectively. Similar antitumor activity was observed upon combining RP4010 with Rituximab or Rituximab + Bendamustine with tumors remaining regressed for the duration of 2-week follow-up post withdrawal of treatment. Conclusions: RP4010, a potent CRAC channel inhibitor, attenuated DLBCL tumor growth as a single agent besides demonstrating remarkable synergy with known agents. Findings provide a rationale for use of this molecule in clinical trials involving naïve or relapsed/refractory DLBCL patients. Citation Format: Srikant Viswanadha, Satyanarayana Eleswarapu, Swaroop Vakkalanka. Efficacy of RP4010, a calcium release-activated calcium (CRAC) inhibitor, in preclinical models of DLBCL [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B128.