Abstract 3069: Efficacy of RP4010, a calcium release-activated calcium (CRAC) channel inhibitor, in preclinical models of gastrointestinal cancers

Abstract

Abstract Background: Calcium Ca(2+) signals and the underlying Ca(2+) channels and transporters are known to influence development, growth, and metastasis of many cancers. Calcium release-activated calcium (CRAC) channel proteins, STIM and Orai, have been shown to play a role in cancer progression and metastasis. Here we investigate the impact of RP4010, a CRAC channel inhibitor, in GI [pancreatic ductal adenocarcinoma (PDAC), gastric cancer (GC) and pancreatic neuroendocrine tumors (PNETs)] cellular and patient derived tumor models. Methods: GI cancer cell lines [3 PDAC and one normal human pancreatic ductal adenocarcinoma (HPDE); 3 GC cells and 2 PNET cell lines] were exposed to RP4010 in the presence or absence of standard of care drugs such as gemcitabine, nab-paclitaxel, or everolimus. Cell growth inhibition was evaluated using MTT. Apoptosis was determined by Annexin V FITC and 7AAD assays. Alterations in markers associated with the CRAC channel pathway were evaluated using RT-PCR and Western Blotting. In vivo efficacy was evaluated in gastric cancer sub-cutaneous xenograft as well as a hyaluronan positive PDAC patient derived xenograft in the presence or absence of chemotherapeutic agents. Results: CRAC channel inhibition by RP4010 resulted in cancer cell selective growth inhibition (IC50s in the low micro M range). Growth inhibition was concurrent with apoptosis at similar doses. RP4010 synergized with gemcitabine and nab-paclitaxel in PDAC; nab-paclitaxel and docetaxel in GC (CI<1), and significantly enhanced the activity of everolimus in PNETs. RT-PCR and Western Blotting revealed that RP4010 caused a reduction in NFATC1, NFAT2, Akt, mTOR and related markers associated with CRAC channel pathway signaling. The combination treatment led to superior suppression of several CRAC channel regulated genes. RP4010 (given at 50 mg/kg daily for 4 weeks) as a single agent reduced tumor weight/volume in a hyaluronan positive (stroma +ve) PDAC PDx model. Anti-tumor activity of RP4010 was enhanced in the presence of gemcitabine-nab-paclitaxel (RP4010 50 mg/kg orally+50 mg/kg i.v once a week for 3 weeks and 30 mg/kg nab-paclitaxel once a week for 3 weeks). Residual tumor tissue analysis to capture CRAC channel pathway inhibition in vivo is currently ongoing. Conclusion: Our studies indicate that RP4010, a novel CRAC channel inhibitor could be a viable therapeutic option in GI cancers that need further clinical evaluation. A multi-center Phase I/IB dose-escalation trial evaluating the safety and efficacy of RP4010, a CRAC channel inhibitor in patients with relapsed or refractory Lymphomas is currently ongoing in USA (ClinicalTrials.gov Identifier: NCT03119467). Citation Format: Irfana Muqbil, Rachel Sexton, Gabriel Mpilla, Anteneh Tesfaye, Steve Kim, Philip A. Philip, Amro Aboukameel, Srikant Viswanadah, Kumar V. Penmesta, Ramzi M. Mohammad, Asfar S. Azmi. Efficacy of RP4010, a calcium release-activated calcium (CRAC) channel inhibitor, in preclinical models of gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3069.