Abstract 1129: Sigma receptors: Novel targets for the treatment of highly malignant tumors

Abstract

Abstract Introduction. More than 7 million patients are diagnosed with cancer every year, and approximately 24 million new cases of cancer will probably be registered by 2035. Over the past decades, numerous cancer targets have been identified and, despite promising results in this field, the discovery of novel targeted therapies is still a largely unmet need. Sigma receptors (SRs), more highly expressed in tumor cells than in normal cells, have aroused the interest of the scientific community because of increasing evidence of their involvement in proliferation and survival signaling pathways of cancer cells. Glioblastoma (GBM) and pancreatic cancer (PCa) are two of the most aggressive and lethal solid tumors. GBM patients usually relapse within 7-10 months of the end of first-line treatment with median survival of about 14.6 months while PCa is the fourth most fatal cancer in both men and women, with median survival of 6-12 months. Little or no improvement in prognosis has been obtained over the past 20 years. Thus, new approaches to the treatment of both tumors are urgently needed. In the present work, 3D GBM primary cultures endowed with stemness features and PCa cell lines were used to evaluate the antitumor activity of a dual S1R and S2R ligand RC-106, a novel sigma receptor modulator. Methods. RC-106 tissue distribution studies were performed in mice. PCa cell lines were assessed by cytotoxic assay (CellTiter 96® AQueous One Solution Cell Proliferation Assay). Molecular analyses were performed by qRT-PCR and Western blot. Apoptosis and cell cycle were analyzed by flow cytometry. GBM primary cultures were isolated from surgical tumor samples. A rotatory cell culture system (RCCS) was used to obtain 3D cell cultures. Growth and morphology of the colonies were monitored by open-source AnaSP and ReViSP software tools. Molecular analyses were performed by flow cytometry and qRT-PCR. 3D cell viability was measured using CellTiter-Glo® 3D Cell Viability Assay. Apoptosis and cell cycle were analyzed by flow cytometry. Results. RC-106 preferentially accumulate in mice pancreas and brain after intravenous administration, supporting the use of sigma receptor modulators as a novel therapy for these tumors. Treatment with RC-106 strongly inhibited cell proliferation and survival regardless of the type of cancer investigated. 25 μM of the drug impaired the in vitro clonogenic ability of tumor cells, an effect lasting for up to 42 days, the longest time tested. RC-106 also led to the induction of substantial apoptosis mediated by caspase 3 and 9 activation, and to a modulation of the Akt pathway. Furthermore, treatment with RC-106 significantly reduced the growth of human GBM and PCa spheroids. Conclusions. (RC-106) represents the hit compound of a new class of dual-action ligands targeting S1R and S2R potentially useful for the treatment of cancer disease. Citation Format: Michela Cortesi, Sara Pignatta, Simona Collina, Andrea Rocca, Alice Zamagni, Chiara Arienti, Michele Zanoni, Luigino Tosatto, Daniela Bartolini, Evandro Nigrisoli, Annamaria Marra, Marta Rui, Anna Tesei. Sigma receptors: Novel targets for the treatment of highly malignant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1129. doi:10.1158/1538-7445.AM2017-1129