Abstract 1932: Cationic amphiphilic drugs as a potential new treatment option for patients with high risk non-muscle invasive bladder cancer
| Autor: | Joost L. Boormans, Ellen C. Zwarthoff, Eline Ruigrok, Janneke van Uhm, Gabri van der Pluijm, Maaike H. van der Mark, Marja Jäätelä, Geertje van der Horst, Emily Ploeg, Rob C.M. Pelger, Arjanneke F. van de Merbel, Chris H. Bangma |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Cancer Research. 79:1932-1932 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2019-1932 |
| Popis: | Urothelial carcinoma of the bladder (UCB) is the fifth most common cancer in the western world. UCB present either as non-muscle-invasive BC (NMIBC) or as muscle-invasive carcinomas (MIBC). NMIBC is characterized by a high risk of recurrence and even progression to MIBC based on clinicopathological risk factors. Despite radical surgery and extensive chemotherapy, the outcome of MIBC patients is poor. High-risk NMIBC is treated with adjuvant intravesical instillations with Bacillus Calmette-Guérin (BCG). However, a substantial number of patients do not tolerate BCG or do not respond. Novel therapy for patients who do not tolerate BCG or in who are BCG unresponsive is a clear unmet clinical need. Drug repositioning of existing FDA-approved drugs could be a promising opportunity. Recently, cationic amphiphilic drugs (CADs), including commonly used antidepressants, antihistamines and antipsychotics were found to preferentially induce lysosomal cell death in transformed cells. In this study, we evaluated the potential anti-tumor efficacy and toxicity of these drugs in in vitro assays, in vivo preclinical models, and in and ex-vivo cultured patient-derived bladder cancer tissue slices. Treatment with CADs resulted in a significant dose-dependent decrease in proliferation and viability of multiple human UCB cell lines (a.o. RT4, TCC-SUP, and UM-UC-3) in vitro. Consistent with previous data regarding the ability of CADs to induce lysosomal membrane permeabilization in other solid cancer cells, we observed lysosomal puncta formation, which is a hallmark of lysosomal leakage. Strikingly, instillation of CADs in preclinical in vivo models of orthotopically growing human UM-UC-3 UCB resulted in a significant reduction in orthotopic as well as metastatic tumor burden. In line with these data, treatment of 39 patient-derived ex vivo cultured UCB slices with penfluridol resulted in significant anti-tumor responses ranging from complete regression to a significant reduction of the tumor.In vivo experiments revealed that normal mouse urothelium is not affected upon bladder instillation of CADs (weekly instillation of penfluridol for 5 weeks) in non-tumor bearing nude mice. In addition, penfluridol treatment of ex vivo cultured normal human urothelium only marginally affected the tissue. In conclusion, we demonstrated that CADs can target UCB cells and might be a promising novel approach for treatment of UCB. Citation Format: Geertje van der Horst, Arjanneke F. van de Merbel, Eline Ruigrok, Maaike H. van der Mark, Emily Ploeg, Marja Jäätelä, Janneke van Uhm, Rob C. Pelger, Chris H. Bangma, Joost Boormans, Gabri van der Pluijm, Ellen C. Zwarthoff. Cationic amphiphilic drugs as a potential new treatment option for patients with high risk non-muscle invasive bladder cancer [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 1932. |
| Databáze: | OpenAIRE |
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