Abstract 2417
Background
An atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive tumor of the central nervous system that generally occurs in children under three years of age. There is no effective chemotherapy in most AT/RT patients. Within a tumor, small subpopulation cells called cancer stem cells do not respond to or are resistant to conventional anticancer drugs. In previous our studies, we observed the expression of aldehyde dehydrogenase (ALDH), a stem cell marker in AT/RT cells. Based on this, we confirmed the anticancer effect using disulfiram (DSF) known as ALDH inhibitor. Herein, we have investigated the anticancer effect of DSF with cisplatin in order to improve the effectiveness of AT/RT treatment.
Methods
Patient-derived primary cultured cells and established cell lines were utilized in vitro experiments. The combination effects of DSF with cisplatin was confirmed by cell viability, flow cytometry, ELISA and immunofluorescence analysis. The mechanism was identified by western blot analysis. Tumor volumes and survival rates were analyzed via bioluminescence live imaging in an AT/RT orthotopic xenograft mouse model to verify in vivo therapeutic effects.
Results
Our results demonstrate the anticancer effects of the combination of DSF and cisplatin both in vitro and in vivo. The combined treatment significantly inhibited the cell viability and ALDH enzyme activity of all AT/RT cells. The combination of DSF and cisplatin has been shown to modulate C-jun and ATF3 protein expression and activate PARP to induce apoptosis much more effectively. Importantly, the combination of DSF with cisplatin resulted in decreased tumor volume and increased long-term survival rate in AT/RT animal models.
Conclusions
Our study suggests that combination therapy of DSF and cisplatin can be used as a novel treatment strategy for AT/RT, which is difficult to treat with conventional chemotherapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Grant from the Seoul National University Hospital Research Fund (04-2018-0280) and a grant from the National Research Foundation (NRF) of Korea (2017R1A2B2008422).
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
1267 - Genetic landscape of KEAP1 and NFE2L2 mutated cancers from the AACR GENIE database
Presenter: Mark Zaki
Session: Poster Display session 1
Resources:
Abstract
878 - β-arrestin1 is involved in the Ras-induced malignant transformation
Presenter: Takashi Shibano
Session: Poster Display session 1
Resources:
Abstract
4143 - Incidence of second cancer among PLWHIV: retrospective observational study of a series of 601 patients in the French CANCERVIH network
Presenter: Jean-Philippe Spano
Session: Poster Display session 1
Resources:
Abstract
5145 - A challenging task – Identifying carcinoma of unknown primary (CUP) patients according to ESMO guidelines: the CUPISCO trial experience
Presenter: Chantal Pauli
Session: Poster Display session 1
Resources:
Abstract
1737 - Incidence and Outcome of chronic lymphocytic leukemia with Deletion 17p: An Indian experience; challenges and opportunities
Presenter: Ajay Gogia
Session: Poster Display session 1
Resources:
Abstract
2596 - Driving solo? Investigation into collaborating mutations in SDH-deficient neoplasia
Presenter: Jonathan Killian
Session: Poster Display session 1
Resources:
Abstract
1499 - The potential of a novel antiangiogenic VEGFR1-D2 binding peptide in oncology therapeutics
Presenter: Afsaneh Sadre Momtaz
Session: Poster Display session 1
Resources:
Abstract
1775 - First-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumors
Presenter: Mayu Yunokawa
Session: Poster Display session 1
Resources:
Abstract
4584 - First-in-human study of ABBV-621 in patients (pts) with previously treated sold tumors: Dose-optimization cohorts
Presenter: Emiliano Calvo
Session: Poster Display session 1
Resources:
Abstract
3620 - Safety, efficacy, PK and PD biomarker results of the first-in-human study of mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor BAY 1436032 in patients (pts) with mIDH1 advanced solid tumours
Presenter: Wolfgang Wick
Session: Poster Display session 1
Resources:
Abstract