Preclinical validation of a novel therapeutic strategy for choroid plexus carcinoma Journal Article


Authors: Martin, B.; Garman, T.; Laramee, M.; Wang, A.; Zhang, X.; Beck, E.; Wilson, K.; Klumpp-Thomas, C.; McKnight, C.; Xu, X.; Hagen, N.; Holland, D.; Dahmane, N.; Thomas, C. J.; Souweidane, M.
Article Title: Preclinical validation of a novel therapeutic strategy for choroid plexus carcinoma
Abstract: Choroid plexus carcinoma (CPC) is a rare infantile brain tumor with an aggressive clinical course that often leaves children with debilitating side effects due to aggressive and toxic chemotherapies. Development of novel therapeutical strategies for this disease have been extremely limited owing to the rarity of the disease and the paucity of biologically relevant substrates. We conducted the first high-throughput screen (HTS) on a human patient-derived CPC cell line (Children Cancer Hospital Egypt, CCHE-45) and identified 427 top hits highlighting key molecular targets in CPC. Furthermore, a combination screen with a wide variety of targets revealed multiple synergistic combinations that may pave the way for novel therapeutical strategies against CPC. Based on in vitro efficiency, central nervous system (CNS) penetrance ability and feasible translational potential, two combinations using a DNA alkylating or topoisomerase inhibitors in combination with an ataxia telangiectasia mutated and rad3 (ATR) inhibitor (topotecan/elimusertib and melphalan/elimusertib respectively) were validated in vitro and in vivo. Pharmacokinetic assays established increased brain penetrance with intra-arterial (IA) delivery over intra-venous (IV) delivery and demonstrated a higher CNS penetrance for the combination melphalan/elimusertib. The mechanisms of synergistic activity for melphalan/elimusertib were assessed through transcriptome analyses and showed dysregulation of key oncogenic pathways (e.g. MYC, mammalian target of rapamycin mTOR, p53) and activation of critical biological processes (e.g. DNA repair, apoptosis, hypoxia, interferon gamma). Importantly, IA administration of melphalan combined with elimusertib led to a significant increase in survival in a CPC genetic mouse model. In conclusion, this study is, to the best of our knowledge, the first that identifies multiple promising combinatorial therapeutics for CPC and emphasizes the potential of IA delivery for the treatment of CPC. © 2023 Elsevier B.V.
Keywords: chemotherapy; cell death; melphalan; drug discovery; cell culture; brain; tumors; central nervous systems; mammals; in-vitro; pediatric brain tumors; glycoproteins; pharmacokinetics; brain tumors; pharmacokinetic; antibiotics; targeted drug delivery; therapeutic strategy; controlled drug delivery; choroid plexus carcinoma; paediatric brain tumours; chemogenomic; intra-arterial delivery; chemogenomics
Journal Title: Journal of Controlled Release
Volume: 357
ISSN: 0168-3659
Publisher: Elsevier B.V.  
Date Published: 2023-05-01
Start Page: 580
End Page: 590
Language: English
DOI: 10.1016/j.jconrel.2023.04.016
PUBMED: 37054779
PROVIDER: scopus
PMCID: PMC10174050
DOI/URL:
Notes: Article -- Export Date: 1 May 2023 -- Source: Scopus
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