Preclinical validation of a novel therapeutic strategy for choroid plexus carcinoma

by Selleckchem | Aug 19 2023

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.

Comments:

The study you described is significant as it represents the first high-throughput screen conducted on a human patient-derived choroid plexus carcinoma (CPC) cell line, leading to the identification of potential molecular targets in CPC. The rarity of CPC and the lack of biologically relevant substrates have hindered the development of effective therapeutic strategies for this aggressive brain tumor, which often affects infants and can result in debilitating side effects due to current chemotherapies.

The researchers performed a combination screen using various targets and identified multiple synergistic combinations that may serve as novel therapeutic approaches against CPC. Based on in vitro efficiency, central nervous system (CNS) penetrance ability, and translational potential, two combinations were further validated in both in vitro and in vivo models. These combinations involved the use of DNA alkylating or topoisomerase inhibitors in conjunction with an ataxia telangiectasia mutated and rad3 (ATR) inhibitor, specifically topotecan/elimusertib and melphalan/elimusertib, respectively.

Pharmacokinetic assays demonstrated that intra-arterial (IA) delivery had superior CNS penetrance compared to intravenous (IV) delivery. Moreover, the combination of melphalan/elimusertib exhibited higher CNS penetrance than topotecan/elimusertib. This finding is crucial because effective delivery to the brain is often a challenge in the treatment of brain tumors.

The mechanisms underlying the synergistic activity of melphalan/elimusertib were investigated through transcriptome analyses, which revealed 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). These findings shed light on the molecular mechanisms involved in the therapeutic response of CPC to this particular combination.

Importantly, the study also demonstrated the significant increase in survival achieved through IA administration of melphalan combined with elimusertib in a CPC genetic mouse model. This result underscores the potential of IA delivery as a treatment strategy for CPC.

In summary, this study represents a significant milestone in CPC research by identifying multiple promising combinatorial therapeutic options and highlighting the potential of IA delivery for the treatment of this rare and aggressive brain tumor. These findings provide a foundation for further investigations and potential clinical trials aimed at improving the outcomes for children with CPC while minimizing the adverse effects associated with current treatment modalities.