TRLS-04. PRECLINICAL VALIDATION OF A NOVEL THERAPEUTIC STRATEGY FOR CHOROID PLEXUS CARCINOMA

Choroid plexus carcinoma is a very rare pediatric tumor located in the fourth and lateral ventricles of the brain. It is known to have a severe clinical history and significant side effects because of intensive and noxious chemotherapies. Due to the disease’s rarity and the scarcity of biologically relevant substrates, the advance of new therapeutical techniques for this condition has been exceedingly constrained. A human patient-derived CPC cell line (CCHE-45, Children Cancer Hospital Egypt) was subjected to a high-throughput screen (HTS); 427 top hits were identified, highlighting critical molecular targets in CPC. Additionally, a combination screen with numerous different targets identified synergistic combinations that lead the way for brand-new CPC therapies. Based on in vitro efficiency, 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 studies revealed greater CNS penetrance via intra-arterial (IA) delivery compared to intravenous (IV) delivery, as well as increased CNS penetrance for melphalan/elimusertib combination. Transcriptome analysis was used to evaluate the mechanisms of melphalan/elimusertib synergistic effect; deregulation of several carcinogenic pathways (e.g. MYC, mTOR, p53) as well as the activation of vital biological processes were revealed (e.g. DNA repair, apoptosis, hypoxia, interferon gamma). In a CPC genetic mouse model, IA administration of melphalan and elimusertib significantly increased survival. To the best of our knowledge, this work is the first using human CPC cells to identify several prospective combinatorial treatments and it highlights the effectiveness of IA delivery for the treatment of CPC.