Boosting antitumor immunity to treat pediatric choroid plexus carcinoma
Choroid plexus carcinoma (CPC) is an aggressive and rare malignant disease mainly observed in young children with a median progression-free survival of ~13 months. Chemotherapy, radiotherapy, and surgery are the only currently available therapeutic options in children with CPC. A prospective clinical trial CPT-SIOP-2000 showed the clinical benefit of carboplatin/etoposide/vincristine combo therapy in CPC patients, with 62% and 47% progression-free survival rates at 5 and 10 years, respectively. Elimusertib/melphalan, Dinaciclib, and triptolide, are also shown to inhibit CPC cell growth in the in vitro and/or in vivo preclinical models. However, the clinical benefits of these treatments remain limited, with critical concerns about toxicity in children. There are lack of reliable biomarker studies that define effective treatment strategies in pediatric CPC, which are important for achieving better therapy outcomes, as seen in many successful cancer treatments. No targeted therapies have been approved by the FDA for pediatric CPC. These challenges highlight an unmet clinical need for new effective therapiesto combat this deadly disease in children.
Project Goals
We recently undertook efforts to screen FDA-approved drugs in two integrated cross-species CPC modelsincluding human CPC cells and mouse CPC tumor spheroids and identified Selinexor asthe top candidate for effectively killing CPC. Selinexor is a specific exportin 1 inhibitor that has been FDA approved for the treatment of multiple myeloma and diffuse large B-cell lymphoma and is safe in children. The objectives of this proposal are to evaluate therapeutic potential of Selinexor in the preclinical pediatric CPC models and to understand the mechanism behind thistargeted therapy. To this end, we have developed a genetic mouse model of CPC, which resembles human CPC. By integrating this valuable genetic mouse model with patient-derived CPC cells, we will conduct thorough studies with two specific aims to achieve our proposed objectives. The multi-pronged approaches we proposed ensure a direct clinical relevance and a strong scientific rigor of this project. Insights gained from this project may pave the way for a more effective and less toxic therapeutic option against CPC, a currently incurable disease in children.
