Treating the underserved-developing transformative therapies for choroid plexus carcinoma

For more than two decades brain tumors have remained the most common cause of cancer-related death in children. Identifying cures for the rarest brain tumors has proved particularly difficult, since limited patient numbers severely impede studies of tumor biology and clinical trials. Progress has also been limited by the use of inaccurate preclinical pipelines that fail to identify drugs with therapeutic activity in patients. This is because current drug pipelines typically: (i) focus on repurposed drugs alone, rather than brain tumor-specific therapies; (ii) employ poorly characterized subcutaneous tumor xenografts, rather than accurate orthotopic models of pediatric brain tumors; (iii) do not assess the survival benefit of new treatments relative to that afforded by existing combination neurosurgery, radiation and chemotherapy; and (iv) cannot be used to develop combination regimens of conventional and novel treatments. Preclinical pipelines that accurately predict effective drugs are especially important for rare brain tumors, since imprecise selection of drugs condemns entire generations of children with these tumors to ineffective clinical trials. Thus, research that accounts for the rarity and unique biology of these tumors is critical if we are to offer these children and their families a hope of cure. To this end, our collaborators’ recently established the United Kingdom’s first Cancer Research UK Children’s Brain Tumor Centre of Excellence (CRUK-CBTCE): a transformative initiative, organized around an innovative biology-driven drug development pipeline, with the specific intent of generating curative, brain tumor specific treatments for children, wherever they live. The CRUK-CBTCE has enabled the congregation of a critical mass of expert personnel, infrastructure and global collaborations; but it does not support the actual studies that will use this infrastructure to generate specific treatments. Here, we propose to exploit the infrastructure provided by the CRUK-CBTCE to conduct the first tranche of pipeline studies. Our goal is to develop at least three new, ‘clinical trial-ready’ treatments, specifically for children with choroid plexus carcinoma (CPC) and/or supratentorial C11orf95-RELA ependymoma (ST-EP-RELA) – two rare and aggressive childhood brain tumors. Fewer than 20 children are diagnosed with either CPC or ST-EP-RELA each year in the UK. It is therefore not surprising that no new treatments of these tumors have been developed in the last 30 years and even ‘standard’ therapy for these children remains controversial. Regardless of the treatment these children receive, the majority will relapse within 5 years of diagnosis. Our research strategy is centered around an innovative, biology-driven, drug discovery and development pipeline that integrates a multi-disciplinary team of leading experts in developmental and pediatric brain tumor biology, medicinal chemistry, pharmacology, and adult and pediatric preclinical and clinical trials as well as patient and parent advocates. The assembly of such a team, drawn from multiple countries and institutions, with the sole focus of developing new treatments of pediatric CPC and ST-EPN-RELA is unprecedented. We have already developed genetically engineered and patient-derived xenograft mouse models of CPC and ST-EP-RELA, and confirmed that these recapitulate the histology and molecular biology of the human disease. We have also characterized the sensitivity of these models to concurrent neurosurgery, radiotherapy, and chemotherapy, and used them in high-throughput screening (HTS) of over 1.2 million compounds. Our HTS studies have pinpointed potential new treatments for further study. Importantly, these include both existing drugs that can be repurposed for rapid translation to the clinic, as well as new chemical entities and natural products.