Choroid plexus carcinoma (CPC) is a cancer of specialized tissues deep inside the brain that produce cerebrospinal fluid. CPC is a childhood cancer, particularly affecting infants under 3 years old. It is also rare, affecting only 2% of children with brain tumors or less than 50 children each year in the USA. Because of its rarity, CPC has not attracted the attention of the research community; there have been few publications on CPC and no advances in the treatment of this disease over the last 25 years, even though more than half of affected children die within 5 years. Our scientific team aims to improve the poor outcome for children with CPC by developing novel targeted drug therapies of proven efficacy, which can be incorporated into clinical trials after 3 years of intensive research.

Our CPC team brings together expertise from two of the leading North American children's cancer hospitals, St. Jude Children's Research Hospital and the Hospital for Sick Children in Toronto. Our expertise spans the fields of clinical pediatric neuro-oncology, neuropathology, developmental neurobiology, molecular genetics, mouse models of cancer, drug development/screening, and toxicology, and our institutions benefit from significant core scientific resources that facilitate multidisciplinary research programs. Critical for this project, our team benefits from having access to a large series of more than 80 human CPCs and a novel mouse model of CPC.

Specific Aim 1 of the project involves analysis of childhood CPCs and mouse model CPCs for genetic mutations. The human tumors are from the largest cohort of rigorously characterized patients in the world. Using modern array-based methods, we can screen the DNA of CPC tumor cells to determine which genes might have critical tumor-generating mutations. Confirmation that mutations discovered through such screens can affect a gene's activities in the cancer cell, and are present in both human and mouse model tumors and will allow us to produce a priority list of gene candidates with the most potential to cause CPCs through their mutations. This information has direct clinical relevance since it will allow us to identify possible new drug targets that we will study in the later phases of the project. Furthermore, it will provide the wider research community with an unprecedented resource to plan other studies of CPC.

Specific Aim 2 involves a high-throughput drug screen, which can determine the activity of thousands of drug compounds against cancer cells using robotic technology. Cells from CPCs generated in our mouse model will be treated with thousands of compounds previously not tested in this disease. These include FDA-approved chemotherapies as well as new 'smart' drugs that target the gene mutations identified in Specific Aim 1. This technology has been used rarely to develop therapies for childhood cancer and never for CPC. Promising new agents from this screen will be tested in our mouse model in Specific Aim 3.

Specific Aim 3 will take lead compounds from the high-throughput drug screen and determine their efficacy against CPCs generated in our mouse model. These will be tested against a control for their anti-tumor activity using both clinical (MRI brain scanning and examination) and pathological (microscopic assessments of tumor growth or death) measures. Evaluation of a novel therapeutic agent's toxicity is an important element of its development. Newborn animals are particularly susceptible to the toxic effects of drugs, and because of the young age of CPC patients, we plan a systematic toxicological screen of the compounds in normal young rats, in accordance with FDA recommendations, as well as in tumor-bearing mice. Using the resources of our Veterinary Pathology core, this screen will involve a detailed assessment of different organs by microscopy.

By identifying lead compound(s) for the treatment of CPC, our proposal has great potential to significantly accelerate the eradication of the disease and improve patient care. Furthermore, our comprehensive comparative analysis of mutations in human and mouse CPC will provide crucial genetic data for future studies of the disease. Finally, this proposal will set the standard for conducting appropriate developmental toxicology studies of agents aimed at treating cancers in very young children.