The Simmons Family Foundation Collaborative Research Grant

 

Title:

Integrative Systems Biology Approaches for MB subtyping and Therapeutic Target and Drug Discovery

Description:

Medulloblastomas (MBs) are the most common malignant brain tumors of childhood, accounting for 20 - 25% of pediatric brain tumors1. Despite aggressive treatment with surgery, radiation to the brain and spine, and multi-drug chemotherapy for approximately 1 year, only about 50-60% of children survive 10 years after diagnosis 2,3. Essentially all survivors have extensive neurological and cognitive deficits, largely due to aggressive treatment, which prevent them from leading independent lives as adults. Recent studies have clearly indicated that they can be divided into at least 4 molecular subclasses based on gene expression profiles and these subtypes have prognostic significance5-7. Two of the subtypes are already known to be associated to the SHH pathway and the WNT pathway. However, the underlying pathways or mechanisms of the other two subtypes are still elusive.

To advance conventional therapy, we first need to accurately distinguish high-risk patients who need more treatment from good risk patients who can be put into long-term remission with lower doses of therapy that are less toxic to the nervous system. Furthermore, new molecular therapies are needed that specifically target tumor cells, leaving normal brain intact. We hypnotize that the systemic study of molecular pathways of different MB subtypes hold great potential for stratification of the sub-populations of patients with different risks, and prioritize the key targets, drugs and combinations for the nontoxic targeted therapy. In this proposal, we propose to develop a novel systems biology approach by integrating three different levels of genomic information, i.e., genotype and copy number, mRNA expression, and microRNA expression to characterize the releated molecular signaling pathways in these subtypes of MBs, and prioritize a list of potential drugs and pairwise drug cocktails targeting on these signaling pathways. As a good start point, we will conduct high content screening (HCS) to validate the top ranked drugs (compounds) and the cocktails on cell populations.