Genetics-based diseases have proven difficult to develop therapies that bring the disease into remission without significant side effects. The central theme of the Mount Sinai Pilot Center for Precision Disease Modeling is to leverage the advantages of Drosophila and mouse genetics and stem cell technology to build a ‘functional network platform’ designed to identify therapeutics for colorectal cancer and Rasopathies. Our long-term objective is to further develop a platform and pipeline that can be adapted to a broad range of diseases, and share our platform with the applied science community.
This Specialized Center is supported by the Office of the Director, National Institute of Health, project # 1U54OD020355, program officer Oleg Mirochnitchenko. Project dates 8-1-2015 to 7-31-2020.
Genetics-based diseases have proven difficult to treat due to the complexity of the disease in the context of the whole body. At the Mount Sinai Pilot Center for Precision Disease Modeling, we are working to provide to the community a novel discovery platform designed to develop drugs and identify truly personalized therapeutics in a rapid, rational, and cost effective manner.
The Center leverages the advantages of the fruit fly Drosophila to build a ‘functional network platform’ designed to identify therapeutics that address disease complexity. We then use stem cell approaches to explore the most promising leads in a human cell context. Our overall objective is to further develop a platform and pipeline that can be adapted to a broad range of diseases.
We are currently focused on two diseases—colorectal cancer and RASopathy—to develop and demonstrate the strength of our platform to address both a rare Mendelian disease and one of the most common cancers. As our platform matures, we will offer a readily accessible standard operating procedure that will most efficiently bring our platform to the applied science community.
Featured in a new publication (Sonoshita et al, 2017 in press), we have used our Drosophila-chemistry platform to design a new generation of lead compounds for RET-dependent tumors. Using fly genetics to identify "pro-targets" and "anti-targets", we tuned the FDA approved drug Sorafenib to a better chemical space for RET-dependent tumors. The results were exceptionally improved activity in a mouse TT cell xenograft when benchmarked against Sorafenib (parent compound) and Cabozantinib (standard of care for RET-dependent Medullary Thyroid Carcinoma).
A key approach to our platform is the development of multi-targeting therapeutics. Working with SAGE Bionetworks, we are pleased to announce the Multi-targeting Drug DREAM Challenge. This challenge seeks to diversify the methods used to design drugs. Recent data supports the view that drugs designed to target multiple proteins can show increased efficacy, reduced toxicity, and in the case of cancer reduced susceptibility to emergent resistance. The challenge offers two medically-relevant sets of targets and anti-targets and asks participants to predict compounds with those activities. Submissions will be experimentally validated for desired binding activity by a commercial lab and for novelty by the challenge board. If you are interested in forming a team to participate an introductory webinar on Nov. 29, 2017 will discuss the challenge and present an "interactome" visualization of participant connections, to help stimulate team formation.
Advancing Drosophila Platforms for Therapeutics Discovery.
Novel Approach to Developing Polypharmacological Lead Compounds.
Using Human Induced Pluripotent Stem Cells for Drug Discovery in the RASopathies.
PDX-TIC: A Novel Platform for Discovery and Validation of Therapeutic Targets.
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