Our goal is to explore the biology of therapeutics. Why do lead compounds work well in model systems but most fail in clinical trials? Our lab is devoted to embracing complexity, both in our models and in the therapeutics we are developing. Oh, and we use the fruit fly Drosophila as our starting point.
We explore two categories of disease: cancer [thyroid, colorectal, breast, lung] and Mendelian (inherited) diseases [RASopathies, Tauopathies]. We use flies and mammalian models (cell lines, mouse xenografts) to explore therapeutic mechanisms, to develop new lead compounds, and to execute a fly-to-bedside clinical trial where we treat cancer patients. Please explore our website to see our innovative approaches to therapeutics.
The primary focus of our laboratory is cancer. We contribute to the cancer field in two broad ways. First, we build highly complex Drosophila models designed to capture the genomic complexity of individual human colorectal, thyroid, lung, and breast cancer patients. These ‘fly avatars’ allow us to explore how altering 5-15 genes in a single transgenic animal alters tumor progression and drug response.
Our second approach is drug development. Working with our close collaborators Arvin Dar, Avner Schlessinger, and their teams, we have developed a novel platform—combining fly genetics with medicinal and computational chemistry—to develop lead compounds that attack the cancer network in the context of the whole animal. These ‘Tumor Calibrated Inhibitors’ represent a new way towards addressing drug liabilities including resistance and toxicity.
Fly-To-Bedside Clinical Trial
Based on our work exploring the relationship between genomic complexity and drug resistance, we opened a fly-to-bedside clinical trial as part of the Center for Personalized Cancer Therapeutics, and published our first fly-to-patient report (PMID: 31131321). For more details, see our CPCT web site.
The RASopathies are a family of inherited disorders characterized by mutations that activate the RAS/ERK signaling network. Patients present with a broad palette of developmental and post-natal defects. Currently, only symptomatic care is available for affected individuals. We are working with Bruce Gelb and colleagues to develop 14 new RASopathy models, exploring the biology and developing new lead therapeutics.
Tauopathies are a family of neurodegenerative diseases (Alzheimer’s, Pick’s, FTDP-17, etc.) that are driven by abnormal Tau protein. We are working with Alison Goate and colleagues on inherited Tauopathy isoforms. Using previously developed Drosophila models, we are using our fly/chemistry platform to explore new avenues for candidate therapeutics. Promising hits then are assessed in human models.