A Fly Approach to Disease
Cancer has proven a difficult disease to achieve significant long-term advances in patient survival; improvements in survival are often measured in months. My laboratory has undertaken a genetic and drug screening approach targeting cancer—and more recently diabetes and rare genetic diseases—using the fruit fly Drosophila. We use an integrated approach: genes and drugs identified in flies are then brought to rodent models and ultimately to clinical trials; sequencing and histological data from humans are then brought back to our fly models to allow us to develop increasingly sophisticated fly models.
My laboratory has developed a Drosophila model for Medullary Thyroid Carcinoma (MTC). Targeting oncogenic Ret to the eye, we phenocopied many aspects of the human syndrome (Figure). With this model in hand, we utilized a classical genetic modifier screen to identify 140 factors that function in the oncogenic process. More recently we have developed models for lung, breast, and colorectal cancers, exploring both the biology and therapeutics response for each tumor type.
Personalized Fly Avatars and Center for Personalized Cancer Therapeutics
Our data and others have emphasized the complexity of tumor biology. For example, we found that most drugs that work well in genetically simple fly and mouse models of colorectal cancer (e.g., Ras) work poorly in more complex models (e.g., Ras-Pten-Apc-P53). This mirrors the remarkably high failure rate of candidate therapeutics in cancer clinical trials.
To address this complexity, we developed technology to build fly cancer models that target 12 or more genes altered in a single patient, providing a unique opportunity to capture complex tumors in a whole body context. The Center for Personalized Cancer Therapeutics is using this technology to create personalized fly avatars for each enrolled patient; robotics-based screening is then used to identify candidate drugs or drug cocktails tailored to each patient (Figure). This open-label clinical trial represents a uniquely personalized approach to treating cancer patients.
We used our fly MTC model as a screen to identify vandetanib, a kinase inhibitor that was subsequently approved for MTC (see Figure above). More recently we have collaborated with Arvin Dar, Avner Schlessinger, and colleagues to develop a new approach to creating complex drug leads. Built by combining fly genetics with medicinal and computational chemistry (Figure), these “polypharmacology” based compounds are designed to address disease complexity at the level of the whole body by inhibiting multiple targets defined in our genetic screens. Our goal is address disease by embracing its complexity, with therapeutics designed to address networks not single targets.
Wecollaborated with Tom Baranski's laboratory to create a model system for Type 2 Diabetes. Flies placed on a high-carbohydrate diet demonstrate a broad range of defects that share important properties with human diabetics: obesity, hyperglycemia, insulin resistance, etc. lead to aspects of diabetic cardiomyopathy (heart failure) and diabetic nephropathy (kidney failure; see Figure). We are exploring the mechanisms by which these organs fail, and are working towards candidate therapeutics. We have also initiated studies using fly models of the inherited diseases Rasopathies and Tauopathies, with the goal of using our maturing platforms to both understand the disease and identify therapeutics best tailored to the whole body. In each case—cancer, diabetes, genetic diseases—our goal is the same: capture the whole body complexity of the disease and develop therapeutic leads designed to address both efficacy and whole body toxicity.