Ross L Cagan, PhD

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.

Cancer 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.

Cancer Drugs

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.

Other Diseases

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.

Das TK, Esernio J, Cagan R. . Cancer research 2018 May;.

Das TK, Cagan RL. Non-mammalian models of multiple endocrine neoplasia type 2. Endocrine-related cancer 2018 Feb; 25(2).

Sonoshita M, Scopton AP, Ung PM, Murray MA, Silber L, Maldonado AY, Real A, Schlessinger A, Cagan RL, Dar AC. A whole-animal platform to advance a clinical kinase inhibitor into new disease space. Nature chemical biology 2018 Jan; 14(3).

Schlessinger A, Abagyan R, Carlson HA, Dang KK, Guinney J, Cagan RL. Multi-targeting Drug Community Challenge. Cell chemical biology 2017 Dec; 24(12).

Das TK, Cagan RL. KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub. Cell reports 2017 Sep; 20(10).

Cagan R, Meyer P. Rethinking cancer: current challenges and opportunities in cancer research. Disease models & mechanisms 2017 Apr; 10(4).

Bangi E, Murgia C, Teague AG, Sansom OJ, Cagan RL. Functional exploration of colorectal cancer genomes using Drosophila. Nature communications 2016 Nov; 7.

Levinson S, Cagan RL. Drosophila Cancer Models Identify Functional Differences between Ret Fusions. Cell reports 2016 Sep; 16(11).

Levine BD, Cagan RL. Drosophila Lung Cancer Models Identify Trametinib plus Statin as Candidate Therapeutic. Cell reports 2016 Jan;.

Hirabayashi S, Cagan RL. Salt-inducible kinases mediate nutrient-sensing to link dietary sugar and tumorigenesis in Drosophila. eLife 2015 Nov; 4.

Cagan R. Drug screening using model systems: some basics. Disease models & mechanisms 2016 Nov; 9(11).

Na J, Sweetwyne MT, Park AS, Susztak K, Cagan RL. Diet-Induced Podocyte Dysfunction in Drosophila and Mammals. Cell reports 2015 Jul;.

Hirabayashi S, Baranski TJ, Cagan RL. Transformed Drosophila cells evade diet-mediated insulin resistance through wingless signaling. Cell 2013 Aug; 154(3).

Dar A, Das T, Shokat K, Cagan R. Chemical Genetic Discovery of Targets and Anti-targets for Cancer Therapy. Nature 2012; 486(7401).

Johnson R, Sedgwick A, D’Souza-Schorey C, Cagan R. Role for a Cindr-Arf6 axis in patterning emerging epithelia. Mol. Biol. Cell 2011;(22(23)): 4513-4526.

Vidal M, Salavaggione L, Ylagan L, Wilkins M, Watson M, Weilbaecher K, Cagan R. A Role for the Epithelial Microenvironment at Tumor Boundaries: Evidence from Drosophila and Human Squamous Cell Carcinomas. Am J Pathol 2010; 176(6): 3007-3014.

Cordero J, Macagno J, Stefanatos R, Strathdee K, Cagan R, Vidal M. Oncogenic Ras diverts a host TNF tumor suppressor activity into tumor promoter. Dev Cell 2010; 15(18(6)): 999-1011.

Vidal M, Warner S, Read R, Cagan R. Differing Src signaling levels have distinct outcomes in Drosophila. Cancer Research 2007; 67(21): 10278-10285.

Vidal M, Larson D, Read R, Cagan R. Drosophila Csk regulates oncogenic growth through multiple mechanisms. Developmental Cell 2006; 10(1): 33-44.

Vidal M, Wells S, Ryan A, Cagan R. ZD6474 supresses oncogenic Ret isoforms in a Drosophila model for Type 2 Multiple > Endocrine Neoplasia Syndromes and Papillary Thyroid Carcinoma . Cancer Research 2005; 65(9): 3538-3541.

Bao S, Cagan R. Preferential Adhesion mediated by Hibris and Roughest Regulates Morphogenesis and Patterning in the Drosophila Eye . Developmental Cell 2005; 8(6): 925-935.

Read R, Goodfellow P, Mardis E, Novack N, Cagan R. A Drosophila model of Multiple Endocrine Neoplasia Type 2. Genetics 2005; 171: 1057-1081.

Read R, Bach E, Cagan R. Drosophila C-terminal Src kinase negatively regulates organ growth and cell proliferation through inhibition of the Src, Jun N-terminal kinase, and STAT pathways . Mol Cell Biol 2004; 24(15): 6676-6689.

Hays R, Wickline L, Cagan R. Degradation of a Drosophila IAP by the morgue ubiquitin conjugase. Nature Cell Biology 2002; 6: 425-431.

Powell P, Wesley C, Spencer S, Cagan R. Scabrous mediates long-range signaling by Notch. Nature 2000; 409: 626-630.