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Cagan Lab - Research

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.


Adult fly eyes expressing the oncogenic (cancer-causing) RetM955T isoform show aspects of transformation. The 'rough' eye is rescued by feeding the RET fly moderate doses of the kinase inhibitor vandetanib. Large-scale screens are accomplished with robotics-based screening equipment.


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.


A whole animal approach to developing new therapeutics led to AD80 and AD81, promising anti-cancer agents that target multiple key kinases.


Other Diseases

    We collaborated 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.


The fly heart (green) and fly kidney ‘nephrocyte’ (red) fail on a high sugar diet.

   

 
lab info



Ross Cagan
PROFESSOR &
ASSOCIATE DEAN
Director, Center for Personalized Cancer Therapeutics
ross.cagan@mssm.edu

212-241-1427 (office)
212-241-0135 (lab)
212-860-9279 (fax)

lab members:
Bangi, Erdem
Das, Tirtha
Diaz, Jennifer
Esernio, Jessica
Hirabayashi, Susumu
Levine, Ben
Levinson, Sarah
Liang, Hsiao-Lin
Na, Jianbo
Smibert, Peter
Sonoshita, Masahiro
Teague, Alex

see photos and more here.
mailto:ross.cagan@mssm.edu?subject=caganlab.htmlcaganlab.htmlcaganlab.htmlcaganlab.htmlcaganlab.htmlcaganlab.htmlcaganlab.htmlcaganlab.htmlcaganlab.htmlcaganlab.htmlcaganlab.htmlcaganlab.htmlcaganlab.htmlshapeimage_16_link_0shapeimage_16_link_1shapeimage_16_link_2shapeimage_16_link_3shapeimage_16_link_4shapeimage_16_link_5shapeimage_16_link_6shapeimage_16_link_7shapeimage_16_link_8shapeimage_16_link_9shapeimage_16_link_10shapeimage_16_link_11shapeimage_16_link_12shapeimage_16_link_13
key publications

2013
Hirabayashi S, Baranski T, and. Cagan R. 
Transformed Drosophila Cells Evade Diet-Mediated Insulin Resistance Through Wingless Signaling.
Cell, 154(3):664-75.

Na J, Musselman LP, Pendse J, Baranski TJ, Bodmer R, Ocorr K, and Cagan R. 
A Drosophila Model of High Sugar Diet-Induced cardiomyopathy. 
PLOS Genetics, Jan;9(1):e1003175.

2012
Dar, A, Das, T., Shokat, K., and Cagan, R. 
Chemical Genetic Discovery of Targets and Anti-targets for Polypharmacological Treatment of Cancer. 
Nature, 486(7401):80-4.

2011
Johnson R., Sedgwick A, D’Souza-Schorey C, and Cagan R. 
Role for a Cindr-Arf6 axis in patterning emerging epithelia.
Mol. Biol. Cell, 22(23):4513-26.

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

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., 176(6): 3007-14.

2007
Vidal, M., Warner, S., Read, R. and Cagan, R.
Differing Src signaling levels have distinct outcomes in Drosophila.
Cancer Research, 67(21): 10278-85.

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

2005
Bao, S. and Cagan, R.
Preferential Adhesion mediated by Hibris and Roughest Regulates Morphogenesis and Patterning in the Drosophila Eye.
Developmental Cell 8(6), 925-35.

Read, R., Goodfellow, P., Mardis, E., Novack, N., and Cagan, R.
A Drosophila model of Multiple Endocrine Neoplasia Type 2.
Genetics 171, 1057-81.

Vidal, M., Wells, S., Ryan, A., and Cagan, R. 
ZD6474 supresses oncogenic Ret isoforms in a Drosophila model for Type 2 Multiple Endocrine Neoplasia Syndromes and Papillary Thyroid Carcinoma.
Cancer Research 65(9), 3538-41.

2004
Read, R., Bach, E., and 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 24(15), 6676-89.

2002
Hays, R., Wickline, L., and Cagan, R.
Degradation of a Drosophila IAP by the morgue ubiquitin conjugase.
Nature Cell Biology 6, 425-31.

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


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