Prof Ross Cagan - Biology of Therapeutics

Introduction

Cagan Ross The Cagan laboratory uses Drosophila to explore the biology of therapeutics. Data from several laboratories including our own have highlighted the role of genomic complexity in cancer drug resistance. To explore this, we have developed genomically complex fly models of cancer (colorectal, thyroid, breast, lung) and rare genetic diseases (primarily RASopathies). These act as a starting point for our work in mammalian models, both directly and with our collaborators.

Each personalised fly 'avatar' line models a different patient, each with typically 5-15 altered genes. While targeted therapies are effective in '2-hit' models, 12-hit models—even with many of the same cancer drivers—are often resistant to these same therapies.

We are leveraging our fly platform containing dozens of avatar lines to explore changes in transformation that come with genomic complexity. This has led to an ongoing 'fly-to-bedside' clinical trial in which 'personalised fly avatars' are used to identify therapeutic cocktails unique to each patient.

Further, we are working with chemists to address disease complexity through drug cocktails and through building a new generation of 'network-based' novel lead compounds that address tumour and rare disease complexity through multi-targeted 'polypharmacology'.

Other funding:

Lab Report

pdf Cagan Lab Report (912 KB)

Key Publications

Das TK, Gatto J, Mirmira R, Hourizadeh E, Kaufman D, Gelb BD, Cagan R. Drosophila RASopathy models identify disease subtype differences and biomarkers of drug efficacy. iScience. 2021;24(4):102306.

Bangi E, Smibert P, Uzilov AV, Teague AG, Gopinath S, Antipin Y, Chen R, Hecht C, Gruszczynski N, Yon WJ, Malyshev D, Laspina D, Selkridge I, Wang H, Gomez J, Mascarenhas J, Moe AS, Lau CY, Taik P, Pandya C, Sung M, Kim S, Yum K, Sebra R, Donovan M, Misiukiewicz K, Ang C, Schadt EE, Posner MR, Cagan RL. A Drosophila platform identifies a novel, personalized therapy for a patient with adenoid cystic carcinoma. iScience. 2021;24(3):102212.

Bangi E, Ang C, Smibert P, Uzilov A, Teague A, Antipin Y, Chen R, Hecht C, Gruszczynski N, Yon W, Malyshev D, Laspina D, Selkridge I, Rainey H, Moe A, Lau CY, Taik P, Wilck E, Bhardwaj A, Sung M, Kim S, Yum K, Sebra R, Donovan M, Misiukiewicz K, Schadt E, Posner M, and Cagan R. A Personalized Platform Identifies Trametinib Plus Zoledronate For A Patient With KRAS-Mutant Metastatic Colorectal Cancer Science Advances 2019;5(5):eaav6528.

Ung P, Sonoshita M, Scopton A, Dar A, Cagan R, Schlessinger A. Integrated computational and Drosophila cancer model platform captures previously unappreciated chemicals perturbing a kinase network. PLoS Comput Biol. 2019; 15:e1006878.

Das TK, Esernio J, Cagan R. Restraining Network Response to Targeted Cancer Therapies Improves Efficacy and Reduces Cellular Resistance. Cancer Research 2018;78:4344-59.

*Sonoshita, M., *Scopton, A., Ung, P., Murray, M., Silber, L., Maldonado, A., Real, A., Schlessinger, A., **Cagan, R., **Dar, A. A Whole Animal Platform to Advance A Clinical Kinase Inhibitor Into New Disease Space. Nature Chemical Biology 2018;14:291-98. *Co-first authors; **co-corresponding authors.

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

*Dar AC, *Das T, Shokat KM, and Cagan R. Chemical Genetic Discovery of Targets and Anti-targets for Polypharmacological Treatment of Cancer. Nature 2012;486:80-4. *Co-first authors.