Drug Design and Disease Models: We can do it better in Drosophila.

Dr. Ross Cagan

     Last night’s “Future Advances in Drosophila Research” session of the Drosophila Research Conference concluded with Ross Cagan‘s eloquent defense of using Drosophila for better drug design and better disease models. He argues that Drosophila has significant advantages, including genetics, generation time, and tools, over other organisms (sorry mice) to model complexity (and complex diseases) He started with the premise that single genes that drive diseases such as cancer are not always the best therapeutic targets. Why? Because often times targeting their activity is highly toxic to the cell. He then went on to describe a Drosophila model for medullary thyroid carcinoma (MTC). About 95% of all MTC cases are due to genetic mutations that activate the RET kinase. Despite the fact that Drosophila do not have thyroids, Dr. Cagan was able to model MTC in the fly by directing expression of RET kinase mutants responsible for MTC in the eye which led to tumor growth:

Model for MTC in the Drosophila eye

     Furthermore, when he directed the expression more globally, the flies died before reaching adulthood. He then went on to describe a drug that was highly effective at rescuing these phenotypes known as AD1. Surprisingly, AD1 was not a very effective inhibitor of RET kinase activity or in his words the “world’s worst kinase inhibitor.” It wasn’t very specific and it wasn’t very effective. But this broad spectrum behaviour of AD1 was precisely why it was effective at rescuing the defects in the fly. RET kinase is a protein that regulates the activity of other kinases such as RAS, Src, PI3K (all of which are involved in cancer). Guess what? AD1 was targeting all of them. When the activity of other structurally similar compounds, AD2 and AD3, were compared to AD1 they were less efficacious because they were unable to target all of those other kinases. More importantly, since AD1 was “the world’s worst kinase inhibitor” it displayed little toxicity to the animal as a whole indicating that tumors might have lower tolerance thresholds for drugs than the entire animal. All of which to say is that a focused approach on a single target over a multitarget approach is not always the best course given that cancer is a complex disease.

     This multitarget approach segued nicely into the second part of his talk where he focused on building better models for disease in Drosophila. He highlighted the work done by a post doc in his lab, Erdem Bangi (a former graduate student the Wharton lab where I work in now), who is designing a better model for colorectal cancer. Treatment for colorectal cancer is an unmet need in the healthcare. Building on the idea of multiple targets and the fact that tumors often exhibit mutations in multiple closely associated genes rather than just one gene, Dr. Bangi is creating mutant flies with different combinations of mutations in different genes. We’re talking double, triple and quadruple mutants. In these multiple mutant flies, Dr. Bangi found that drugs that were previously effective in models where only one particular gene was mutated were effectively useless. This harkens back to the original premise that targeting the single gene driving disease is not always the best approach. Dr. Bangi is now using these multiple mutant flies to design and discover more effective drugs.

     The work highlighted by Dr. Cagan last night is important in that it represents a shift in how we discover drugs and how we should think about treating diseases. Rather than just taking a chemical and testing to see if it can rescue a particular phenotype, this research underscores the importance of knowing the role of multiple gene targets in disease progression. His talk highlighted not only the value of basic research in drug discovery and design but also the intrinsic advantages of Drosophila as a model organism. Can we do it better in Drosophila? Come on everybody altogether: Yes we can! (and my pandering to Chicago continues…)

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