Fly Model Identifies Targeted Combination Therapy for NSCLC

Combining a drug indicated for melanoma with a common cholesterol-lowering drug may control the growth of non-small cell lung cancer (NSCLC), according to research in fruit flies and human lung cancer cell lines that was recently published in Cell Reports.1 The combination uses trametinib, which is FDA-approved for melanoma, and fluvastatin, a cholesterol-lowering drug.

Lung cancer continues to be the number 1 cancer killer, causing more deaths than breast, prostate, colon, and pancreatic cancers combined. It is typically discovered at later stages, when treatments are not successful. Furthermore, current therapies are highly toxic. Researchers are seeking targeted therapies that are effective and not harmful to unaffected tissues.

In this study, researchers used the fruit fly Drosophila as a model organism in which they developed a multigene lung cancer model so they could better understand the mechanisms that promote tumors in NSCLC. The research team was led by Ross Cagan, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York. Their research targeted 2 of the most common genetic mutations associated with NSCLC: Ras and PTEN (P13K).

"We developed Drosophila lung cancer models by targeting Ras alone and in combination with PTEN knockdown in the tracheal system of the fruit fly," said Cagan, professor in the Department of Developmental & Regenerative Biology, senior associate dean of the Graduate School of Biomedical Sciences, and director of the Center for Personalized Cancer Therapeutics at Icahn School of Medicine at Mount Sinai. "This led to formation of tumor-like growths."

A robotics-based screening approach allowed the researchers to screen a library of 1192 FDA-approved drugs for any that suppressed tumors in the fly. They identified several that improved overall survival. They then further explored combining 2 drugs, the FDA-approved melanoma drug trametinib and fluvastatin, a common cholesterol-lowering drug. Oral administration of these drugs inhibited Ras and PI3K pathway activity, respectively, and combining both drugs led to suppression of tumor formation.

"Our study results suggest a new drug cocktail that is effective in both human lung cancer cell lines and fly models," said Cagan. "Next steps are to further explore this possibility in human trials in order to assess if it will help patients, but these 2 drugs make sense from a variety of studies and we find that they act together through multiple mechanisms to control cancer growth in the laboratory."

Cagan explained that fruit flies are an important animal tool in the fight against cancer. They provide new understanding of disease biology on the molecular and genetic level, leading to treatments that more specifically kill cancer cells. Use of this knowledge to screen several different drugs, or combinations of drugs, is emerging as an important approach to cancer treatment.

REFERENCE

1. Levine BD, Cagan RL. Drosophila lung cancer models identify trametinib plus statin as candidate therapeutic. Cell Rep. 2016;14(6):1477-1487. doi:10.1016/j.celrep.2015.12.105.

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