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 In Respiratory

Lung cancer tumours were prevented in mice by a novel small molecule that directly activates a tumour suppressor protein.

45 researchers, including eight students from the Young Scientist Foundation and Mark R Chance, PhD, Vice Dean for Research at Case Western Reserve School of Medicine, collaborated to screen a series of drug-like molecules for their ability to reactivate PP2A in lung cancer cells and prevent lung cancer tumors in mice.

The prototype drug molecules were created from FDA-approved medications by Michael Ohlmeyer, PhD, Associate Professor at Icahn School of Medicine at Mount Sinai.

The team found that one particular prototype drug can attach to a subunit of the PP2A protein, effectively activating the enzyme.

The study is the first to use a small molecule to directly activate an enzyme that removes phosphate molecules.

The prototype drug also prevented lung cancer cells from proliferating in laboratory models, including mouse models. Mice injected with the drug had fewer lung cancer tumours and did not experience weight loss or behavioural abnormalities associated with other cancer medications. In the mouse models, the drug was comparably effective to currently available combination therapies used to slow lung cancer progression.

To confirm exactly where the drug attaches to PP2A, the researchers also developed lung cancer cells with specific mutations at the putative drug binding site.

Mice with tumours created from the mutated cancer cells did not benefit from the prototype drug, as the drug could not attach to and reactivate PP2A. The results confirmed that the prototype drug attaches to PP2A at two specific amino acids within a subunit of the enzyme, information that could help inform other drug developers.

Author, Goutham Narla, MD, PhD, Pardee-Gerstacker Professor in Cancer Research, Associate Professor at Case Western Reserve University School of Medicine and member of the Case Comprehensive Cancer Centre Cleveland, Ohio.

‘This is the first example ever of a cancer drug that directly binds to and activates an enzyme that removes phosphate molecules.

‘Therefore, our findings could have broad applicability to the treatment of a large number of human cancers, including lung cancer as we demonstrated in this paper.’

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