In September 2016, Paola Scaffidi's research group at the Crick reported in the journal Science that a key regulatory protein histone H1.0 is often turned off in cancer cells. It appeared that silencing H1.0 may be key to cancer cells' immortal properties. Finding a way to reactivate production of this protein could potentially lead to a new way to arrest tumor growth.
Paola and her group have a detailed knowledge of these biological processes in cancer cells. Using the small molecule library and high-throughput screening (HTS) facility available in-house at the Crick, she has screened several thousand small molecules to try and unlock the mechanisms that control H1.0 production. Working with chemists at AstraZeneca, Paola has analysed data from the screen.
She says her team and the AstraZeneca chemists take complementary approaches to handling the results.
"I think about physiological effect, and the question 'will the molecule affect the behavior of cancer cells?'" says Paola. "The Discovery Sciences team at AstraZeneca focuses on the biological target and the question 'which specific protein are you targeting with the molecules - or hits - identified in the screen?'"
It has been useful for me to work together and merge the two approaches to handle the results."
In the future, the AstraZeneca team may also support the project by supplying new compounds that are structurally similar to hits identified in the screen in order to validate them.
The collaboration is still in the early stages. But if screening does reveal a molecule of interest, the team will test it in vivo in animal models of cancer. Paola's ultimate goal is to determine whether pharmacological modulation of H1.0 can restore normal levels of the protein and so halt tumour growth.
