“Our work is relevant for almost all cancers,” says Professor Sonia Rocha, Executive Dean for Institute of Systems and Integrative Biology at the University of Liverpool. “When I started in this area, I thought it was relevant mostly to solid cancers, but it turns out that even blood cancers use the pathways we investigate.”
The metabolic pathways that Rocha’s lab and wider colleagues are unravelling are related to hypoxia – the depletion of oxygen to low levels in the cell. Under low oxygen conditions, cellular mechanisms are activated that protect cancer cells from existing pharmaceutical therapies, leading to drug resistance. In a molecular double-whammy for the patient, these mechanisms allow the cancer cells to better utilise nutrients and space to survive in the low oxygen conditions that typically kill normal cells.
How do cancer cells pull of this deadly trick? It comes down to certain proteins called transcription factors, which are gene controllers in charge of turning on and off parts of the DNA to protein synthesis process. Drug targets are usually enzymes, but Rocha says that in the last two to three years, they've been able to actually target the transcription factors that up until now I've been out of reach from the pharmaceuticals industry.
“In our area of low oxygen deprivation research, there is one major family of transcription factors called hypoxia inducible factors (HIF), and their discovery warranted the Nobel Prize in Physiology and Medicine in 2019,” Rocha explains. And this family of HIF transcription factors is the common target because all cells use it and cancer metabolic processes sends it into overdrive.
“At present we can only target one of the three components of this HIF master regulation family, but it's very promising because there are certain types of cancers, such as breast cancer as well as renal cancer, where this targeting particular subtype of regulator is the driver force for the survival.”
Rocha says Liverpool is well placed to improve the therapies related to the HIF family of transcription factors, because the university has significant expertise the many tumour sites affected which is an area of excellence. “We're very lucky in Liverpool to have amazing shared research facilities, and a lot of this work needs collaboration. We can go from the atomic level, using both NMR and then x-ray crystallography, all the way to preclinical imaging in our advanced microscopy facility to see how things are moving using real-time cell imaging.”
Previous research by Rocha and colleagues has found a link between inflammation and hypoxia. Many cancer patients experience inflammation as a normal response to damage, but the storm on inflammatory cytokines can activate the HIF-regulated hypoxia response. This work found a key part of the puzzle as to why inflammation was so often associated with negative outcomes in cancer patient care.
The work is catalysed by the Liverpool Research Cancer Institute, a strategic initiative to build on existing expertise to accelerate research translation towards improved patient outcomes. It’s a collaboration between the University of Liverpool, the Clatterbridge Cancer Centre – now ably served by an ultra-modern new building – and Northwest Cancer Research and Liverpool Health Partners. Working with patient-facing clinical researchers was a key motivation for Rocha to take her work to Liverpool.
Rocha’s work continues with efforts to understand HIF interactions with chromatin and histones – key sites for gene expression control– to develop better drug therapies, alongside efforts to better implement existing enzyme-based pharmaceuticals.
Back to: Liverpool Cancer Research Institute