METOXIA

Metastatic tumours facilitated by hypoxic tumour micro-environments

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 Obiettivo del progetto (Objective)

'Recent research suggests that the hypoxic micro-environment of tumours is one of the major drivers of metastatic spread of cancer. Furthermore, hypoxic tumour micro-environments may result in treatment resistance of cancer cells, therefore causing a double effect of reducing the potential of a successful treatment of the cancer patient. This project seeks to clarify the roles and functions of the hypoxic tumour micro-environment in relation to the survival of solid tumours likely to metastasise. We will gain new knowledge about molecular mechanisms behind hypoxia-driven metastasis, like the epithelial-mesenchymal transition (EMT) by several routes: (a): mechanisms related to cell growth- and cell proliferation (UPR, mTOR, CA9, HIF, Notch, and VHL), (b): angiogenesis and lymphangiogenesis, (c): metabolism and pH-regulation (d): the handling of reactive oxygen species (ROS). We will generate animal models for the study of the role of hypoxia in metastases and develop a bio-bank of tumour and blood samples for molecular diagnostic studies. We will identify and develop advanced imaging techniques and biomarkers and identify micro-metastases in bone marrow of patients to assist in the selection of appropriate stratification of the actual primary tumour’s and metastases’ micro-environmental conditions. We will also create a machine-learning based classifier of tumour hypoxia. The consortium has the necessary expertise to perform proof-of-principle clinical testing of new treatment strategies. We will thus perform clinical tests of new drugs developed to attack the regulatory mechanisms selected from the pre-clinical work and possible synergisms of combined treatments. We will also test new radiotherapy strategies for treatment of primary as well as metastatic tumours. Cancer types chosen for clinical studies are non-small-cell lung carcinoma, squamous cell carcinoma of the larynx, prostate cancer, primary breast cancer and rectal cancer.'

Introduzione (Teaser)

Understanding how tumours spread and generate metastases is central to therapy. A large consortium of European scientists focused on hypoxia for answers.

Descrizione progetto (Article)

Cancer tumours are characterised by areas with lower oxygen levels compared to normal tissues, a phenomenon known as hypoxia. Emerging evidence indicates that hypoxia may negatively impact the outcome of radiotherapy and chemotherapy by reducing sensitivity, hampering drug access or inducing tolerance.

To survive unfavourable environmental conditions, cancer cells activate protective regulatory mechanisms, among them the ability to migrate to new areas in the body. Based on this hypothesis, the EU-funded 'Metastatic tumours facilitated by hypoxic tumour micro-environments' (http://www.metoxia.uio.no/ (METOXIA)) study set out to investigate the molecular mechanisms underlying hypoxia-driven metastasis. The aim was to help identify small molecules that could reduce metastasis and improve patient outcome.

METOXIA focused considerable efforts on determining the effect of the hypoxia inducing factor (HIF)and Notch on various essential cellular functions including metabolism and angiogenesis. In particular, inhibitors against the HIF-activated carbonic anhydrase IX protein reduced the metastatic potential of experimental tumours and raised their sensitivity to therapy. Additional putative hypoxia-activated targets include proteins that are implicated in pH regulation, metabolism and cell growth.

Scientists demonstrated that variations in tumour-oxygenation between deeper and more moderate hypoxia influences metastasis and response to therapy. This information will significantly impact both future research and the design of anti-cancer therapeutics.

An important deliverable of the METOXIA consortium was a list of hypoxia genes envisioned to predict the efficacy of hypoxic intervention. When tested in a large randomised phase III study, this hypoxia gene signature helped identify cancer patients who could be sensitised to radiotherapy.

METOXIA partners patented the generated inhibitor compounds and envision screening them in clinical tests in the near future. They have set up a spin-off company to further develop the patented inhibitors.

METOXIA activities provided basic knowledge into various mechanisms activated by tumour hypoxia. This improved understanding should lead to novel anti-cancer targets and new treatment strategies.