Selecting Hypoxic Tumours for Treatment Modification

Research Question: Can hypoxia biomarkers personalised treatment improve cancer outcomes?

Cancers that are hypoxic (have a high percentage of regions of low local O2 concentration) are refractory to radiotherapy but benefit from hypoxia modification. However, there are no biomarkers to identify patients with hypoxic tumours. The gold standard for determining tissue O2 concentration is the O2-electrode which takes measurements at several sites within the tumour. However, this necessitates insertion of a needle into multiple regions of the tumour so is invasive and provides only a localised hypoxia status. Other hypoxia biomarkers that identify hypoxia have been derived from cell surface protein expression, gene expression or imaging outputs. Proteins expressed on the tumour cell surface of hypoxic cells include CA9 and glut1 but the expression of these proteins is not specific to hypoxia and is highly heterogeneous within tumours. Whilst expression of HIF1 by hypoxic tumours has been shown not to predict benefit from hypoxia-modification. Gene signatures are a set of genes in which the collective changed expression has been validated to demonstrate diagnosis, prognosis or predict therapeutic response. Gene expression is consistently altered across tumours with high hypoxic fractions meaning that they are robust indicators of hypoxia status.

Using RNA extracted from archived material (Formalin fixed paraffin embedded tumour tissue) our gene-expression signature-based biomarkers for bladder, head and neck, prostate, sarcoma, cervical and lung cancers have been validated by demonstrated prognosis in each of the cancer groups. Further the 24 gene bladder cancer hypoxia signature has been shown to be predictive of benefit from hypoxia modification for patients with hypoxic tumours receiving radiotherapy. A recent review of predictive biomarkers in cancer treatment has shown that this is the only predictive biomarker for hypoxia-modification during radiotherapy.

Hypoxic regions in tumours can also be identified using MRI techniques including O2-senstive MRI (OE-MRI) and Intravoxel incoherent motion imaging. Combining imaging with gene expression data results in more accurate assessment of hypoxic status and identify tumour subtype which further contributes to personalised clinical decisions. MRI-based techniques also facilitate localized personalization approaches, e.g., for hypoxia-directed focal radiotherapy dose escalation.

Primary Question/Objective:

Short objective; to establish trials to test if personalised use of established hypoxia-targeted treatments with radiotherapy improves survival and work with the North West Genomics Hub to progress implementing our tissue hypoxia test for delivery across the NHS.

Medium objective; integrate MR imaging in the workflow for measuring hypoxia in at least two tumour sites.

Secondary Question/Objective:

• Integrate radiological parameters with the hypoxia biomarker for personalising treatment.
• Can blood-based biomarkers be early response biomarkers.

Inclusion criteria

This will be tumour site dependent.

Bladder:

• Older than age 18 years.
• Patients having radiotherapy at the Christie NHS Foundation Trust suitable for imaging on an MRI scanner.
• Able to give informed consent.

Cervix:

• Older than age 18 years.
• Patients having radiotherapy at the Christie NHS Foundation Trust suitable for imaging on an MRI scanner.
• Able to give informed consent.

Prostate:

• Older than age 18 years.
• Patients having radiotherapy at the Christie NHS Foundation Trust suitable for imaging on an MRI scanner.
• Able to give informed consent.

Exclusion criteria

This will be tumour site dependent

Bladder:

• Any contraindications to MRI identified after MRI safety screening including completion of an MRI Safety Screening Form.
• Unable to tolerate MRI scans.
• Pregnancy.

Cervix:

• Any contraindications to MRI identified after MRI safety screening including completion of an MRI Safety Screening Form.
• Unable to tolerate MRI scans.
• Pregnancy.

Prostate:

• Any contraindications to MRI identified after MRI safety screening including completion of an MRI Safety Screening Form.
• Unable to tolerate MRI scans