Crown: improving animal irradiation can unlock failed drug candidates

The image-guided radiotherapy is better for animal welfare

The ability to pinpoint radiotherapy in animal testing could give failed cancer drug candidates a new lease of life, says preclinical CRO (contract research organisation) Crown Biosciences.

Rajendra Kumari, Chief Scientific Officer of PRECOS, a UK division of Crown, told preclinical irradiation on small animals has until now not caught up with techniques used in the clinic. Traditionally, crude methods such as lead shielding are used to prevent small animals’ overexposure to irradiation. But due to mice’s tiny size, this system largely fails and almost the whole animal receives irradiation.

This caused animal welfare problems. If you were trying to give 15 gray to a patient, you’d split treatment over five days. But this is too much for the animal, and we see adverse effects after only two days, and have to stop treatment.

Because animals do not receive the full dose, drug developers cannot be confident in carrying forward their findings about combined irradiation and drug therapy through to later phases, Kumari said.

Crown has started using a small animal radiation research platform (SARRP) from Xstrahl Life Sciences, which it claims gives better clinical prediction by matching the technique used on patients.

In the clinic, image-guided systems are programmed to locate the tumour in the body, which could be deep inside the bone or brain. Irradiation is not delivered by a single beam any more but by multiple beams in different arcs. That way, if you have a tumour in your lungs, you can avoid the surrounding lung tissue and other organs and skin.

“By targeting from multiple angles, you minimise the side effects to nearby areas and still deliver irradiation to the isocentre when you add up the doses.

Pipeline hopes

The ability to fully dose small animals with irradiation opens up the opportunity to hone combination drug and radiotherapy treatments for cancer, including re-examining failed drug candidates, especially for cancers which become treatment-resistant.

Crown is seeing demand for the platform from clients who want to “go back and reposition some of their drugs that have previously failed” at preclinical when tried in combination with cruder irradiation, Kumari told us.

Kumari described immunotherapies as a particularly exciting area for this kind of combined treatment. "Originally it was thought irradiation caused immunosuppression. That was very true in the clinic but now we’re not delivering such high doses.

Another application for the technology is to add irradiation to trials on mice with fully competent immune systems, she said. Irradiation can release signals from an original tumour which improves the body’s immune surveillance, meaning better protection against secondary tumours or metastatic sites: “We’ve only been able to do that with the new irradiation.

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