New way to test drugs for children’s cancers
A new way of testing potential drugs for children’s cancers has been developed, taking account of the wide genetic diversity of these diseases – and reducing use of laboratory mice.
Research presented at the virtual 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics argued that it is possible to evaluate drugs on a single mouse.
Prof Peter Houghton, director of the Greehey Children’s Cancer Research Institute, San Antonio, USA, who worked with Children’s Cancer Institute in Australia, said: “Over the past decade, genetic studies have shown that cancers in children that were once considered homogenous in nature are in reality quite heterogenous, and may represent different diseases that would respond differently to treatments.
“More importantly, such differences may be exploited therapeutically. Conventional drug testing in mice can identify active drugs but is restricted by the number of cancer mouse models that can be used due to resource constraints.”
Prof Houghton said one of the limitations of using conventional testing is that it uses ten mice per treatment group, meaning only a limited number of tumour models can be used, which may not necessarily reflect the genetic or epigenetic diversity of the clinical disease.
“We retrospectively analysed data from the [Pediatric Preclinical Testing Program] and asked a simple question, ‘would we have obtained the same results if we had used one mouse per treatment rather than ten mice?’,” he said.
In this study, patient-derived xenografts from 90 acute lymphoblastic leukaemias and 50 solid tumours in children were used to evaluate small molecule drugs and antibody-drug conjugates (ADCs).
The researchers found that the results for response were similar to conventional testing. The team’s analysis of more than 2,100 drug/tumour model studies showed that 78% of single mouse tests correctly recapitulated the average response from testing according to the conventional experiment design with around 95% agreement.
They prospectively investigated conventional testing and single mouse testing for topotecan, birinapant and eltanexor in acute lymphoblastic leukaemias and for two ADCs – trastuzumab-deruxtecan and mCD276-PBD – in solid tumours.
Research led by Prof Richard Lock from the Children’s Cancer Institute in Australia used 80 to 90 different patient-derived leukaemia xenograft models, and for solid tumours between 31 to 34 models.
They found that while the conventional approach provided statistically significant results in the few models tested, the single mouse testing allowed for identification of subgroups of tumours that have exceptional responses to particular drugs.
“Results from conventional testing and single mouse testing were essentially identical in 47 studies where both approaches used the same tumour model,” said Prof Houghton.
“In the leukaemia study we used 90 mice, whereas to attain the same information using conventional testing would have required 1,800 mice. For the solid tumours, it was 34 mice as opposed to 680 mice.”
Houghton PJ, Kurmasheva RT, Erickson S, Smith MA, Lock RB, Evans K, Toscan C. (2020) “Prospective Validation of Single Mouse Testing (SMT) by the Pediatric Preclinical Testing Consortium (PPTC)”, EORTC Abstract no: 37, presented in the Poster Discussion session 'Cancer therapeutics: preclinical modeling and patient stratification', 22.00-23.10 hrs Saturday 24 October.
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