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New method matches drugs with faulty DNA replication, helping identify childhood cancer drug candidates

The IMI-funded ITCC-P4 project’s methodology helped identify some of the best targets in childhood tumours that could be candidates for treatment with adult therapies

15 February 2022
Mother with child image by Bricolage via Shutterstock
Drugs originally developed for adult cancers could offer hope as options for paediatric cancer patients. But which ones? Image by Bricolage via Shutterstock

There is an urgent need to identify new therapies for childhood cancer tumours. Drugs originally developed for adult cancers could offer hope as options for paediatric cancer patients. But which ones?

To help answer this question, the researchers in the IMI-funded ITCC-P4 project created a unique methodology called a Target Actionability Review (TAR), which involves a review of published studies that identify potential matches between mechanism-of-action based anti-cancer drugs and specific cancer types. Such a strategy has not been applied to the paediatric cancer population before.

Clinical development of novel mechanism-of-action based agents often requires robust preclinical data. The TAR methodology offers a new science-based way to figure out which drugs could be selected and prioritised. The methodology also helps to identify matches with strong preclinical ‘proof of concept’ that may have a higher likelihood of response to treatment.

They also highlight where further research is necessary.

The ITCC-P4 team applied the TAR methodology to extensively review the existing science on a phenomenon called replication stress to see which proteins and pathways (series of actions involving these proteins) involved in this process could be singled out as promising targets for drugs. The review included only publications that concern replication stress in paediatric tumours.

Replication is a process that results in the duplication of a person’s genome during cell division. Any condition that compromises it is called replication stress. Replication stress is a major cause of genome instability and is linked to the generation of pre-tumour and tumour cells. Thus, replication stress is also a potential vulnerability or 'target' for cancer therapy.

Most promising targets

In total, 145 publications related to targeting replication stress in paediatric tumours were systematically reviewed as part of this Target Actionability Review. An emphasis was placed on two things: DNA repair pathways and cell cycle checkpoint control. According to the authors, “Although various targets in these pathways have been studied in paediatric tumors to a different extent, the results of this literature search show that ATR, CHK1, PARP or WEE1 are the most promising targets using either single agents or in combination with chemotherapy or radiotherapy in neuroblastoma, osteosarcoma, high-grade glioma or medulloblastoma.”

“Targeting these pathways in other paediatric malignancies may be beneficial as well, but here, the evidence was more limited. The evidence for other targets (such as ATM and DNA-PK) was also limited but showed promising results in some malignancies and requires more studies in other tumour types.” The project created an extensive overview of targeting replication stress across 16 paediatric tumour types, which can be explored online using an interactive heatmap.

The authors’ evaluation further established and tested the Target Actionability Review methodology, which involves four major steps, for the systematic in silico evaluation of selected compounds and corresponding actionable molecular targets and pathways, for different paediatric solid tumours. This evaluation can be done before in vitro and in vivo testing to assess the relevant literature and the existing genomic data on the tumours in question.

The TAR, including study scores, key data summaries and source information, is publicly available through the R2 Genomics Analysis and Visualization Platform.

ITCC-P4 is supported by the Innovative Medicines Initiative, a partnership between the European Union and the European pharmaceutical industry.