Αρχική World News Kinder and more effective – why childhood cancers need specific treatments

Kinder and more effective – why childhood cancers need specific treatments

There is a real need for more tailored therapies for young people with cancer. For this year’s Childhood Cancer Awareness Month, clinician scientist Dr Sally George tells us about her work on neuroblastoma and why childhood cancers really do need specific research to develop the most effective treatments.

Despite the differences in disease biology, children with cancer are almost always treated with cancer therapies that were developed for adults.

While children may benefit from novel therapies developed for adult cancers, the mutational spectrum in paediatric cancers is different. This is why Cancer Research UK are investing in this field to better understand the underpinnings of this disparate group of diseases and develop more effective and less toxic treatments.

Most adult cancers occur due to an accumulation of mutations over time. In contrast, embryonal tumours occur in young children, and are often driven by one key mutation in a specific tissue at a critical developmental timepoint.

Neuroblastoma is a common embryonal tumour of childhood, arising in the developing sympathetic nervous system. While it has a heterogenous clinical phenotype, it most commonly presents as an aggressive cancer, associated with poor survival – although, some neuroblastomas do spontaneously regress. As a developmental malignancy, neuroblastoma can also spontaneously transdifferentiate – that is, it can change its cellular makeup – between a more mature noradrenergic state and a more immature neural crest like state. This plasticity is associated with therapy resistance and is perhaps unsurprising, given that neuroblastoma arises in pluripotent cells.

“Current standard therapy for clinically high-risk neuroblastoma constitutes some of the most intensive treatments given to any child or adult with cancer”

My work focuses on a clinically distinct, therapy resistant group of neuroblastoma patients characterised by loss of function mutations in the ATRX gene. ATRX is a chromatin re-modelling protein with broad functions including the maintenance of genomic stability and transcriptional regulation. In previous work I identified specific DNA damage repair vulnerabilities as a result of ATRX mutations. However, little is known about the transcriptional deregulation that arises following ATRX loss of function, and how this contributes to oncogenesis.

Complex regulation

Current standard therapy for clinically high-risk neuroblastoma constitutes some of the most intensive treatments given to any child or adult with cancer and includes multi-agent chemotherapy, radiotherapy, surgery and immunotherapy. Most children initially respond to therapy, however neuroblastoma with ATRX alterations is more likely to be refractory to chemotherapy and follow a slowly progressive, ultimately fatal disease course.

Like many embryonal malignancies, ATRX-neuroblastoma is an example of an aggressive paediatric malignancy, arising prenatally, in pluripotent cells. The resistance to standard chemotherapeutics is likely related to the cell of origin in addition to the genetic drivers. ATRX plays a critical role in normal tissue development. It is responsible for the maintenance of compact, inaccessible chromatin and for gene silencing by different interactions at both gene promotors and intragenic regions. However, in normal central nervous system development, ATRX also promotes the expression of neuronal lineage-specific genes. Taken together, this highlights the complex nature of epigenetic regulation mediated by ATRX, not only resulting in gene repression but also gene activation in specific tissues and at specific developmental timepoints.

However, the programme of epigenetic dysregulation arising from loss of normal ATRX function in the developing sympathetic nervous system, and how this contributes to oncogenic reprogramming, is incompletely understood.

“ATRX-neuroblastoma is just one example of an aggressive embryonal malignancy where novel treatments are urgently needed, as conventional therapies have reached the limits of both efficacy and tolerability”

For my upcoming CRUK funded work I am using induced pluripotent stem cell and transgenic murine models to identify the effect of ATRX mutations in sympathetic precursor cells – the cell of origin of neuroblastoma. By identifying the programme of transcriptional deregulation which arises as a result of ATRX loss of function and understanding how co-operating events drive oncogenesis, my aim is to identify druggable targets for this difficult to treat group of patients.

New treatments, new challenges

ATRX-neuroblastoma is just one example of an aggressive embryonal malignancy where novel treatments are urgently needed, as conventional therapies have reached the limits of both efficacy and tolerability. Precision medicine approaches hold great promise to improve outcomes, and in the UK children with cancer now have increasing access both to molecular profiling and targeted agents through multi-arm early phase clinical trials such as ESMART.

With this significant progress comes new challenges. Given that paediatric cancer is rare, how do we prioritise which novel agents to test and in which subgroups? Innovative, biomarker-rich, clinical trial designs are required to maximise the information that can be obtained from small numbers of patients. However, even for small clinical trials, international collaboration is often needed, which will inevitably increase complexity and expense. Paediatric cancers are rarely strategic priorities for pharmaceutical companies and therefore access to new therapies remains a significant challenge.

To improve outcomes for aggressive embryonal tumours such as neuroblastoma, we must work together across the scope of developmental and cancer biology to identify critical pathways driving oncogenesis and their associated therapeutic vulnerabilities.

If we are to improve outcomes for paediatric specific cancers, then paediatric specific approaches are required.

September is Childhood Cancer Awareness Month. Each year in the UK, around 4,400 children and young people are diagnosed with cancer. We’re determined to overcome the challenges holding back progress, to help more 0-24-year-olds with cancer survive with a good quality of life. We’re working to develop a strong, long-lasting community of children’s and young people’s cancer researchers in the UK and providing the tools and infrastructure this community needs to accelerate progress.

This September, join the conversation on social media using #CCAM

Find out more about our work in paediatric cancer research

Dr Sally GeorgeAuthor:

Dr Sally George is the recipient of a Cancer Research UK Clinician Scientist Fellowship Grant. She is a Clinical Research Fellow at The Institute of Cancer Research and The Francis Crick Institute and an Honorary Consultant Paediatric Oncologist at The Royal Marsden Hospital.

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