Brighton & Hove Albion

Kinder and more practical – why childhood cancers want particular therapies – Most cancers Analysis UK

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

Despite differences in disease biology, children with cancer are almost always treated with cancer therapies designed for adults.

While children can benefit from novel therapies for cancer in adults, the spectrum of mutations in cancers in children is different. It is for this reason that Cancer Research UK is investing in this area to better understand the fundamentals of these diverse groups of diseases and to develop more effective and less toxic treatments.

Most adult cancers develop because of an accumulation of mutations over time. In contrast, embryonic tumors occur in young children and are often triggered by a key mutation in a particular tissue at a critical point in development.

Neuroblastoma is a common childhood embryonic tumor that arises in the developing sympathetic nervous system. Although it has a heterogeneous clinical phenotype, it most often presents itself as an aggressive cancer associated with poor survival – although some neuroblastomas spontaneously regress. As a developmental malignancy, neuroblastoma can also spontaneously transdifferentiate between a more mature noradrenergic state and an immature neural crest-like state – that is, it can change its cellular composition. This plasticity has been linked to resistance to therapy and may not come as a surprise given that neuroblastoma occurs in pluripotent cells.

“The current standard therapy for clinically high-risk neuroblastoma is one of the most intense treatments given to any child or adult with cancer.”

My work focuses on a clinically diverse, therapy-resistant group of neuroblastoma patients who are characterized by loss of function mutations in the ATRX gene. ATRX is a chromatin remodeling protein with broad functions including maintaining genomic stability and regulating transcription. In previous work I have identified specific weaknesses in the repair of DNA damage as a result of ATRX mutations. Little is known, however, about the transcriptional deregulation that occurs after loss of ATRX function and how it contributes to oncogenesis.

Complex regulation

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

Like many embryonic malignancies, the ATRX neuroblastoma is an example of an aggressive pediatric malignancy that develops prenatally in pluripotent cells. Resistance to standard chemotherapeutic agents is probably related to the genetic drivers as well as the cell of origin. ATRX plays a vital role in normal tissue development. It is responsible for maintaining compact, inaccessible chromatin and for gene silencing through various interactions on both gene promoters and intragenic regions. However, in the normal development of the central nervous system, ATRX also promotes the expression of neuronal lineage-specific genes. In summary, this underlines the complex nature of the epigenetic regulation mediated by ATRX, which not only leads to gene repression, but also to gene activation in certain tissues and at certain times of development.

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

“The ATRX neuroblastoma is just one example of an aggressive embryonic malignancy in which new treatments are urgently needed as conventional therapies reach the limits of effectiveness and tolerability.”

For my upcoming CRUK-funded work, I am using induced pluripotent stem cells and transgenic mouse models to identify the effects of ATRX mutations in sympathetic progenitor cells – the cell of origin of neuroblastoma. By identifying the program of transcriptional deregulation that arises as a result of ATRX dysfunction and understanding how cooperative events drive oncogenesis, my goal is to identify drug targets for this difficult-to-treat patient population.

New treatments, new challenges

The ATRX neuroblastoma is just one example of an aggressive embryonic malignancy in which new treatment methods are urgently needed, as conventional therapies reach the limits of effectiveness and tolerability. Precision medicine approaches show promise in improving outcomes and in the UK, children with cancer now have increasing access to both molecular profiles and targeted agents through multi-arm early stage clinical trials such as ESMART.

With this significant advance comes new challenges. Since cancer is rare in children, how do we prioritize which novel drugs should be tested in which subgroups? Innovative, biomarker-rich clinical trial designs are required to maximize the information that can be obtained from a small number of patients. But international collaboration is also often required for small clinical studies, which inevitably increases the complexity and effort. Childhood cancer is rarely a strategic priority for pharmaceutical companies, and access to new therapies remains a major challenge.

In order to improve outcomes in aggressive embryonic tumors such as neuroblastoma, we need to work together across developmental and cancer biology to identify critical signaling pathways for oncogenesis and the associated therapeutic vulnerabilities.

If we are to improve outcomes for pediatric specific cancers, pediatric specific approaches are needed.

September is Child Cancer Awareness Month. Around 4,400 children and adolescents develop cancer in the UK every year. We are determined to meet the challenges that are holding back progress to help more 0-24 year olds with cancer survive with a good quality of life. We are working to build a strong, lasting community of cancer researchers for children and adolescents in the UK and to provide the tools and infrastructure that community needs to accelerate progress.

Join the conversation on social media this September with #CCAM

Learn more about our Work in childhood cancer research

Author:

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

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