Advances in Neuroblastoma Research (ANR)
Toronto, June 18-21, 2012
Selected meeting highlights:
- Animal and cell line models of advanced neuroblastoma
- TARGET update
- New animal models of neuroblastoma
- Clinical trials for high risk neuroblastoma
- Towards personalised medicine
- Novel genetic markers and new drugs
- Parents Symposium
- Future meetings
Immunotherapy for neuroblastoma formed a large number of the presentations at the meeting, particularly involving advances in therapy targeting GD2, a molecule that has been shown to be specifically associated with neuroblastoma tumours. Evidence was presented showing some of the biggest improvements in neuroblastoma outcome in the last 10 or 15 years from targeting GD2 with monoclonal antibodies. Further improvements to this approach are in the pipeline, including the use of antibodies targeting closely related molecules that have more restricted expression. These approaches have the potential to avoid the pain associated with peripheral nervous system effects, and offer novel immunization approaches.
Animal and cell line models of advanced neuroblastoma. Data were presented demonstrating the successful and reproducible generation of cell lines and mouse xenografts from peripheral blood samples of neuroblastoma patients following disease progression. Such samples offer examples of refractory disease and represent an important advance in clinically useful models of neuroblastoma particularly given the rapid development in the personalized medicine approaches. These lines provide better representation of relapsed neuroblastomas and neuroblastomas that are particularly resistant to treatment, allowing researchers to home in on the cases most in need of new therapies, and enabling pre-clinical testing of new targeted therapies in the most relevant models. Such cell line models provide an ongoing resource for the neuroblastoma community.
There was an update from the TARGET (Therapeutically Applicable Research to Generate Effective Treatments) neuroblastoma project. TARGET has been established with the aim of identifying, through the use of genetic technologies, the genetic drivers of high-risk neuroblastoma since these could provide valuable therapeutic targets. The results presented uncovered few actionable mutations occurring with sufficient frequency to be useful in contributing more broadly to personalised medicine approaches at the current time. However data from sequencing and genome wide association studies have identified some interesting leads. For example, mutations resulting in inactivation of the ATRX pathway were observed in older patients with neuroblastoma and may be a useful marker of chronic disease in adolescents and young adults as well as a potential target for therapy. Given the link between ATRX and telomere maintenance, the work also suggests that the use of certain drug classes (eg telomerase inhibitors) may not be as effective in this group of patients. The work overall also highlights the need for approaches in addition to sequencing in order to accelerate target/drug discovery. In this regard there were numerous new candidate approaches presented at the conference that are being established through screening, development and preclinical testing programs.
New animal models of neuroblastoma. The MYCN transgenic mouse model has been the mainstay of animal models for studying neuroblastoma for many years and will continue to be important. However, a number of other models have now been developed involving a range of other important genes including ALK and caspase-8, as well as offering the potential of studying this childhood disease during different stages of development, including metastasis. A zebrafish model was also presented suggesting advantages over other animal models, including a capacity for direct examination of candidate genes using gene-knockout approaches and more rapid screening to identify potential small molecule drugs. This model could thus speed up the process for novel drug discovery while drug candidates themselves can be used to dissect novel genetic pathways in neuroblastoma.
Clinical trials for high risk neuroblastoma
Results from a number of clinical trials involving children with high risk neuroblastoma were presented. Of particular interest, the use of the small molecule ALK (anaplastic lymphoma kinase) inhibitor, Crizotinib, showed some promising anti-tumor activity in a Phase I dose escalation study. Another Phase II study of imatinib mesylate in patients with metastatic neuroblastoma showed encouraging results. Of 24 children enrolled in the study, seven major responses (29%) were observed with 5 complete responses lasting up to 52 months and 2 partial responses lasting up to 29 months. Two additional patients (8.3%) had stable disease up to 8 months.
Towards personalised medicine
While showing promise for targeted therapies, the results from a number of recent clinical trials also highlight the need to ensure that new targeted therapies are tested on the appropriate subsets of patients. Identification of these patients, and the development of new targeted therapies, should be greatly assisted by the creation of a new database, iINRGdb (interactive International Neuroblastoma Risk Group database) which “will provide physicians, scientists, and other members of the INRG community with access to multiple datasets pertaining to childhood neuroblastoma, including biological data, phenotypic measures, and clinical outcomes, enabling studies that will move us closer to developing “personalized” approaches for all children with neuroblastoma”. Also assisting progress towards personalised medicine is the development of additional experimental models in the form of cell lines and xenografts.
Novel genetic markers and new drugs
A range of potential markers for stratifying neuroblastoma or with a role to play in neuroblastoma tumorigenesis was presented. In particular, one study demonstrated that targeted expression of the Lin28B gene to neural crest cells (the neuroblastoma cell of origin) can drive neuroblastoma tumour formation in mice. The research also highlighted the link between this gene and MYCN, suggesting that targeting Lin28B itself may be a potential new therapeutic approach, particularly in aggressive MYCN-driven neuroblalstoma. In addition, results were presented using a pre-clinical model, showing that treatment involving a new drug, CBLC137, in combination with currently used chemotherapeutic drugs showed powerful anti-tumour activity with potential as a new treatment approach for refractory neuroblastoma.
Attendees were also able attend a Parents Symposium that included a series of facilitated round table discussions on a range of topics including: New drugs and clinical trials; ALK and personalized medicine; Immunotherapy; Survivorship, late effects and aftercare; and Relationships and social issues.
ANR 2014 will be held in Cologne, Germany, while ANR 2016 will be held in Cairns, Australia.