Novel neuroblastoma driver: a potential target for therapeutics

Introduction

Neuroblastoma is a complicated cancer of the nervous system that primarily affects children, particularly those under the age of five. It is characterised by the development of tumours originating from neural crest cells involved in the formation of the adrenal glands and sympathetic nervous system. As the most common extracranial solid tumour in infancy and childhood, neuroblastoma represents a significant challenge in paediatric oncology due to its complex biology and variable prognosis.

Recent advancements have brought hope by identifying a novel genetic driver, IGF2BP1, implicated in the aggressive progression of the disease. The University Medicine Halle team's breakthrough in pinpointing IGF2BP1's role is significant. It paves the way for understanding the molecular underpinnings of neuroblastoma. Additionally, it opens the door to potentially transformative targeted therapies. By elucidating the mechanisms through which IGF2BP1 drives tumour growth—specifically through its interaction with oncogenes such as MYCN—researchers are making significant progress. They are closer than ever to devising strategies that could arrest the disease's development. This progress could significantly improve patient outcomes.

The importance of this discovery cannot be overblown, as it provides a crucial target for therapeutic intervention, potentially leading to the development of more effective, less toxic treatments. This is a significant step towards not only enhancing survival rates but also the quality of life for affected children worldwide.

IGF2BP1: a key player in neuroblastoma and potentially other tumours

The IGF2BP1 gene has emerged as a crucial element in neuroblastoma pathogenesis. It functions as an RNA-binding protein that enhances the stability and translation of mRNA transcripts. These transcripts encode oncogenic proteins, significantly impacting tumour behaviour. Oncogenes are genes that have the potential to cause cancer by promoting uncontrolled cell division and tumour growth. The activation of IGF2BP1 leads to the increased expression of several key oncogenes, including BIRC5 and MYCN. These are known to drive the growth and malignancy of neuroblastoma cells. This discovery marks a substantial leap in understanding the molecular dynamics at play within neuroblastoma cells, offering a novel avenue for targeted intervention. By stabilising and enhancing the translation of mRNA transcripts encoding these oncogenic proteins, IGF2BP1 plays a crucial role in promoting tumour growth and malignancy. Understanding this interaction provides a strategic point of intervention, potentially leading to targeted therapies that could inhibit the harmful effects of IGF2BP1 and significantly improve patient outcomes. 

Moreover, the IGF2BP1 role extends beyond neuroblastoma. Its expression has been detected in various other cancers, where it similarly promotes tumour growth and survival. For example, IGF2BP1 has been implicated in the progression of colorectal, breast, and lung cancers, suggesting a broader oncogenic role. This consistent pattern across different cancers underscores its potential as a universal therapeutic target.

The broad impact of IGF2BP1 on multiple tumour types also highlights the potential for developing cross-cancer therapeutic strategies. By targeting IGF2BP1, it may be possible to design treatments that are effective against multiple forms of cancer, thus maximising the impact of research and development efforts in oncology. This could lead to the creation of a new class of anticancer drugs that inhibit IGF2BP1, offering hope to patients with various malignancies. However, targeting this gene presents challenges. IGF2BP1 is involved in beneficial processes such as normal cell growth and repair. For instance, it plays a role in stabilising mRNA during cell division, which is crucial for tissue regeneration. Inhibiting IGF2BP1 might impair these processes, leading to issues such as poor wound healing or reduced immune function. Additionally, its inhibition could potentially affect other normal cellular functions, posing a risk of unintended side effects. Thus, while targeting IGF2BP1 holds promise, understanding its role in healthy cells is essential to developing therapies that are both effective and safe.

Research into IGF2BP1’s mechanisms has also revealed that it might be instrumental in initiating an “oncogene storm”. This is a rapid and intense expression of oncogenes that drives aggressive tumour growth. It also leads to resistance to conventional therapies. Conventional therapies typically refer to standard cancer treatments such as chemotherapy, radiation therapy, and surgery. For example, chemotherapy drugs like doxorubicin and cisplatin are designed to kill rapidly dividing cells, but the oncogene storm can enable tumour cells to become resistant to these drugs by enhancing their survival mechanisms. Similarly, radiation therapy aims to damage the DNA of cancer cells, but the increased expression of oncogenes can repair this damage more effectively, allowing the tumour to persist. This understanding provides a crucial insight into how cancer cells exploit molecular mechanisms to thrive and evade treatment, thereby pointing to strategic points of intervention. Current research is exploring how targeted therapies can be developed to specifically inhibit the effects of the oncogene storm, potentially overcoming resistance to these conventional treatments. This understanding provides a crucial insight into how cancer cells exploit molecular mechanisms to thrive and evade treatment, thereby pointing to strategic points of intervention.

MYCN’s role in neuroblastoma: a pivotal transcriptional driver

MYCN is a member of the MYC family of transcription factors, which play critical roles in cell cycle progression, apoptosis, and cellular transformation. In neuroblastoma, MYCN is particularly notorious for its strong association with high-risk disease and poor clinical outcomes, making it a main point of cancer research. High-risk disease in neuroblastoma is characterised by factors such as advanced stage at diagnosis, unfavourable histology, and the presence of MYCN amplification. For example, Stage 4 neuroblastoma, where the cancer has spread to distant lymph nodes, bone, bone marrow, liver, skin, or other organs, is considered high-risk.

Poor clinical outcomes in these cases often include a lower survival rate and a higher likelihood of relapse after treatment. Studies have shown that children with MYCN-amplified neuroblastoma have a significantly lower 5-year survival rate compared to those without MYCN amplification. This is because MYCN amplification drives rapid tumour growth and metastasis, making the cancer more aggressive and difficult to treat. Additionally, these patients often exhibit resistance to conventional therapies such as chemotherapy and radiation, which further complicates treatment and negatively impacts prognosis.

Specific examples of poor clinical outcomes include frequent relapses and the development of resistance to multiple lines of therapy. Despite intensive treatment regimens, including high-dose chemotherapy followed by stem cell transplant and radiation therapy, the overall survival rate for high-risk neuroblastoma remains below 50%. This bare reality underscores the critical need for novel therapeutic strategies that can effectively target MYCN and improve outcomes for patients with high-risk neuroblastoma.

In general, MYCN amplifies in approximately 20% to 25% of neuroblastoma cases, leading to a dramatic increase in its protein expression. This overexpression is a known marker for aggressive disease and has been linked to rapid tumour progression and resistance to standard therapies. Standard therapies for neuroblastoma typically include a combination of surgery, chemotherapy, and radiation therapy. For instance, chemotherapy drugs such as cyclophosphamide and vincristine are commonly used to shrink tumours before surgical removal. However, the overexpression of MYCN can enhance the tumour’s ability to repair DNA damage caused by these treatments, making them less effective. Radiation therapy, which uses high-energy particles to destroy cancer cells, also becomes less effective as MYCN overexpression promotes survival pathways within the cells. The interaction between MYCN and IGF2BP1 creates a formidable axis that drives the malignant characteristics of neuroblastoma cells.

Functionally, MYCN amplifies the effects of IGF2BP1 by synergising its activity. This synergy is evident in their mutual enhancement of oncogenic signalling pathways. MYCN enhances the transcription of numerous genes involved in cellular proliferation and survival. While IGF2BP1 stabilises the mRNAs of these genes, ensuring their sustained expression and activity within the cell. This interaction not only accelerates tumour growth but also contributes to the genomic instability that is characteristic of high-risk neuroblastoma.

Besides, the role of MYCN extends beyond merely amplifying gene expression. It fundamentally alters the cellular landscape by modulating the expression of genes involved in metabolism, differentiation, and angiogenesis, thus shaping the tumour microenvironment to favour cancer growth and metastasis. Recent studies have also uncovered MYCN’s role in repressing the transcription of genes involved in cellular differentiation, thereby maintaining the cells in a more primitive, stem-like state that is conducive to cancer progression.

The discovery of the “oncogene storm”, a phenomenon triggered by the cooperative action of MYCN and IGF2BP1, highlights the critical need for targeted therapeutic strategies that can disrupt this deleterious synergy. By focusing on this interaction, researchers aim to develop novel treatments that can more effectively curb the aggressive nature of MYCN-amplified neuroblastoma.

The potential for therapeutic intervention

The discovery of the IGF2BP1 and MYCN interaction not only deepens our understanding of neuroblastoma pathogenesis but also marks a significant step towards developing targeted therapeutic interventions. The small molecule BTYNB, which disrupts this interaction, has shown promising results in preclinical studies. By inhibiting the oncogene-enhancing effect of IGF2BP1 on MYCN, BTYNB effectively reduces tumour growth and could potentially improve the efficacy of existing treatment protocols.

Current research is exploring the application of BTYNB in combination with other therapeutic agents. Combining BTYNB with existing chemotherapy drugs or novel targeted therapies may enhance treatment efficacy and prevent the onset of resistance. This combinatorial approach could be particularly effective in high-risk neuroblastoma cases, where conventional treatments often fall short. Additionally, understanding the pharmacodynamics and optimising the dosing schedule of BTYNB are critical areas of ongoing research to maximise its therapeutic potential and minimise side effects. This includes studying how the drug is absorbed, distributed, metabolised, and excreted in the body to ensure optimal efficacy. For instance, researchers are investigating the timing and dosage that maximise tumour reduction while minimising toxicity. Examples include adjusting the frequency of administration to maintain therapeutic levels and combining BTYNB with other agents to enhance its effects. These efforts aim to maximise its therapeutic potential and minimise side effects.

Furthermore, the ability of BTYNB to impair tumour growth without the severe side effects associated with conventional chemotherapy presents an opportunity to reduce the treatment burden on patients. This aspect is crucial, especially in paediatric oncology, where the long-term health of young patients is a significant concern. Future therapeutic strategies could see BTYNB becoming part of a first-line treatment for neuroblastoma, either as a standalone therapy or in combination with other treatments.

Future directions

The ground-breaking discovery of the IGF2BP1-MYCN interaction in neuroblastoma provides solid initial results with BTYNB, and the identification of IGF2BP1 as a key driver in neuroblastoma opens several avenues for future research. One critical area involves further elucidation of the molecular mechanisms underlying IGF2BP1’s influence on neuroblastoma progression. Continued research is necessary to dissect the finer details of the molecular pathways modulated by IGF2BP1 and MYCN. This includes understanding the downstream effects of their interaction and identifying other molecular players involved in the signalling cascade. Insights from such studies could reveal novel personalised therapeutic targets and help in designing drugs that can more precisely disrupt these pathways.

Additionally, given the role of IGF2BP1 in various cancers, research should also explore its potential as a universal cancer target. Comparative studies across different cancer types could identify shared patterns of IGF2BP1 activity, offering opportunities to develop broad-spectrum anticancer strategies.

Developing targeted delivery mechanisms that can direct BTYNB or other similar drugs specifically to neuroblastoma cells could significantly enhance therapeutic outcomes and reduce side effects. Research into nanoparticle-based delivery systems or conjugated molecules that seek out cancer-specific markers could be particularly fruitful. Additionally, investigating other compounds that can target IGF2BP1 or MYCN could provide alternative therapeutic options or complementary strategies to overcome resistance.

Strategic integration of new therapies into existing treatment protocols needs careful planning. This includes determining the optimal sequencing of therapies and identifying which combinations are most effective for various subtypes of neuroblastoma based on genetic characteristics.

Clinical trials are essential to transitioning laboratory findings to clinical applications. Designing and implementing rigorous clinical trials to test the efficacy and safety of BTYNB, both as a monotherapy and in combination with other therapies, is crucial. These trials should incorporate robust biomarker studies to tailor therapies based on genetic profiles and monitor patient responses more effectively.

Lastly, addressing the challenge of drug delivery remains paramount. Developing drug delivery systems that can effectively target tumour sites with minimal off-target effects could improve the therapeutic index of treatments like BTYNB. Research in this area will not only benefit neuroblastoma patients but also advance the field of targeted cancer therapy in general. Importantly, given the young age of neuroblastoma patients, it is imperative to consider long-term outcomes and quality of life in therapeutic development. Efforts must be made to ensure that new treatments are not only effective but also minimise the long-term health impacts often associated with aggressive cancer therapies.

Conclusion

The identification of IGF2BP1 as a pivotal driver in the pathogenesis of neuroblastoma, particularly in concert with MYCN, marks a significant milestone in paediatric oncology. This discovery not only enhances our molecular understanding of one of the most challenging childhood cancers but also sets the stage for the development of targeted therapeutic strategies that could revolutionise treatment paradigms.

The potential of BTYNB, a small molecule inhibitor that disrupts the IGF2BP1-MYCN interaction, underscores the power of targeted therapy. In preclinical models, BTYNB has demonstrated a promising ability to inhibit tumour growth effectively and with fewer side effects compared to traditional chemotherapy. Such advancements herald a new era in treatment where therapy is not only about fighting the disease but also preserving the quality of life for the youngest patients.

However, the journey from laboratory to clinic is filled with challenges that require innovative solutions and collaborative efforts. These challenges include ensuring the safety and efficacy of new treatments, overcoming drug resistance, and achieving precise delivery to tumour sites. The future of neuroblastoma treatment lies in the ability to refine these emerging therapies through rigorous research, optimise their delivery, and integrate them seamlessly into existing treatment protocols. Additionally, the exploration of IGF2BP1's role across various cancer types may provide insights that transcend paediatric oncology, offering new hope for comprehensive cancer treatment strategies.

As the research advances, it will be crucial to maintain a multidisciplinary approach, combining the expertise of molecular biologists, clinical researchers, and pharmacologists to ensure that these new discoveries translate into safe and effective treatments. The engagement of global health communities in these efforts will be essential to address the diverse and complex nature of cancer treatment across different populations.

All in all, the path forward is marked by significant potential and profound responsibility—to continue the search for knowledge and to translate that knowledge into therapies that not only extend life but also enhance the lived experiences of patients during and after treatment. With continued dedication and innovation, the future for children battling neuroblastoma looks increasingly hopeful.

Written by Sara Maria Majernikova

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