Neuroblastoma presents a unique challenge in pediatric oncology, primarily affecting children under two years old. Despite advancements in childhood cancer therapies, about half of the high-risk neuroblastoma cases remain refractory to current treatments, underscoring an urgent need for innovative strategies. Central to the aggressiveness of these tumors is the protein N-MYC, a member of the MYC family well-known for its oncogenic prowess and direct association with poorer patient outcomes.

Efforts to develop drugs targeting MYC proteins have been stymied historically by their ambiguous structural nature. Unlike conventional proteins that assume stable three-dimensional conformations, MYC proteins exhibit intrinsic disorder—they are protean in shape, constantly shifting between multiple conformations. This structural fluidity poses a formidable barrier to classical drug design approaches that rely on inhibiting fixed, well-defined binding pockets on target proteins.

Professor Maria Sunnerhagen’s team at Linköping University tackled this challenge head-on by focusing on the specific interaction between N-MYC and the kinase Aurora A, a relationship that contributes to tumor cell proliferation and survival. Aurora A itself is a well-characterized oncogenic kinase implicated in mitotic control and cancer cell cycle dysregulation. Disrupting the binding interface between these two proteins promised a novel avenue to selectively hinder oncogenic processes without collateral damage to healthy cellular functions mediated by MYC.

To elucidate the elusive interaction surface between N-MYC and Aurora A, the researchers deployed an interdisciplinary arsenal that combined nuclear magnetic resonance (NMR) spectroscopy, advanced artificial intelligence modeling, and biochemical assays. NMR proved instrumental in capturing transient and dynamic interactions at atomic resolution, overcoming the inherent challenges posed by N-MYC’s structural plasticity. AI algorithms complemented empirical data by predicting conformational ensembles and interaction hotspots within the protein complex.

Their investigation pinpointed the MB0-MBI region of N-MYC as the critical segment involved in binding with the N-lobe domain of Aurora kinase A. This fine mapping revealed that although N-MYC lacks a stable folded structure, it nonetheless acts through a defined region to mediate this pathogenic protein-protein interaction, providing a tangible target for future therapeutic intervention. The researchers further identified a small molecule capable of effectively uncoupling N-MYC from Aurora A, demonstrating proof of concept that these “undruggable” oncogenic interfaces may indeed be pharmacologically targetable.

This achievement was the culmination of close collaboration with an international team including Professor Linda Penn’s group at the University of Toronto, which brought complementary expertise in cellular pharmacology and cancer biology. The synergy between structural biologists, chemists, and computational scientists was vital in overcoming the complexity of MYC biology and advancing the project from mechanistic study toward translational potential.

Beyond its immediate impact on neuroblastoma research, the study carries broader implications for cancer therapeutics. MYC proteins drive a spectrum of malignancies, yet attempts to inhibit them have remained an elusive holy grail for oncology drug discovery. By demonstrating that specific dynamic interactions involving MYC proteins can be dissected and pharmacologically disrupted, this work paves the way for a new class of precision medicines aimed at transcription factors historically deemed intractable.

Importantly, the researchers emphasize the necessity of selectivity in targeting MYC functions. Since MYC proteins regulate vital processes in normal cell proliferation, indiscriminate inhibition could result in unacceptable toxicity. The small molecule identified exhibits specificity, intervening only in the pathological interface without broadly abrogating MYC activity. This level of precision minimizes potential side effects and enhances the therapeutic index of future drug candidates.

The study also epitomizes the growing role of multidisciplinary approaches in tackling challenging biomedical problems. Integrating biophysical techniques like NMR with AI-driven molecular modeling accelerates discovery by uncovering cryptic binding interactions invisible to traditional methods. As computational power expands and experimental methods refine, this hybrid approach signals a paradigm shift in drug discovery, especially for targets once considered inaccessible.

Dr. Johanna Hultman, the doctoral candidate spearheading the experimental work, described the elusive nature of N-MYC as a “worthy opponent,” highlighting the perseverance and innovation required. The team’s success reflects an evolving understanding of intrinsically disordered proteins—not as insurmountable obstacles, but as dynamic participants in cellular signaling susceptible to well-designed molecular interventions.

Looking ahead, the researchers plan to entrust their findings to researchers in clinical cell biology and pharmacology to validate the efficacy and safety of the identified small molecule in cellular and animal models. This translational step is critical to moving from bench to bedside, with the hope that these insights will culminate in effective neuroblastoma treatments and improved survival for children affected by this devastating disease.

The funding for this research was generously provided by national and international agencies including the Swedish Research Council, the Swedish Cancer Society, the Canadian Institutes of Health Research, and the European Research Council. This support underscores the global commitment to overcoming childhood cancers through innovative science.

In summary, this landmark study not only charts new territory in understanding protein dynamics in cancer biology but also delivers a strategic blueprint for drugging the undruggable. By revealing how the N-Myc MB0-MBI region dynamically interacts with the N-lobe of Aurora kinase A and demonstrating disruption with small molecules, the scientists illuminate a promising path forward in the fight against neuroblastoma and potentially other MYC-driven malignancies.

Subject of Research: The dynamic interaction between the N-Myc MB0-MBI region and the N-lobe of Aurora kinase A as a therapeutic target for neuroblastoma.

Article Title: The N-Myc MB0-MBI region interacts specifically and dynamically with the N-lobe of Aurora kinase A

News Publication Date: 24-Feb-2026

Web References:
http://dx.doi.org/10.1038/s41467-026-69725-1

References:
Hultman, J., Morad, V., Tanner, E., Kenney, T. M. G., Pietras, Z., Khare, L. P., Derbyshire, D., Resetca, D., Arrowsmith, C. H., Aili, D., Ekström, S., Penn, L. Z., Wallner, B., Ahlner, A., & Sunnerhagen, M. (2026). The N-Myc MB0-MBI region interacts specifically and dynamically with the N-lobe of Aurora kinase A. Nature Communications. https://doi.org/10.1038/s41467-026-69725-1

Image Credits:
Olov Planthaber/Linköping University

Keywords:
N-MYC, Aurora kinase A, neuroblastoma, protein-protein interaction, intrinsically disordered proteins, cancer therapeutics, nuclear magnetic resonance, AI modeling, oncogenic proteins, drug discovery, childhood cancer, molecular targeting

Neuroblastoma, a cancer originating in nerve tissue, typically arises from immature neural crest cells that fail to differentiate properly. This failure results in cells locked in a developmental limbo, endowing the tumor with remarkable plasticity — the ability to shift between distinct cellular states. These transitions between an adrenergic state, characterized by differentiated cells more susceptible to treatment, and a mesenchymal state, marked by less differentiated and therapy-resistant cells, have long perplexed oncologists. This dynamic plasticity enables tumor cells to evade therapies targeting a specific cellular identity, contributing to relapse and therapeutic failure. The newly published research exposes a yet underestimated degree of this plasticity, revealing that tumor cells can undergo multidirectional state transitions, exacerbating treatment challenges.

The team, led by Jun Yang, MD, PhD, from the Department of Surgery at St. Jude, focused their efforts on leveraging a unique class of compounds known as molecular glues. These small molecules exert their anti-cancer effects by binding specific target proteins and recruiting them to the cell’s degradation machinery, effectively “gluing” them together for destruction. Indisulam, a molecular glue drug, acts by targeting RBM39, an essential RNA splicing factor critical for neuroblastoma cell survival. By promoting the degradation of RBM39, indisulam disrupts RNA splicing processes, triggering cell death. Despite potent initial anti-tumor activity, prior models consistently encountered tumor relapse, indicating the presence of resistance mechanisms yet to be elucidated.

To dissect the resistive behavior, the researchers employed a triangulated approach, integrating genetic mouse models, patient-derived xenografts, and cell line-based systems. Surprisingly, each model exhibited distinct RNA sequencing profiles and patterns, a reflection of neuroblastoma’s profound heterogeneity. This variability hindered identification of a uniform therapeutic target and underscored the complexity of cellular states within tumors. However, leveraging sophisticated computational analyses projecting tumor profiles onto developmental trajectories, the team uncovered a remarkable phenomenon: neuroblastoma cells not only transit between adrenergic and mesenchymal states but also acquire novel traits during these shifts, suggesting an adaptive plasticity far more elaborate than previously recognized.

This revelation explained why monotherapies targeting single cell populations had limited efficacy. “Because tumors are a mixture of numerous subpopulations that can dynamically interconvert, targeting all of these simultaneously with drugs is not feasible due to toxicity concerns,” Dr. Yang noted. Instead, an alternative strategy was required—one that could neutralize tumor plasticity itself or exploit vulnerabilities shared across cellular states. Indisulam’s unique mode of action opened a new therapeutic window, but how to enhance its durability became the critical question.

Investigations revealed that treatment with indisulam triggered an innate immune response within the tumor microenvironment. Notably, the researchers observed recruitment of natural killer (NK) cells—potent immune effectors capable of direct tumor cell killing independent of prior sensitization. NK cells play a vital role in immune surveillance and are increasingly recognized as formidable adversaries against cancer cells. The induction of NK cell infiltration suggested that indisulam not only inhibits tumor intrinsic pathways but also activates an extrinsic anti-tumor immune mechanism.

Complementing these findings, the study detected upregulation of GD2, a glycosphingolipid abundantly expressed on neuroblastoma cells’ surfaces and a validated target for immunotherapy. GD2-targeted therapies, such as anti-GD2 monoclonal antibodies, have significantly improved outcomes in high-risk neuroblastoma by mediating antibody-dependent cellular cytotoxicity (ADCC). By combining indisulam with anti-GD2 antibodies, the researchers harnessed a dual mechanism: indisulam directly activated NK cells, enhancing their cytotoxic potential, while anti-GD2 antibodies flagged tumor cells for elimination through ADCC. This synergy translated into a “one-two knockout punch,” yielding complete tumor eradication in preclinical models regardless of the tumor’s cellular state.

This therapeutic breakthrough addresses a critical unmet need in neuroblastoma treatment. High-risk patients—who constitute nearly half of all cases—typically face aggressive therapies involving high-dose chemotherapy with substantial toxicity and relapse rates approaching 50%. Traditional treatment paradigms have struggled due to insufficient druggable targets and the tumor’s remarkable ability to evade single-targeted agents. The indisulam-immunotherapy combination circumvents this challenge by exploiting tumor biology and orchestrating an immune response that doesn’t rely solely on the tumor’s inherent molecular features, but rather leverages the immune system’s adaptable and potent cytotoxic arsenal.

The research team undertook extensive validation of this therapeutic approach across various experimental platforms. Beyond observing therapeutic efficacy, they conducted mechanistic studies illuminating the interplay between RNA splicing disruption, immune activation, and tumor plasticity. By uncovering the pleiotropic roles of indisulam—both as a molecular glue affecting key splicing factors and as an immunomodulatory agent—they have provided a conceptual advance that could reshape how molecular glues are perceived and employed in cancer therapy.

Beyond the immediate clinical implications for neuroblastoma, these findings carry broader significance for oncology. Tumor plasticity and heterogeneity represent formidable obstacles across multiple cancer types, undermining precision medicine efforts. This study exemplifies how combining targeted molecular degradation strategies with immune-based interventions can surmount these hurdles, highlighting a paradigm shift towards composite therapeutic regimens that address both intrinsic tumor cell biology and extrinsic tumor-immune system interactions.

Continuing this promising line of inquiry, the St. Jude team plans to further optimize the combination strategy and advance it toward clinical trials. Rigorous safety and efficacy assessments in human subjects will be paramount to translate these preclinical successes into viable treatments for children afflicted with neuroblastoma. Moreover, expanding understanding of molecular glue drugs’ immunomodulatory properties could unlock new avenues for their use across various malignancies characterized by dynamic cellular states and immune evasion.

The collaborative nature of this study, involving researchers from St. Jude, The Institute of Cancer Research in London, Max Planck Institute of Biochemistry, Eisai Inc., Nationwide Children’s Hospital, and The University of Tennessee Health Science Center, underscores the multidisciplinary effort required to unravel such complex biological phenomena. Funded by major grants from the American Cancer Society, the National Cancer Institute, and the American Lebanese Syrian Associated Charities (ALSAC), this comprehensive research initiative embodies a concerted push to confront and conquer childhood cancers.

In summary, this study conclusively demonstrates that tumor plasticity in neuroblastoma is more intricate and multidirectional than previously acknowledged, rendering traditional monotherapies inadequate. However, by harnessing the dual forces of indisulam-induced RNA splicing disruption and immune system activation—amplified through synergy with anti-GD2 immunotherapy—the researchers have devised a potent therapeutic approach able to thwart tumor adaptability and achieve complete responses in preclinical models. This advancement offers renewed hope for children battling neuroblastoma and opens a promising frontier for integrating molecular glue compounds within immune oncology paradigms.

Subject of Research: Neuroblastoma plasticity and therapeutic intervention combining molecular glues and immunotherapy

Article Title: ‘Molecular glue’ harnesses the power of the immune system to treat neuroblastoma

News Publication Date: September 17, 2025

Web References:

• St. Jude Neuroblastoma Information
• Jun Yang Lab at St. Jude
• St. Jude Research Departments
• St. Jude Homepage
• St. Jude Progress Magazine
• St. Jude Twitter

References:
Yang, J., Singh, S., Fang, J., Jin, H., Van de Velde, L.-A., Cortes, A., et al. (2025). Molecular glue-induced degradation of RBM39 combined with immunotherapy achieves complete responses in neuroblastoma. Nature Communications. https://doi.org/10.1038/s41467-025-63979-x

Image Credits: St. Jude Children’s Research Hospital

Keywords: Neuroblastoma, Immunotherapy, Molecular glue, Indisulam, Tumor plasticity, RNA splicing, Natural Killer cells, GD2, Antibody-dependent cellular cytotoxicity (ADCC), Pediatric cancer

Historically, the care for pediatric cancer patients has largely relied on genomic testing—analyzing the DNA of the cancer cells in order to identify mutations that could be targeted by specific therapies. However, genomic testing alone can sometimes fail to identify actionable treatments, particularly for rare types of cancer. The current study sought to bridge the gap between genomics and proteomics, the study of proteins, suggesting that this combined approach could unveil crucial insights into tumor behavior and provide new, actionable strategies for treatment.

A particular case highlighted by the research involved a patient diagnosed with a rare and aggressive pediatric cancer that had shown a resistance to traditional chemotherapy. After previous attempts to find an effective drug based solely on genomic testing yielded no viable options, the team turned to proteomic analysis. By focusing on the proteins expressed by the tumor, researchers were able to uncover metabolic vulnerabilities that genomics had overlooked.

The integrated use of sertraline, a well-established antidepressant, emerged as a potential treatment. The research team discovered that the cancerous tumor heavily relied on an enzyme known as SHMT2, which is crucial for its metabolic processes. Utilizing sertraline to inhibit this enzyme enabled researchers to target the tumor’s energy sources effectively. This innovative therapeutic application underscores the importance of exploring non-traditional uses for existing drugs in cancer treatment.

To understand how this approach could be implemented in real-world clinical settings, the researchers developed a distinctive experimental model utilizing chicken eggs as hosts for tumor cells. This method, which allows for the growth of a tumor in a simplistic, yet biocompatible environment, serves as an avatar for the actual tumor present in the patient. By cultivating a patient’s tumor within the egg, researchers could assess the tumor’s reaction to potential treatments in a matter of weeks—an invaluable advantage when time is of the essence in cancer treatment.

Previous methodologies often required extensive periods for drug evaluation, leaving patients to wait indefinitely for treatment options. The rapid feedback loop enabled by using chicken eggs accelerates the process of evaluating drug efficacy. In this specific case, the research team was able to confirm the effectiveness of sertraline in targeting the tumor’s metabolism swiftly, illustrating the practical applications of proteomic exploration combined with novel hosting strategies.

Upon presenting their findings to a panel of experts from the PROFYLE initiative, the team affirmed sertraline as the most promising treatment option for the patient at that time. The results showcased this personalized treatment strategy’s potential, resulting in a notable deceleration of the patient’s tumor growth, although it was essential to recognize that the treatment did not yield a complete cure. Indeed, the journey toward effective cancer treatment is rarely linear, and the researchers acknowledge that further investigation into supplementary or alternative therapies is necessary.

The implications of this research extend beyond the confines of a single case; the goal is to adapt and apply this innovative method to other pediatric patients across Canada. The findings illuminate the importance of personalized medicine in pediatric oncology, advocating for approaches that embrace the complexity of cancer biology rather than relying solely on conventional methods.

Overall, the study emphasizes the importance of interdisciplinary collaboration in advancing cancer research, bringing together expertise from various fields to develop innovative solutions for complex health challenges. As the scientific community continues to strive for improved outcomes for children battling cancer, the integration of proteomics and creative experimental models promises to play a pivotal role in reshaping future treatment paradigms.

In conclusion, the combination of genomic insights with proteomic understanding highlights a critical shift in cancer research, one that stands to benefit innumerable young patients in the future. The innovation born from this study instills hope not only in the realm of pediatric oncology but also in the broader spectrum of cancer treatment, paving the way for more adaptive, responsive, and personalized therapeutic strategies.

Subject of Research: Human tissue samples
Article Title: Proteomics and personalized PDX models identify treatment for a progressive malignancy within an actionable timeframe
News Publication Date: 1-Apr-2025
Web References: Access for Kids Cancer
References: EMBO Molecular Medicine
Image Credits: Paul Joseph/UBC

Keywords: Cancer research, proteomics, pediatric oncology, clinical research, drug development.

Traditionally, children diagnosed with this condition receive a standardized treatment regimen that includes surgery, chemotherapy, and radiation therapy. However, while some children may respond favorably to these interventions, others face the grim prospects of rapid tumor relapse due to the aggressive nature of their specific cancer subtype. This disparity in treatment response underscores the urgent need for accurate tumor classification methods, allowing for tailored therapeutic strategies that meet individual patient needs.

The researchers, led by Dr. Alberto Delaidelli, a postdoctoral fellow at UBC, in collaboration with esteemed colleagues from BC Cancer and BC Children’s Hospital, have introduced a scientifically rigorous approach that leverages proteomics—an innovative field focused on protein analysis within biological systems. By examining the intricate protein expressions in nearly 400 clinical tumor samples, Dr. Delaidelli’s team was able to pinpoint MYC, a crucial protein that displayed a marked presence in the most aggressive cases of medulloblastoma.

The revelation that MYC-positive tumors are significantly more likely to exhibit resistance to treatment and a higher risk of relapse is critical in shaping future treatment protocols. By integrating immunohistochemistry (IHC)—a widely employed and accessible laboratory technique—the researchers have established a diagnostic test that can be performed rapidly, achieving results within a single day. This is in stark contrast to existing methods reliant on expensive and time-consuming genetic testing, which are often exclusive to specialized laboratories.

What sets this new test apart is not merely its swiftness but also its potential accessibility across global healthcare infrastructures. Dr. Sorensen, a distinguished scientist at BC Cancer and leading figure in this study, emphasizes that this methodology can be executed in standard pathology labs worldwide, making it feasible for hospitals in both developed and developing nations. This democratization of diagnostic capabilities could facilitate timely and appropriate treatment decisions for pediatric patients, ensuring that those in dire need of intensive therapy receive it without delay.

As medulloblastoma continues to be the leading cause of cancer-related mortality in children, this research is particularly timely. In Canada and the United States alone, approximately 500 cases are reported annually. Nevertheless, the landscape of pediatric oncology remains fraught with difficulties, ranging from the complexities of diagnosing various tumor subtypes to the implementation of effective treatment strategies that do not compromise the long-term quality of life for young patients.

The implications of this research extend far beyond immediate clinical applications; it opens avenues for future studies aimed at understanding the molecular mechanisms that drive tumor aggression and resistance. By fostering a deeper understanding of these biological underpinnings, the scientific community can innovate new therapeutic agents designed to target these specific pathways, potentially transforming the prognosis for young patients diagnosed with this formidable disease.

Particularly concerning is the fact that treatments such as radiation, while effective, can yield severe long-term side effects. Children exposed to radiation therapy often grapple with cognitive deficits, developmental delays, and various other challenges as they transition into adulthood. By employing the MYC test to accurately gauge the necessity of radiation in individual cases, medical professionals can mitigate the risk of administering overtreatment, focusing instead on personalized care that prioritizes the child’s well-being and future development.

This research is further bolstered by its collaborative nature, involving experts from multiple Canadian cities and international institutions, including a notable participation from Heidelberg, Germany. Such partnerships reflect a growing trend in scientific research where global networks aim to tackle pressing health issues through shared knowledge and resources, enhancing the capacity for rapid translation of laboratory findings into clinical practice.

In allowing for swift diagnosis and treatment decision-making, the MYC test represents not just a technical advancement, but a paradigm shift in pediatric cancer care—a beacon of hope for families facing the daunting challenges posed by medulloblastoma. Medical professionals are now equipped with the tools necessary to make more informed decisions that align with the unique needs of each patient, fostering a future where personalized medicine becomes the norm rather than the exception.

As this test gains momentum in clinical practice, it is poised to redefine the standards of care in pediatric oncology. With the push for more precise and individualized treatment approaches, and with research continually illuminating new pathways for intervention, the future of pediatric cancer care appears increasingly promising. As families rally behind their young patients, this advancement provides a renewed sense of hope in the fight against one of the most aggressive forms of childhood cancer.

By bridging the gap between groundbreaking research and practical application, the team at UBC not only contributes to the academic body of knowledge surrounding medulloblastoma but also reinforces the importance of translating these discoveries into tangible clinical benefits for patients across the globe. This is a pivotal moment for medical science, where the collaboration of experts results in innovations that hold the potential to save lives and improve the quality of life for generations of children to come.

The ongoing development and validation of this MYC-focused diagnostic tool augur well for the evolution of pediatric oncology, cementing the role of proteomics as a transformative discipline in understanding and combatting cancer. As medical practitioners worldwide adopt these findings, the implications reach far beyond medulloblastoma, resonating throughout the broader landscape of cancer research and treatment.

By fostering collaboration, accelerating research, and prioritizing patient-centric care, the next era of cancer treatment could very well be marked by a commitment to innovation, access, and tailored solutions that recognize and address the complexities of individual cases. The unwavering efforts of researchers and clinicians will ultimately determine the trajectory of pediatric oncology, highlighting the vital intersection of science, compassion, and hope in the quest to conquer cancer.

Subject of Research: Cells
Article Title: High-resolution proteomic analysis of medulloblastoma clinical samples identifies therapy resistant subgroups and MYC immunohistochemistry as a powerful outcome predictor
News Publication Date: March 5, 2025
Web References: Neuro-Oncology
References: DOI – 10.1093/neuonc/noaf046
Image Credits: Not available

Keywords: Brain tumors, Children, Medulloblastoma, Cancer research.