Neuroblastoma remains one of the most devastating childhood cancers, accounting for nearly 15% of oncological deaths in this age group. As a tumor originating from the stem cells of the sympathetic nervous system, its progression can vary wildly - from mild forms that may regress spontaneously to aggressive types requiring complex treatment.
Latest data obtained by Captor in collaboration with Lund University indicates the potential application of Targeted Protein Degradation (TPD) technology in treating neuroblastoma with MYCN gene amplification. Future research into GSPT1 protein degraders may contribute to improving the chances of effective treatment.
Neuroblastoma and the fate of the MYCN gene
Neuroblastoma is a solid tumor most located in the adrenal glands or sympathetic ganglia. A particularly critical clinical challenge is the subgroup of patients with MYCN gene amplification (MYCN-amplified neuroblastoma). This gene, present in excessive copies in approximately 20-30% of patients, acts as a master regulator of tumor growth, making cancer exceptionally aggressive and resistant to standard chemotherapy.
Symptoms can be non-specific, ranging from swallowing difficulties and vomiting to general malaise. Consequently, it is often mistaken for less serious conditions. Rapid detection and the implementation of effective treatment are crucial for the prognosis. In Poland, about 70 new cases are diagnosed annually, while global incidence reaches over 5,000 children per year. Up to a quarter of diagnosed cases involve MYCN amplification; in this population, the prognosis is uncertain, and 5-year survival often does not exceed 50%.
The amplification of the MYCN oncogene is a hallmark of neuroblastoma aggressiveness. The rapid multiplication of gene copies leads to the overproduction of the MYCN protein, a transcription factor. The presence of elevated levels of this protein results in the constitutive activation of genes driving the cell cycle. Additionally, MYCN induces intensive glycolysis and ribosome synthesis, leading to uncontrolled cancer cell proliferation. A key element of this aggressive phenotype is the suppression of apoptosis (programmed cell death) mechanisms, rendering the cancer cells resistant to the cytotoxic effects of standard chemotherapy.
Intensive therapy according to the COJEC protocol
Due to its structure, the MYCN protein is considered pharmacologically "undruggable," so neuroblastoma treatment strategies focus on achieving maximum cytoreduction in the shortest possible time. The current standard of care for children with high-risk neuroblastoma in Europe is the Rapid COJEC, developed by SIOP Europe. This is an intensive, multi-drug chemotherapy protocol consisting of eight courses administered at short, 10-day intervals. It includes cytostatic drugs such as cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide, which cause DNA damage, prevent repair, and halt mitotic cell division. The high dose intensity of the COJEC is designed to break the cancer cells' resistance to death by accumulating genetic damage faster than the cell can repair it.
While this protocol achieves an initial response in many patients, it carries significant limitations. The intensity of treatment leads to severe side effects, such as profound myelosuppression, nephrotoxicity and ototoxicity (hearing loss). A significant portion of patients do not achieve full remission, and the disease often returns in a chemoresistant form. Severe infectious complications frequently make it impossible to continue such an intensive regimen.
For patients successfully treated via COJEC, the price of success is often very high. Most survivors face serious late-term effects, including growth problems, thyroid dysfunction, infertility (particularly after cyclophosphamide), and an increased risk of heart failure later in life. Regarding the therapy's efficacy, despite maximizing dose intensity in the COJEC protocol, survival rates in the highest-risk group have plateaued. Further dose increases are impossible due to the risk of patient death from treatment toxicity.
Despite targeting the mechanisms behind tumorigenesis, the COJEC protocol lacks specificity toward healthy tissues. Conversely, the search for more precise therapeutic strategies is limited by the inability to target the MYCN oncogene directly. One possible direction is to modulate related cellular mechanisms characteristic of cancer cells using indirect and potentially milder therapeutic interventions.
GSPT1 protein degradation and its consequences
A recent article published in the Journal of Experimental & Clinical Cancer Research presents findings on the therapeutic potential of GSPT1 protein degraders in treating chemoresistant MYCN-amplified neuroblastoma. The GSPT1 protein is a factor responsible for the correct termination of protein synthesis and the regulation of the cell's transition through the division cycle. In oncological diseases, the role of this protein becomes critical, as its excess allows aggressive cancer cells to multiply uncontrollably and mass-produce the oncoproteins necessary for their survival.
Initial analyses showed that high GSPT1 expression strictly correlates with the presence of MYCN amplification and a poorer prognosis in neuroblastoma. Therefore, directly targeting and degrading GSPT1 could be a key aspect in developing new therapies. Reducing GSPT1 levels induces proteotoxic stress and a protein synthesis block in cancer cells, effectively bypassing the pharmacological inaccessibility of the MYCN oncogene and inducing cell death.
Preclinical results of the CTX-18 degrader and curative perspectives
The study details the mechanism and consequences of GSPT1 protein degradation triggered by molecular glue degraders developed by Captor Therapeutics. These molecular glues induce the proximity of GSPT1 and cereblon protein (an E3 ligase). The formation of a complex between these proteins results in GSPT1 being redirected to the proteasome and removed by the cellular protein degradation system.
In preclinical studies, the compound CTX-18 demonstrated efficacy that goes beyond the tumor growth inhibition seen in classic therapies. In xenograph models (mice transplanted with donor cancer cells) with induced chemoresistant neuroblastoma, CTX-18 achieved the desired pharmacological effects. Low oral doses of the degrader led to rapid disease remission and the complete disappearance of tumors. Unlike COJEC chemotherapy, which slows disease progression, the application of CTX-18 allowed the animals to survive without recurrence for over 150 days, resulting in a long-lasting effect. CTX-18 targets GSPT1, and a secondary effect of its degradation is a drastic reduction in the level of the MYCN protein itself.
In the long term, these results may point toward the possibility of developing curative treatment with reduced toxicity; however, they currently remain at the preclinical research stage.
Potential benefits of targeted GSPT1 degradation
Introducing targeted protein degradation technology to neuroblastoma treatment opens entirely new perspectives for patients. Neuroblastoma, which most often affects children and infants, represents a massive diagnostic and therapeutic challenge. The results provide the foundation for a new therapeutic approach that could significantly improve patient quality of life by limiting the toxicity of standard protocols and minimizing the risk of complications.
While the results of the studies conducted so far are very promising, further research is necessary to confirm the efficacy and safety of targeted protein degradation technology in treating neuroblastoma. The development of the CTX-18 degrader has the potential to fill a significant therapeutic gap in pediatric oncology as a potential first-in-class therapy. Positive preclinical results, supported by years of developed know-how, provide the basis for continuing research projects in the field of targeted protein degradation.
