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Paper Abstract

Is CX-4945, the next-generation medulloblastoma drug?

Medulloblastoma (MB) is one of the most common types of pediatric brain cancer. It affects children between the ages of 4 to 10 years and accounts for about 25% of all pediatric central nervous system tumors. It originates in the cerebellum (the lower back region of the brain), which controls balance, movement, and coordination. Although the exact cause of this type of cancer is unknown, genetic conditions, age, and gender may all play a role as a causative factor. In young adults, MBs are much less frequent and they tend to develop in elderly people [1], [2].

Medulloblastoma: current treatment strategies

MB is a highly aggressive cancer that usually spreads quickly and can be deadly if left untreated. The current standard treatment for MB is surgery followed by radiation therapy and chemotherapy. Unfortunately, these treatment modalities do not work always and may cause considerable neurocognitive impairments, secondary tumors, and morbidity.

 

The main approach for anti-MB medications that are under research is selectively targeting abnormally regulated genes or proteins in each MB subgroup. The development of targeted therapeutics for MB has risen along with our understanding of the relevant molecular pathways disrupted in the disease. Compared to conventional cytotoxic therapy, targeted medicines have demonstrated special advantages in maintaining efficacy and toxicity [3].

What is CX-4945 and how will it treat Medulloblastoma?

A severely diminished quality of life and neurocognitive impairments are experienced by MB survivors. To improve the quality of life of these patients, newer and more efficient treatments are therefore required. A pro-survival kinase and therapeutic target in the management of numerous human cancers is the casein kinase 2 (CK2) protein kinase. CK2 expression and activity are elevated, and its participation in numerous tumorigenic pathways has been shown to support its growth-related roles in various cancers, including MB. Thus, combining CX-4945 with other inhibitors resulted in synergistic effects in the induction of cell death. As a result, CX-4945 represents a viable therapeutic option for the treatment of MB when used in combination therapy.

 

Casein kinase 2 (CK2) inhibitors are promising targets for anti-cancer therapy because it:

 

  • Controls the activity of many genes involved in cell growth and survival

  • Supports a variety of oncogenic signaling pathways

 

However, research is now being done on CK2 function in MB. According to current research, CK2 drives hundreds of phosphorylation events during MB growth. It has been revealed that using CK2 inhibitors in combination with routine therapies increases their efficacy. As a result, CK2 inhibitors like CX-4945 are employed in multiple cancer therapies.

 

CX-4945, also known as silmitasertib, is an exciting therapeutic option because it is a:

 

  • Small molecule

  • Can be administered orally

  • Highly selective inhibitor of CK2 that can cross the blood-brain barrier

 

Earlier studies showed that CX-4945 could inhibit cell proliferation in the MB cells without harming normal cells or causing side effects. Additionally, it has been determined to be safe, with no evidence of weight loss or hair loss in experimental animals. The drug CX-4945 has been approved by the FDA for use in treating recurrent  Sonic hedgehog (SHH)-driven MB, as it is a highly selective CK2 inhibitor and a prospective treatment [4], [5].

Medulloblastoma.jpg

CX-4945: it’s already in trials

CX-4945, which induces cytotoxicity and apoptosis, is now undergoing clinical trials for the treatment of MB. It is currently being evaluated in a Phase 1/2 clinical trial (NCT03904862) sponsored by the Pediatric Brain Tumor Consortium, in children and adult patients with recurrent MB who may or may not undergo surgery. In this trial, CX-4945 is being studied as a single agent and in combination with other therapies. The primary endpoint is safety, which will be determined by the occurrence of adverse events. The secondary endpoints include progression-free survival (PFS) and overall response rate (ORR) [6].

Future outlook

Children who are MB survivors need symptomatic care to preserve their neurocognitive abilities and improve their quality of life. Research on how to enhance survival quality by preventing cognitive decline and limiting radiation is required because extending survival in MB patients is a vital concern. Potentially effective treatments after surgical resection may be a combination of immunotherapy along with chemotherapy and radiotherapy. It may offer a long-term solution for children who do not require radiation treatment. Future trials might explore the possibility of using CX-4945 in combination with the current treatment modalities.

References

  1. I. Troncon et al., “Multifocal Medulloblastoma in an Adult Patient: Description of a Rare Presentation and Review of the Literature,” Case Rep Pathol, vol. 2020, p. 4502878, Sep. 2020, DOI: 10.1155/2020/4502878.

  2. F. Y. Fang, J. S. Rosenblum, W. S. Ho, and J. D. Heiss, “New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of Pediatric Medulloblastoma,” Cancers, vol. 14, no. 9, Art. no. 9, Jan. 2022, DOI: 10.3390/cancers14092285.

  3. J. Wen and M. K. Hadden, “Medulloblastoma drugs in development: Current leads, trials and drawbacks,” Eur J Med Chem, vol. 215, p. 113268, Apr. 2021, DOI: 10.1016/j.ejmech.2021.113268.

  4. T. Purzner et al., “Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma,” Sci Signal, vol. 11, no. 547, p. eaau5147, Sep. 2018, DOI: 10.1126/scisignal.aau5147.

  5. R. T. Nitta et al., “Casein kinase 2 inhibition sensitizes medulloblastoma to temozolomide,” Oncogene, vol. 38, no. 42, pp. 6867–6879, Oct. 2019, DOI: 10.1038/s41388-019-0927-y.

  6. Pediatric Brain Tumor Consortium, “PBTC-053: A Pediatric Brain Tumor Consortium Phase I/ II and Surgical Study of CX-4945 in Patients With Recurrent SHH Medulloblastoma,” clinicaltrials.gov, Clinical trial registration NCT03904862, Aug. 2022. Accessed: Oct. 06, 2022. [https://clinicaltrials.gov/ct2/show/NCT03904862]. Available: https://clinicaltrials.gov/ct2/show/NCT03904862

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