Developing an Innovative Therapeutic Solution for Patients with WNT-Medulloblastoma

Abstract

Background

Medulloblastoma (MB) is the most common malignant pediatric central nervous system (CNS) tumor, typically arising from the cerebellum or fourth ventricle roof (National Cancer Institute, 2023). MBs are aggressive, often spreading to the spinal cord via cerebrospinal fluid (CSF). Four molecular subtypes are identified in children: WNT-activated, SHH-activated, and Groups 3 and 4, with varying prognoses. WNT-activated MB, comprising ~10% of cases, is associated with the wingless (WNT) signaling pathway and has the most favorable prognosis, with over 95% 5-year survivorship and rare metastasis (Jackson & Packer, 2023).

Thesis Statement

MB predominantly affects children aged 3-10, with a higher incidence in males and those of Caucasian or Hispanic heritage (Raffel, 2014). As MB originates from the cerebellum and extends into the fourth ventricle, patients commonly present with walking and balance disturbances (National Cancer Institute, 2023). CSF blockage leads to obstructive hydrocephalus and elevated intracranial pressure, resulting in early symptoms such as morning headaches, nausea, vomiting, and impaired motor functions (National Cancer Institute, 2023). Given its clinical presentation and prognosis, the proposed diagnosis in the discussed case is WNT MB.

Neurological Basis

WNT MB typically arises from mutations in the CTNNB1 gene, which affects beta-catenin regulation, a key player in the WNT signaling pathway (Kijima et al., 2016). Elevated beta-catenin levels can inactivate the tumor suppressor gene p53, leading to increased cell proliferation and potential metastasis (Maier et al., 2021). Furthermore, paracrine signals from the tumor disrupt the blood-brain barrier (BBB), allowing drugs to penetrate the brain more effectively but also posing risks such as multiple sclerosis and epilepsy (Phoenix et al., 2016).

Proposed Innovative Therapeutic Treatment

Phase 1: IMD & WNT Antagonists

A second tumor resection at the cerebellar vermis and brainstem is proposed. An intratumoral microdevice (IMD), successfully tested on glioblastomas, will be inserted into a metastasized tumor to deliver microdosed drugs, such as WNT antagonists Metformin and WIF-1, directly to the site (Peruzzi et al., 2023; Conza et al., 2023).

Phase 2: Nanoparticles

To prevent further metastasis, PLA-HPG nanoparticles will be administered intrathecally to the CSF, binding to WNT antagonists and ensuring sustained drug delivery (Khang et al., 2023).

These approaches aim to reduce reliance on chemotherapy, thereby minimizing neurocognitive impairments and allowing for targeted, patient-specific treatment (Slika et al., 2023).