Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies

Abstract

Medulloblastoma is the most frequently encountered malignant brain tumor in the pediatric population. The standard of care currently consists of surgical resection, craniospinal irradiation, and multi-agent chemotherapy. However, despite this combination of multiple aggressive modalities, recurrence of the disease remains a substantial concern, and treatment resistance is a rising issue. The development of this resistance results from the interplay of a myriad of anatomical properties, cellular processes, molecular pathways, and genetic and epigenetic alterations. In fact, several efforts have been directed towards this domain and characterizing the major contributors to this resistance. Herein, this review highlights the different mechanisms that drive relapse and are implicated in the occurrence of treatment resistance and discusses them in the context of the latest molecular-based classification of medulloblastoma. These mechanisms include the impermeability of the blood-brain barrier to drugs, the overactivation of specific molecular pathways, the resistant and multipotent nature of cancer stem cells, intratumoral and intertumoral heterogeneity, and metabolic plasticity. Subsequently, we build on that to explore potential strategies and targeted agents that can abrogate these mechanisms, undermine the development of treatment resistance, and augment medulloblastoma's response to therapeutic modalities.

Keywords: cancer stem cells; combination therapy; medulloblastoma; molecular pathways; treatment resistance; tumoral heterogeneity.

Figure 1

Summary of the various drivers of treatment resistance in medulloblastoma.

Figure 2

The different cellular states identified through single-cell RNA sequencing within each of the molecular subtypes of medulloblastoma, which shows the considerable intratumoral heterogeneity that can drive treatment resistance.

Figure 3

The structure of the BBB and mechanisms to overcome it. (Left panel) The BBB is composed of endothelial cells that are connected to each other by tight junctions, and backed up by pericytes and foot processes of astrocytes. This structure impedes the delivery of therapeutic agents to brain tumors. (Right panel) Some of the methods that have been used to overcome the BBB are low-intensity focused ultrasound, which can transiently disrupt the integrity of the BBB, and drug-loaded nanoparticles, which have a better ability to penetrate the barrier. The action of focused ultrasound is dependent on the presence of microbubbles that are injected systemically. These microbubbles which should be present in the blood stream respond to the ultrasound waving through cavitation and contribute greatly to the mechanical disruption of the BBB.

Figure 4

The mechanisms that drive resistance to SMO inhibitors (vismodegib and sonidegib) and potential targeted therapies to overcome them. (A) Hedgehog signaling is initiated with the binding of SHH to its receptor PTCH1. This lifts the inhibition that PTCH1 exerts on SMO and allows the latter to initiate a downstream cascade of events. The cascade starts with lifting the control that SUFU exerts over GLI proteins. This SMO-induced activation of GLI promotes the nuclear translocation of this factor and the subsequent transcription of other effectors in the HH pathway that are involved in tumorigenesis. Other mechanisms that are involved in the activity of GLI proteins are the epigenetic regulators that promote their expression, such as BRD4 and CK2. Vismodegib and sonidegib are used to inhibit the activation of the SHH pathway through their action as direct inhibitors of SMO. The mechanisms implicated in the treatment resistance against these SMO inhibitors mainly involve mutations in proteins, such as SUFU and GLI, that are part of the SHH pathway downstream of SMO or the convergence of other overactivated pathways, such as AKT/PI3K and MEK/ERK, on major players of the SHH pathway. (B) Targeting the aforementioned mechanisms and molecular drivers can abrogate the treatment resistance to SMO inhibitors when used as a combination therapy. This includes the use of direct GLI inhibitors, such as GANT61 and ATO, or inhibitors of the alternative overactivated pathways, such as the PI3K inhibitor, samotolisib, and the MEK inhibitor, trametinib. Additionally, targeting the epigenetic regulator of GLI expression can also be utilized through the inhibition of BRD4 using JQ1 and CK2 using silmitasertib. ATO, arsenic trioxide; BRD4, bromodomain 4; CK2, casein kinase 2; GANT61, GLI antagonist 61; GLI, glioma-associated oncogene; HH, hedgehog; PTCH1, patched 1; SHH, sonic hedgehog; SMO, smoothened.