LAUSR

Simple Summary Medulloblastoma is a form of malignant brain tumor that arises predominantly in infants and young children and can be divided into different groups based on molecular markers. The group of non-WNT/non-SHH medulloblastoma includes a spectrum of heterogeneous subgroups that differ in their biological characteristics, genetic underpinnings, and clinical course of disease. Non-WNT/non-SHH medulloblastoma is currently treated with surgery, chemotherapy, and radiotherapy; however, new drugs are needed to treat patients who are not yet curable and to reduce treatment-related toxicity and side effects. We here review which new treatment options for non-WNT/non-SHH medulloblastoma are currently clinically tested. Furthermore, we illustrate the challenges that have to be overcome to reach a new therapeutic standard for non-WNT/non-SHH medulloblastoma, for instance the current lack of good preclinical models, and the necessity to conduct trials in a comparably small patient collective. Abstract Medulloblastoma is an embryonal pediatric brain tumor and can be divided into at least four molecularly defined groups. The category non-WNT/non-SHH medulloblastoma summarizes medulloblastoma groups 3 and 4 and is characterized by considerable genetic and clinical heterogeneity. New therapeutic strategies are needed to increase survival rates and to reduce treatment-related toxicity. We performed a noncomprehensive targeted review of the current clinical trial landscape and literature to summarize innovative treatment options for non-WNT/non-SHH medulloblastoma. A multitude of new drugs is currently evaluated in trials for which non-WNT/non-SHH patients are eligible, for instance immunotherapy, kinase inhibitors, and drugs targeting the epigenome. However, the majority of these trials is not restricted to medulloblastoma and lacks molecular classification. Whereas many new molecular targets have been identified in the last decade, which are currently tested in clinical trials, several challenges remain on the way to reach a new therapeutic strategy for non-WNT/non-SHH medulloblastoma. These include the severe lack of faithful preclinical models and predictive biomarkers, the question on how to stratify patients for clinical trials, and the relative lack of studies that recruit large, homogeneous patient collectives. Innovative trial designs and international collaboration will be a key to eventually overcome these obstacles.