Abstract
Novel treatment options, including targeted therapies, are needed for patients with medulloblastoma (MB), especially for those with high-risk or recurrent/relapsed disease. Four major molecular subgroups of MB have been identified, one of which is characterized by activation of the sonic hedgehog (SHH) pathway. Preclinical data suggest that inhibitors of the hedgehog (Hh) pathway could become valuable treatment options for patients with this subgroup of MB. Indeed, agents targeting the positive regulator of the pathway, smoothened (SMO), have demonstrated efficacy in a subset of patients with SHH MB. However, because of resistance and the presence of mutations downstream of SMO, not all patients with SHH MB respond to SMO inhibitors. The development of agents that target these resistance mechanisms and the potential for their combination with traditional chemotherapy and SHH inhibitors will be discussed. Due to its extensive molecular heterogeneity, the future of MB treatment is in personalized therapy, which may lead to improved efficacy and reduced toxicity. This will include the development of clinically available tests that can efficiently discern the SHH subgroup. The preliminary use of these tests in clinical trials is also discussed herein.
Highlights
Novel treatment options, including targeted therapies, are needed for patients with medulloblastoma (MB), especially for those with high-risk or recurrent/relapsed disease
Due to its extensive molecular heterogeneity, the future of MB treatment is in personalized therapy, which may lead to improved efficacy and reduced toxicity
The hedgehog (Hh) pathway was first implicated in MB when germline mutations in patched (PTCH) were detected in patients with Gorlin syndrome, a heritable condition associated with an increased risk of MB and certain other cancers including basal cell carcinoma (BCC).[3,4]
Summary
Novel treatment options, including targeted therapies, are needed for patients with medulloblastoma (MB), especially for those with high-risk or recurrent/relapsed disease. Molecular studies have identified pathways involved in the tumorigenesis of many cancers including medulloblastoma (MB), the most common malignant brain tumor in young children.[1,2] The hedgehog (Hh) pathway was first implicated in MB when germline mutations in patched (PTCH) were detected in patients with Gorlin syndrome, a heritable condition associated with an increased risk of MB and certain other cancers including basal cell carcinoma (BCC).[3,4] Since that discovery, profiling studies and other genetic analyses have confirmed the involvement of the Hh pathway in the pathogenesis of MB and BCC.[5,6,7,8,9,10] In addition, inhibitors of the Hh pathway have demonstrated efficacy in MB and BCC.[11,12,13,14,15,16,17,18,19] Vismodegib recently became the first US Food and Drug Administration (FDA)-approved Hh pathway inhibitor based on antitumor activity observed in a phase 2 study in participants with advanced BCC.[13,20] Vismodegib and other agents targeting the Hh pathway are currently being tested in clinical trials in participants with Hh-activated MB.[21] The outcome of these trials may change the landscape of MB treatment, resulting in a more personalized approach with therapies that offer improved efficacy and reduced toxicity. Most survivors suffer from long-term toxicities associated with the current standard-of-care treatment, which includes surgery followed by craniospinal radiation and chemotherapy.2,22,25 – 27 In particular, craniospinal radiation-induced neurocognitive toxicities, which are inversely related to patient age, can be severe.[22,24,25,27] For this reason, craniospinal radiation is not recommended for patients younger than aged 3 – 6 years.[22,24,25] In these patients, postsurgical chemotherapy is suggested and usually includes high-dose chemotherapy with stem-cell rescue.[22]
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