Jessica M. Y. Ng

Malignant rhabdoid tumors arise in several anatomic locations and are associated with poor outcomes. In the brain, these tumors are known as atypical teratoid/rhabdoid tumors (AT/RT). While genetically engineered models for malignant rhabdoid tumors exist, none of them recapitulate AT/RT, for which preclinical models remain lacking. In the majority of AT/RT, LOH occurs at the genetic locus SNF5 (Ini1/BAF47/Smarcb1), which functions as a subunit of the SWI/SNF chromatin-remodeling complex and a tumor suppressor in familial and sporadic malignant rhabdoid tumors. Therefore, we generated mice in which Snf5 was ablated specifically in nestin-positive and/or glial fibrillary acid protein (GFAP)-positive progenitor cells of the developing central nervous system (CNS). Snf5 ablation in nestin-positive cells resulted in early lethality that could not be rescued by loss of p53. However, Snf5 ablation in GFAP-positive cells caused a neurodegenerative phenotype exacerbated by p53 loss. Notably, these double mutants exhibited AT/RT development, associated with an earlier failure in granule neuron migration in the cerebellum, reduced neuronal projections in the hippocampus, degeneration of the corpus callosum, and ataxia and seizures. Gene expression analysis confirmed that the tumors that arose in Snf5/p53 mutant mice were distinct from other neural tumors and most closely resembled human AT/RT. Our findings uncover a novel role for Snf5 in oligodendrocyte generation and survival, and they offer evidence of the first genetically engineered mouse model for AT/RT in the CNS. Cancer Res; 75(21); 4629–39. ©2015 AACR.

The Hedgehog (HH) pathway is an important regulator of embryogenesis that has also been implicated in tumour development. As all HH signalling through the canonical pathway requires Smoothened (SMO), small molecules such as GDC-0449, which inhibit SMO function, completely block all HH pathway signalling regardless of the ligand. Drugs based on cyclopamine and other compounds that target SMO have been developed and are currently in Phase I and Phase II clinical trials. Drugs that target other aspects of the HH signalling pathway are also in development. Initial results suggest that SMO inhibitors will prove useful in the treatment of basal cell carcinoma and in the subtype of medulloblastoma that is dependent on HH signalling. It is important to understand how HH inhibitors could be used to treat other cancers, perhaps in combination with other therapies, which do not carry genetic lesions in the HH pathway, but that rely on HH signalling for disease progression. Improved understanding of cancer biology, particularly the interplay among cancer cells and stromal tissues, will help broaden the usefulness of such agents. The identification of reliable biomarkers that indicate patients who are most likely to benefit from HH inhibitors, including non-invasive imaging approaches, is essential. Understanding resistance mechanisms and developing methods to overcome resistance to SMO inhibitors will also be important in the future. The importance of HH pathways during development and studies in mice indicate that SMO inhibitors in children with medulloblastoma will need to be used with care, so that potential effects on skeletal and brain development are avoided. Given the dramatic responses reported in basal cell carcinoma and medulloblastoma in early trials, it is highly likely that SMO inhibitors will ultimately be approved as new therapeutic agents for treating cancer. This should be viewed as a success for basic, broad-based research in developmental biology, as well as cancer research, which laid a strong foundation for this translational opportunity.