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The molecular genetics of medulloblastoma: an assessment of new therapeutic targets

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Abstract

Medulloblastoma is the most common pediatric primary malignant intracranial neoplasm. The 5-year survival rates vary from 40% to 70% depending on clinical prognostic criteria, and many of the patients who survive exhibit long-term neurocognitive and/or neuroendocrine sequelae. Because of these results, research is required to increase our understanding of the basic biology of medulloblastoma, helping to refine patient stratification, decrease side effects of treatments, identify novel prognostic markers, and discover new less toxic therapies. The recognition that some medulloblastomas occur in familial cancer syndromes has led to some important discoveries in the molecular pathogenesis of medulloblastoma. These syndromes provide us with clues regarding alterations in key signaling or growth factor activation pathways that contribute to medulloblastoma formation. A better understanding of the molecular pathways involved in medulloblastoma formation may allow the discovery of new drugs that act on specific targets, yet many steps must still be taken before clinical use of new drugs. In addition, the identification of a novel signaling pathways in medulloblastoma is often accompanied by the quest for novel pharmacotherapeutics that have the potential to act favorably on this disease.

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Acknowledgments

Dr. Rutka is a Scientist of the Canadian Institutes of Health Research. This work was supported in part by funds through the National Cancer Institute of Canada, the Ontario Cancer Research Network, Brainchild, and the Laurie Berman and Wiley Funds for Brain Tumor Research. Dr. Carlotti was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)—Brazil.

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  1. Division of Neurosurgery, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil

    Carlos G. Carlotti Jr

  2. The Division of Neurosurgery, Suite 1503, The Hospital for Sick Children, and The Arthur and Sonia Labatt Brain Tumour Research Centre, The University of Toronto, 555 University Avenue, Toronto, ON, Canada, M5G 1X8

    Christian Smith & James T. Rutka

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Michael Carter, Bristol, UK

Carlotti, Smith and Rutka are to be congratulated on this concise, comprehensive, and authoritative review.

The unraveling of medulloblastoma genetics undoubtedly emerges as one of the great detective narratives in modern oncology. Its occurrence in recognized familial cancer syndromes led to understanding of how recognized molecular pathways (often those involved in normal tissue and organogenesis) could result in neoplasia when disordered. The elucidation of key signaling pathways such as Hh, Wnt, and Notch has demonstrated the tremendous convergence that exists among multitudes of molecular pathways resulting in the production of a tumor, histopathologically characterized as medulloblastoma. While terms such as Wnt, Hh, and Notch are buzzwords in contemporary neurooncology circles, it is easy to forget that these findings have arisen within the past decade. These are highly complex but fundamental processes, and the authors have done a great service in clearly outlining the nature and key components therein.

They have also outlined an up-to-date understanding of prognosis based on genetic stratification and emphasized the growing importance of clinico-biological modeling as a guide to treatment planning.

There is an excellent review of the current molecular technology in use in the laboratory investigation of tumor genetics. The authors outline a number of vulnerable sites in tumourigenic pathways and the possible routes whereby they may be antagonized therapeutically.

Increasingly, we move from the histopathological toward genetic classification of neoplastic diseases. With this understanding comes a quantum leap in the complexity of the demonstrated molecular systems. This complexity, while perplexing to the student, needs to be grasped, as it continually reveals targets among the signaling processes that may yet be the Achilles’ heel for novel therapeutic attack.

Recent advances in our current understanding of medulloblastoma will undoubtedly be a route map for the investigation of other difficult CNS tumors such as ependymoma and glioblastoma.

I very much hope that similar reviews will follow to guide us through the complexities of the story with these tumors.

Jun Yoshida, Nagoya, Japan

The authors have provided an overview of the genetic alterations in the tumorigenesis of medulloblastoma in a well-organized manner. They first focused on the familial cancer syndromes because some of them are strongly related to medulloblastoma and because clarification of the molecular genetics of these syndromes can lead to a better understanding of the molecular abnormality in medulloblastoma. They have also provided a comprehensive summary of abnormalities in the embryological signaling pathways in medulloblastoma, which are probably among the most important pathways in this tumor because medulloblastoma has the characteristics of neural stem cells and progenitor cells. Furthermore, they describe the strategies currently employed for the comprehensive analysis of gene state, transcriptional profiling, and protein expression. I think such studies using array techniques are gaining increasing importance and are essential for a better understanding of tumor biology. Finally, this paper describes promising approaches for the treatment of medulloblastoma. The authors have emphasized the need to acquire an in-depth knowledge of the molecular biology of medulloblastoma to develop novel therapeutic agents against this tumor, which I also completely agree to.

Dietmar Krex and Gabriele Schackert, Dresden, Germany

Considerable progress has been made in the elucidation of the molecular pathogenesis of medulloblastomas. This has resulted in a tremendous amount of data about genes and proteins of interest that are embedded in complex biochemical pathways and networks. Dr. Carlotti et al. present an excellent review in that field. They focus on three main signaling pathways, explaining their components and interactions and potential meaning for the tumor pathogenesis. The well-structured presentation helps to get a comprehensive and informative overview not only about the current status of the molecular biology of medulloblastomas, but also about recent experimental techniques and current molecular-based therapeutical strategies. They succeed to illustrate the paradigms of translational research, i.e., the interactions and the long way from basic molecular data to novel therapeutic compounds. This, in turn, is not only essential for those involved in Basic Sciences, but it also has a major implication for the generation of new therapeutic approaches and future clinical trials.

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Carlotti Jr, C.G., Smith, C. & Rutka, J.T. The molecular genetics of medulloblastoma: an assessment of new therapeutic targets. Neurosurg Rev 31, 359–369 (2008). https://doi.org/10.1007/s10143-008-0146-4

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