Identification and Characterization of Metastatic Cancer Stem Cells in Medulloblastoma

Brain tumors account for approximately 20% of all childhood cancers and are the leading cause of cancer-related death among children. The most common childhood brain tumor is medulloblastoma, and although cure rates for both infants and older children have improved over the past three decades, children that have metastases at the time of diagnosis are typically incurable. Unfortunately, our understanding of metastasis (the process by which cancer cells detach from the primary tumor, enter into the blood stream, and settle down elsewhere to form a new tumor) is limited, mostly due to the complex process of obtaining metastatic tumor tissue samples from patients.

Cancers consist of numerous cell types with different characteristics, and recent studies have shown that there is a specific type of cancer cell (so-called 'cancer stem cell') that is responsible for maintaining the growth of the tumor and that these cells are typically resistant to conventional therapies. Since the cancer stem cells are required for tumor growth, it is likely that they are also critical for metastasis. To gain a better understanding of the cells and the genetic events that govern metastases, our research will focus on genetically engineered mice that develop medulloblastoma, both with and without metastases. We will use these models to identify the cancer stem cells that are responsible for metastases and the genetic events that allow certain cells to metastasize. Knowing critical genetic events in metastases will enable us to identify a set of genes that can be used to predict if a specific tumor will metastasize. Once we have identified key cells and genes involved in metastases, we will confirm their role using human medulloblastoma samples. A better understanding of metastasis will allow us to predict which patients with medulloblastoma are likely to develop metastases and to identify new ways to kill metastatic cancer cells and improve the prognosis for these patients.

The short-term goal (within 2-3 years) of the project is to identify a set of genes that can be used to predict which tumors are likely to metastasize, whereas the long-term goal (3-8 years) is to develop improved therapies by identifying new ways to target metastatic cancer cells. In a clinical context, this will have significant value for all medulloblastoma patients because it will dictate the course of therapy prescribed for a given patient. Currently, prevention/treatment of metastasis requires irradiation of the entire brain and spinal cord, a treatment that frequently results in substantial damage to the healthy brain tissue and many survivors have serious side effects (such as impaired movement and learning disabilities). Reliable prognostic factors (such as the expression of a set of metastases genes) would permit personalized therapy where only the most aggressive tumors would receive intense treatments, while children with less aggressive tumors would be treated effectively but spared the most detrimental therapies. Furthermore, understanding the genetic events that underlie metastases will likely uncover key features and vulnerabilities of the cells that metastasize, which will allow us to develop drugs that target both the primary tumor and the metastatic tumor.

The major benefit of this kind of tailored therapy is that patients will only receive therapy that is necessary to eradicate the tumor and hence will suffer fewer side effects. The only obvious risks of using such prognostic markers to determine a specific course of treatment is that we will unlikely succeed in accurately predicting the possibility of metastases for every patient since some tumors will change genetically during the course of the disease.

A better understanding of the cells and the genetic events that govern metastases is likely to have considerable effects on advancing the field of cancer research in general, because metastases is a critical event in the progression of many other types of cancer. It is likely that some of the processes that are required for brain tumors to metastasize are also involved in metastases of other cancers.