Characterization of Novel OTX2-semaphorin Gene Signaling Pathways Regulating the ‘Grow and Go’ Arms of Highly Aggressive Medulloblastomas
Brain tumors are the deadliest form of childhood cancer in both the United States and Canada. Medulloblastoma is the most common aggressive type of childhood brain cancer. Treatments such as chemotherapy and radiation have severe side effects and are particularly damaging to the developing brains of young children. There are currently five different kinds of medulloblastomas. My laboratory aims to characterize the cells in the most aggressive forms that help the tumors “grow,” namely the cancer stem cells, as well as those tumor cells that “go” to other parts of the body leading to poor outcomes. By identifying proteins that help the tumors “grow and go,” we will establish a cellular fingerprint that can be exploited for the development of new therapies aimed at targeting the cancer cells while improving the quality of life for childhood cancer survivors.
We have discovered that a protein called OTX2 plays an important role in how the most fatal medulloblastomas arise and progress. Now, we want to further understand how this protein functions, how it controls other genes and how these genes regulate growth and movement of human medulloblastomas both in a dish and when implanted into mice. So far, we know that OTX2 controls genes involved in nervous system development, and this is observed both in a dish as well as a large number of patient samples. Ultimately, our results will open up new avenues for the development of novel, more specific and less toxic therapies that will decrease the aggressive behavior of these tumors.
Project Update - June 2020
In the last year, we have discovered that the master tumor-promoting gene OTX2 can inhibit the expression of other genes involved in nervous system development, and this is observed both in a dish as well as a large number of patient samples. Specifically, we found that OTX2 suppresses genes from a family known as the semaphorins. When these genes are re-activated, we see a decrease in tumor properties not only in a dish but also in biologically relevant preclinical animal models of medulloblastoma. In the next year, we plan to fully characterize how OTX2 regulates these genes and to use this information to identify new avenues for the development of more specific and less toxic therapies that will decrease the aggressive behavior of these devastating tumors in children.