Defining the Role of and Mechanism by Which the Chloride Channel CLIC1 Regulates Brain Tumor Growth
Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children. The conventional treatment that combines surgery, irradiation, and chemotherapy are highly toxic to normal cells and produce lifelong side effects such as lowered IQ, early aging, and increased chance to develop other types of cancer. Therefore, identifying the molecules that fuel aggressive MB tumor growth but are largely dispensable for normal cells is key to develop cancer-specific therapy. Ions, such as potassium, chloride, sodium, or calcium, are essential constituents of every cell in human body. Ion channel proteins form tiny pores to control ion movement in and out of a cell. The movement of ions can change the electrical and physical properties of the cells, which then control many biological processes including tumor growth. We recently found a potassium channel named EAG2 whose function is critically required for MB tumor growth but not normal physiological development. We discovered a drug as a novel EAG2 blocker and demonstrated that the drug had marked efficacy in treating a human MB patient. Therefore, we are pioneers in identifying ion channels as novel regulators for MB and developing channel-targeting therapy. In order to effectively treat MB, a combinatorial therapy in which multiple tumor-specific molecules are targeted is necessary. Therefore, we decided to identify novel ion channels that can regulate MB growth. We found that a chloride channel named CLIC1 is abnormally accumulated in MB cells, and inhibiting CLIC1 slowed down MB growth. We hypothesize that CLIC1 as a novel regulator of MB can be blocked to suppress tumor growth. We will study mouse and human tumors to reveal the mechanism by which CLIC1 regulates MB malignancy. Since we found that mice without Clic1 function are largely normal, our study will form the basis for rational design of a CLIC1-targeted therapy to treat MB and spare normal cells. My career goal is to discover an ion channel network that is uniquely present in brain cancer cells. The identification of this network will provide ample opportunities for us to develop cancer therapies targeting multiple nodes within the network. Completing our study will not only establish CLIC1 as a novel target for treating this devastating childhood brain tumor, but also solidify my research program, which is based on the novel scientific niche in brain tumor therapeutics by targeting ion channels. For my career development, I will acquire mentorship, research resources, as well as learn about clinical aspects of MB from my Mentor Dr. Michael Taylor, a world-renowned leader in the pediatric brain tumor research field and a neurosurgeon who treats MB patients. I will work with scientists in the brain tumor field and beyond to forge collaborations. I will also attend leadership and lab management skill courses and workshops. MB frequently occurs in children, but it can also develop in young adults. Therefore, the military impact of our study is fourfold: on the likelihood for the MB-afflicted children to become future military members, on the active duty Service personnel who are young adults, on their families with children, and on the general population. The projected time for completing our proposed studies is 3 years, and our research will lessen MB-induced burden on both military personnel and the general society. We will uncover the unrealized potential of targeting ion channels as novel cancer therapies. The Peer Reviewed Cancer Research Program Career Development Award will provide me the critical financial support and scientific recognition to solidify a highly competitive and productive research program.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710637
Entities
People
- Xi Huang
Organizations
- Hospital for Sick Children
- United States Army