Researching Brain Cancer: 2005 Research Awards

Baylor College of Medicine, Houston, Texas
Principal Investigator: John Y. Kim, $449,385 over three years.
WIP1 in medulloblastoma growth and genotoxic response

Our research proposal focuses on medulloblastoma (MB). MB is the most common malignant brain tumor of children. Unlike cancers in adults, MB shares certain properties of normal developing brain cells. The formation and growth of MB are influenced by many of the same mechanisms that regulate normal nerve cell maturation. To study how developing brain cells diverge to form a MB, our approach involves a wide range of experimental methods. We have concentrated efforts on a molecule that regulates cancer cell growth, WIP1. The importance of WIP1 has been highlighted by prominent reports on ovarian, breast, and other cancers. Our collaborators have shown how WIP1 counteracts the anti-tumor mechanisms that cells rely upon to prevent tumor formation. This research proposal represents a collaborative effort to translate basic tumor biology research into our studies of WIP1 as a potential therapeutic target in MB.

The questions addressed in our proposal focus on WIP1 in MB, but they originate in the discussions I continue to have with families of patients. What is MB? Where does it come from? How does it grow? Why isn't it always curable? These seemingly simple questions are the most difficult to answer. They hold the keys to improving the care and long-term outcomes of children with MB. By answering these questions with regard to WIP1, we will improve our understanding of how MB grows and responds to treatment.

What is MB? Understanding what defines one type of tumor from another is essential for developing specific treatments. Yet, this deceptively simple issue remains a continuing challenge. With genomic methods, we have cataloged the genetic abnormalities of over 70 MBs from different patients. We have identified WIP1 as a candidate cancer-causing gene that varies widely among tumors. The highest levels appear in tumors that also contain extra copies of chromosome 17q, which is the most common genetic abnormality found in MBs. This suggests that extra WIP1 contributes to the growth of MB. We propose to analyze the effects of increasing WIP1 levels in laboratory-grown MB cells, and expect increased growth and/or decreased tumor cell death (apoptosis) in response to radiation and chemotherapy.

Where does it come from? Because of where it grows in the brain, MB can cause a variety of symptoms and problems. Although the causes remain unknown, MB appears to arise from dividing immature nerve cells of the developing brain. The expanding understanding of normal brain development influences cancer research. During brain growth, nerve cells undergo tightly regulated cell division. Some of the changes that should occur normally, instead go awry and lead to the emergence of pre-cancerous cells that go on to become MB. We have studied these stages of mouse tumor development in ways that are not possible in human tumors. For example, we can alter WIP1 levels in mouse tumors and observe the animals for changes in tumor growth under different conditions (e.g. radiation and chemotherapy). We propose to study the effects of WIP1 in mouse MBs, and expect changes in WIP1 levels to cause matching changes in tumor growth.

How does it grow? We use MB cells grown in the laboratory to study how they grow and respond to treatments. All current treatments attempt to halt tumor growth, but come with a significant price. Surgery to remove tumors cells physically can result in traumatic injury. Radiation therapy kills MB cells by severely damaging DNA, but such damage increases the risk of second cancers forming in surviving cells. Radiation can also permanently damage nerve cells in the developing brain. Chemotherapy medications each carry their own risks to different organs of the body. Several drugs used against MB also damage DNA.

Treated tumor cells unable to repair DNA damage, will instead commit "suicide" (apoptosis). Causing apoptosis is the goal of cancer treatment and depends upon a protein called p53. The p53 gene is abnormal in a majority of human cancers. This allows treated cancer cells to avoid apoptosis and to continue dividing Instead of abnormalities in the p53 gene, mounting evidence suggests that the function of p53 is disrupted in MB. Since we have shown that WIP1 promotes the growth of breast cancer cells by inactivating p53, we expect laboratory-grown MB cells with high-WIP1 levels to grow more aggressively when treated with radiation or chemotherapy, compared to low-WIP1 cells.

Why isn't it always curable? Nothing would provide more joy and satisfaction to an oncologist than to work to the point of obsolescence. Unfortunately, our treatments for MB are not universally successful. Although surgery, radiation, and chemotherapy can eradicate almost every tumor cell in a MB, it theoretically takes only a single cell to resist treatment and to continue dividing. The abnormalities that originally give rise to MB also contribute to their ability to resist our treatments, much in the same way that bacteria and insects can develop resistance to antibiotics and to pesticides, respectively. Such an advantage allows "escapee" tumor cells to survive, while the vast majority of MB cells commit apoptosis when confronted by radiation and chemotherapy.

The challenge is to develop new approaches to overcoming such treatment resistance. WIP1 represents such a potential drug target. Blocking WIP1 might restore the ability of p53 to stop tumor cells from dividing or to increase apoptosis when treated by radiation and chemotherapy. We propose to demonstrate that blocking WIP1 in causes them to stop growing and to commit apoptosis in laboratory-grown MB cells and in mouse brain tumors.

By blocking WIP1, we may be able to restore the ability of p53 in tumor cells to respond to treatment by committing apoptosis sparing normal cells. Ultimately, we hope this leads to the development of more effective and less toxic therapies by specifically targeting WIP1.