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Acute lymphocytic leukemia (ALL) is the most common form of childhood cancer, with about 3,000 new cases in the U.S. per year. The leukemia cells in a patient can become resistant to the drugs used to treat disease, which results in a poor outlook for these children. This study tests a new therapeutic agent (Leukothera®) that specifically eliminates leukemia cells for the treatment of children with ALL.

The overarching goal of this research is to develop a non-invasive technique for cancer therapy. This technique uses High-Intensity Focused Ultrasound (HIFU) to deliver therapy, and Magnetic Resonance (MR) guidance to monitor therapy. MR-guided HIFU enables "surgical procedures" to be performed deep within the body without incisions or punctures, providing a risk-free approach to the treatment of adolescent and childhood cancers. This study aims to overcome a fundamental challenge: How can we use MR-guidance to control HIFU therapy with the individual variations between patients.

Biomarkers are small molecules that can be detected in the body fluids of patients; they often correlate with the presence of a cancer. MicroRNAs are small molecules which have recently been discovered in cells and are responsible for normal development as well as cancer. Recently, microRNAs from tumor cells have been detected circulating in the blood, spinal fluid and urine of patients with cancer. This project aims to identify the microRNA biomarkers in the body fluids of children with brain and spinal cord tumors, which may be valuable as biomarkers of cancer and response to treatment.

Dr. Nicolaides is investigating a new combination of treatments for pediatric brain tumors. Malignant astrocytomas (MA's) are an aggressive and often incurable group of brain tumors. Recent evidence suggests that a fraction of these tumors contain a mutant form of a key growth promoter in the cell- BRAF-V600E. A drug that blocks the function of this cell has recently shown dramatic efficacy in melanomas and has been FDA approved. This drug shows some effect against MA's with BRAF-V600E, however the response is only temporary. In early studies, it has been shown that another pathway (EGFR) may be responsible for this resistance, and this project aims to target the EGFR and BRAF pathways simultaneously to improve effectiveness of the drug.

High levels of the receptor for a specific growth factor have been linked to a type of leukemia where children have a poor survival rate. This project studies the role of the growth factor that stimulates this receptor in the progression of leukemia. Understanding the contribution of the growth factor and its receptor to disease will help researchers develop drugs that can target these molecules and increase survival in children with leukemia.

Brain tumors are the leading cause of cancer-related death in children. Unfortunately, current treatments leave most children that survive with severe disabilities, due to the harsh and nonspecific nature of the therapy. In order to improve overall survival and minimize this toxicity, new treatments that specifically target cancer cells and spare surrounding normal non-cancer cells are needed. To achieve this, Dr. Praveen is working to test and optimize new therapies specifically against cancer cells and not surrounding normal cells.

Identical twins have the exact same DNA sequence. Epigenomic changes might cause freckles on one twin and not the other. Now we know that mutated genes in cancer alter the epigenome. Dr. Thiele is working to identify the epigenetic genes involved in stimulating neuroblastoma growth. Neuroblastoma accounts for over 10% of all deaths in children due to cancer. This project aims to turn off the expression of the different epigenetic genes in the tumor cells and determine which ones, when turned off, cause the tumor cells to stop growing. Then researchers can look for or design drugs that inhibit these genes, to stop tumor growth in patients.

Ewings sarcoma, the second most common bone cancer in children and young adults, is very aggressive. Current treatments are not very effective at curing the disease and patients often experience a recurrence of their cancer. Dr. Van Meir is looking for new and more effective treatments for this type of tumor. His laboratory has found a small molecule (KCN1) that they believe may reduce the growth of Ewings sarcoma. KCN1 binds with EWS-FLI1 which is known to stimulate the growth of Ewings sarcoma. Earlier attempts at using a recombinant EWS-FLI1 to produce targeted therapy have been difficult due to the lack of information about the structural makeup of EWS-FLI1. In this project researchers are investigating 1) How the binding occurs between EWS-FLI1 and KCN1, 2) Whether the KCN1 reduces the expression of the EWS-FLI1 gene that causes Ewings and 3) Does KCN1 interfere with Ewings sarcoma development.

Therapy for children with leukemia is difficult, prolonged, toxic and carries long term-side effects. Previous studies clearly show that the immune system can recognize and destroy leukemia. However, this process is inefficient. Dr. Verneris is working to design drugs that bring elements of the immune system in close contact with the leukemia. This has the immediate effect of killing the leukemia and the long-term potential of "training" the immune system to recognize and remember the leukemia. These drugs are now being tested in clinical trials with impressive results and this research will create more effective forms of this therapy.

Children with advanced cancer experience significant suffering. To improve their comfort, Dr. Wolfe aims to understand how distressing symptoms are evaluated and treated, and also to identify attitudes and behaviors in clinicians and families that may interfere with optimal symptom control. To do so, this project is carefully following what happens when a child reports high distress from pain and other common symptoms during clinic visits, as well as interview providers and families, and review charts. The results will help researchers improve symptom control and will be used to design the PediQUEST Champions intervention aimed at easing suffering in children with cancer.

This research is funded by P.A.L.S. Bermuda with funds raised through the St. Baldrick's Foundation.

Dr. O'Bryan is studying the signals that contribute to the development and growth of neuroblastoma tumors. His lab has found a new gene that is important for tumor growth. Although the gene is not useful for targeting treatment, the researchers are studying the ways that this gene works within the cell. With this information, they may be able to identify new drugs that interfere with its function thus interfering with the growth of neuroblastoma cells. This information may be useful in the development of new, more effective treatments for neuroblastoma patients.

Current treatments for kids with brain tumors don't work as well as they should and they have toxic side effects. Often these brain tumors and also other kinds of tumors outside the brain in kids are caused by mutations in a gene called N-Myc. Since researchers don't understand very well how N-Myc causes cancer, they can't fix it. The goal of this project is to test the idea that N-Myc mutations create bad cells called "cancer stem cells" that are like seeds that grow brain tumors. By testing this idea, Dr. Knoepfler and his lab hope to develop new treatments that are better and safer.

Despite major improvement in outcomes for children and older adults with cancer over the past three decades, there has been little or no improvement in survival among adolescent and young adult (AYA) cancer patients (ages 15-39 years). The reasons for this disparity are not completely understood and likely include many factors, including differences in tumor biology, insurance coverage, clinical trial participation and adherence to treatment. This research aims to produce detailed information about the factors affecting AYA cancer incidence and survival that will help doctors target care and close this gap. The project will also produce detailed information for local cancer care service providers on where to target their efforts, and information that will help clinicians recruit AYA patients most in need of help to clinical trials to address their needs.

Having friends is vitally important for all children. Children surviving brain tumors often have physical problems (jerky movements, slurred speech, etc.) and cognitive delays caused by their disease or treatment. These cancer survivors are frequently described by peers as "not well liked," "having few friends" and "isolated". This puts them at risk for being bullied, dropping out of school, becoming anxious or depressed, and being less likely to marry or have good jobs as adults. Dr. Noll is conducting a research-backed, school-based project to support brain tumor survivors' social involvement by training classmates to be more inclusive of others viewed as "different."

Dr. Phipps is studying what happens to children who were treated with bone marrow transplant for cancer many years ago. This is a very challenging treatment that can cause problems for survivors in a number of areas, including their thinking and learning ability, their physical health, and their ability to have children. He is learning how these children and young adults are faring relative to their healthy peers, to identify factors that lead to better or poorer outcomes so that researchers can develop treatments to prevent any negative effects.

Childhood cancer survivors are at risk for developing long term health problems including heart disease. Dr. Ruble's research finds ways to make survivors healthy by participating in physical activity. Currently less than 50 percent of survivors participate in adequate amounts of exercise, which increases the risk of developing health problems. This project aims to find out the best way to support survivors in changing behaviors and being healthy.

Even though more and more children are being cured of cancer, the treatment can cause major life-long health problems for survivors. Unfortunately, most adult survivors don't seek appropriate medical care to monitor and care for these problems. This project is to study whether or not adult survivors referred to adult-focused follow-up care actually engage in such care and what might get in the way of doing so. The results of the study will help medical providers better prepare young adult survivors to engage in adult-focused follow-up care to assure that they stay as healthy as possible.

Cancer therapy for childhood leukemia is often successful, but not without side effects. Pancreatitis, characterized by severe abdominal pain and inability to digest food, is a severe side effect seen in some children but not others who are similarly treated for leukemia. This side effect is sometimes fatal, and very often causes significant delays in continuing with treatment. This research is to learn the reasons why some children are more likely to develop this side effect than others, with the goal of helping all patients avoid it.

About 80% of children and adolescents diagnosed with cancer become long-term survivors. About half of them develop therapy-induced hearing loss that is cumulative and irreversible. Most at risk are patients with brain tumors, neuroblastomas, osteosarcomas, soft tissue sarcomas, retinoblastomas, hepatoblastomas, or germ cell tumors who need to be treated with cisplatin, combinations of cisplatin and carboplatin, radiation to the head and neck, or combinations of platins and radiation. Therapy-induced hearing loss adversely affects speech and language development, reading ability, communication, academic performance and psychosocial development. It frequently causes stress, social isolation, low self-esteem, and low overall quality of life. This project explores the use of moderate to high doses of dietary selenium as means to reduce or prevent cisplatin-induced hearing loss.

Although most children with leukemia can be cured, chemotherapy frequently causes permanent brain dysfunction in survivors. With previous support from St. Baldricks, Dr. Cole's lab identified promising protective interventions, and he will now test them among those children at greatest risk for brain damage. To identify this population researchers are studying whether variation in neurocognitive function among leukemia survivors is related to specific inherited differences in genes related to repair mechanisms or to metabolism of drugs thought to cause cognitive deficits.