Grants Search Results

Significant challenges remain in the treatment of leukemia that has infiltrated into the central nervous system (CNS). The CNS serves as a sanctuary site for leukemic cells which can relapse and spread to other organs. In particular, T-cell ALL, a sub-type of acute lymphoblastic leukemia (ALL), has a strong propensity to infiltrate the CNS. Dr. Othman's research focuses on a recently identified target protein, CDK5, which has been implicated in the migration of immune cells. These potentially paradigm-shifting investigations promise the development of new biological agents or immune-mediated therapies against CNS leukemia and other devastating childhood tumors of the brain.

Leukemia, a cancer of the white blood cells, is the most common cancer in children. While a majority can expect to be cured with chemotherapy, a significant number either never go into remission, or relapse. One theory as to why certain leukemias do this is that normal, non-cancerous cells in the bone marrow can help small populations of leukemia cells evade chemotherapy-induced death, leading to relapse. This research project focusing on a protein called CXCR4, is to find a way to make chemotherapy more effective and may lead directly to clinical trials in children with high-risk leukemias that will improve cure rates.

Based on progress to date, Dr. Skiles was awarded a new grant in 2013 to fund an optional third year of this fellowship. Vincristine is one of the core anticancer agents used in many childhood cancers. It is associated with cumulative dose-dependent neurotoxicity, often making it necessary to reduce chemotherapy dosage, compromising effective treatment. There is substantial variability in the way vincristine is metabolized from one person to the next. For example, Caucasians develop neurotoxicity much more frequently than African-Americans, probably as a result of genetic differences in a specific drug-metabolizing enzyme. This is of particular importance in African populations where the treatment outcome is poorer than in U.S. populations. Currently, drug dosing recommendations used in Kenya are based on dosing schemas derived in primarily Caucasian patient populations. This study helps develop individualized vincristine dosing parameters based on genetic predictors, which may lead to improved cure rates, as well as less neurotoxicity in long-term cancer survivors both in the U.S. and in Kenya.

Bone marrow transplantation is an important and potentially curative treatment for children with relapsed leukemias. Infections due to a delay in the recovery of the immune system after transplantation are a major cause of complications and even death in these children. T-cells are a type of immune cells that fight infection. Of the various components of the immune system, the T-cells are the one that recover the poorest after bone marrow transplantation. The aim of this project is to understand how VEGF improves T cell production, with the ultimate goal of improving cure rates for children with relapsed leukemias.

With every new pediatric cancer diagnoses, a family is given the most unexpected and stressful news of their lives. This kind of stress makes people more susceptible to post-traumatic stress and depression, and also diminishes the immune system, allowing the body to become sick more often. This project examines the level of chronic stress felt by the parents of children and the factors involved. It is vital that we work to improve the outcomes for both patients and their families.

Neuroblastoma is a cancer that develops in the nervous tissue and most cases occur in children younger than two years old. For patients with high-risk disease overall survival remains poor, thus there is a tremendous need to develop new treatments. This research will allow us to improve the clinical development of a new drug, MLN 8237, which has shown promise in early pediatric clinical trials, and could improve survival in this devastating disease and provide additional targets for therapeutic intervention.

Bone marrow transplantation is a treatment option for children with leukemia. When no bone marrow donor is available, cord blood transplantation is an alternative. This research focuses on two poorly understood aspects of the results of bone marrow transplants: First, the prolonged recovery of the recipient's new immune system. Second, the dominant cord in double cord blood transplantation, in which a patient receives cells from two cords instead of one. Understanding both of these immune processes is key to improving the care and survival of these patients.

Based on progress to date, Dr. Petrosiute was awarded a new grant in 2013 to fund an optional third year of this fellowship. Medulloblastoma, the most common malignant brain tumor of childhood, often exhibits an aggressive growth pattern and causes high morbidity and mortality despite aggressive therapy. This project studies the role of a target protein, CDK5, and related molecules in controlling the invasion and spread of medulloblastoma. These potentially paradigm-shifting investigations promise the development of new biological agents or immune-mediated therapies against medulloblastoma and other devastating brain tumors of childhood.

African-American children with neuroblastoma treated with chemotherapy die or relapse more often than Caucasian children. This research aims to find the genetic factors that may be involved. Our lab gives chemotherapy to white blood cells from healthy volunteers from all over the world. The entire genome for each of these cells is known. By comparing how sensitive or resistant these cells are to chemo against their genetic code, we can find genetic changes that are associated with chemotherapy resistance. This information will help us to personalize therapy and eventually improve cure rates.

Normal genetic variations are responsible for differences in ability to fight infection, metabolize medications, and repair damage to our DNA. One cause of DNA damage is exposure to oxidants and free radicals, which may increase with exposure to radiation, food, and chemicals. This research is to determine some of the genes that make children with Down syndrome 10-20 times more likely to develop leukemia than other children. This could help identify children at risk and help develop new treatments. It may also determine if these genetic changes are present in children without Down syndrome who develop leukemia.

Despite intense treatment, only approximately 50% of children with AML (acute myeloid leukemia) will survive. Many cases of AML have genetic abnormalities that likely contribute to the development of leukemia and impact the outcome of the patient. Two such mutations happen to occur together frequently in AML, mutations in a gene called nucleophosmin and a gene called Flt3. This research studies the relationship between these two gene mutations, to gain insight into the cause of leukemia and how best to treat patients who have these two common genetic mutations.

To continue improving the treatment of childhood leukemia, we must broaden our understanding of cancer biology at the molecular level so we can better exploit the vulnerabilities of cancer cells. Cancer occurs when mutations disrupt the normal cellular machinery that controls cell growth. For example, the production of a protein called TCF-1 is dramatically increased during the critical phase of leukemia development. A better understanding of specific growth regulating proteins such as TCF-1 may allow development of more targeted therapies in the future.

Intracranial Germ Cell Tumors (GCT) are rare brain tumors found mostly in teenagers, and their biology is poorly understood. We are generating the largest comprehensive genetic profiles of these tumors in collaboration with multiple institutions, to help us understand how these tumors arise and what determines their biological and clinical behavior. This may lead to new therapeutic targets. We will also develop a test that requires only small amount of tumor tissue to correctly sub-classify intracranial GCTs, and initiate the first-ever cell lines of these tumors for determining the impact of these genetic abnormalities and for preclinical drug screening.

Low-grade gliomas are the most common brain tumors of childhood. However, they are quite a mixed collection of tumors, varying in aggressiveness and thus outcome for affected children. Diffuse astrocytomas represent about 20-30% of such low-grade gliomas of childhood, and have been recognized to have a relatively poorer prognosis (for recurrence and death) than the other more common variety, pilocytic astrocytomas. Scant evidence has suggested that, like adults, some children with these diffuse astrocytomas fare poorly because they transform to more malignant gliomas, called anaplastic astrocytoma and glioblastoma multiforme. This study aims to clearly document either the prevalence and the timing of this malignant transformation of childhood diffuse astrocytomas. Dr. Zaky began his research at New York University School of Medicine and moved to the Children's Hospital Los Angeles in 2011

Based on progress to date, Dr. Wood was awarded a new grant in 2012 to fund an optional third year of this fellowship. A drug called an ALK inhibitor can successfully attack the most common ALK mutation, which is harbored in 10% of neuroblastomas. To maximize cure rates we must learn how to inhibit every mutation. This project aims to discover how ALK mutations cause neuroblastoma by working out what incorrect messages different mutations send to the cell. Identifying the molecules carrying these messages could provide additional cancer targets to attack. We are especially interested in drugs called kinase inhibitors. This approach could lead to novel targeted therapies which can attack the tumor while sparing healthy cells, leading to higher cure rates.

Since the majority of children with acute lymphoblastic leukemia (ALL) will survive, understanding how to limit the acute and long-term toxicities of treatment is increasingly important. Toxicities of the bone, including fracture and osteonecrosis, are serious complications. Dr. Vrooman's project accesses how bone mineral density changes in children being treated for ALL, so future interventions may decrease skeletal morbidity in these children. She is funded by P.A.L.S. Bermuda with funds raised through the St. Baldrick's Foundation.

The Ewings sarcoma family of tumors (ESFTs) is the second most common cancer of bone and soft tissue in children, and has a 20-30% overall survival rate in those children with widespread disease. Dr. Dela Cruz is working to understand the pathways involved in the development of ESFTs, which will be essential to discovering new molecular targets to treat and cure these patients.

Based on progress to date, Dr. Mulcahy-Levy was awarded a new grant in 2011 to fund an optional third year of this fellowship. Understanding how cancer cells die is important in designing new therapies and improving the effectiveness of currently used therapies to cure childhood cancers. One element of cell death is called autophagy, a system the cell uses to break down as it dies, the focus of Dr. Mulcahy-Levy's project.

This new doctor is supported for training to specialize in pediatric oncology research, funded for 2 years or more.

This new doctor is supported for training to specialize in pediatric oncology research, funded for 2 years or more.