Grants Search Results

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.

Based on progress to date, Dr. Braun was awarded a new grant in 2014 to fund an additional year of this Scholar award. Approximately one-third of human cancers harbor mutations in RAS genes, causing malignant cells to proliferate inappropriately. In pediatric oncology, RAS mutations are particularly common in leukemias. Unfortunately, the RAS protein is a difficult molecule to attack with drugs. An alternate approach is to target other proteins that are required partners for RAS to exert its control. Some types of cancer are dependent on rare "cancer stem cell" populations with unique properties. This research is to discover how cancer stem cells are affected by mutations that activate RAS, and to use this information to devise novel therapies.

Based on progress to date, Dr. Dallas was awarded a new grant in 2013 to fund an additional year of this Scholar award. Hematopoietic cell transplantation is a potential cure for various pediatric cancers. Approximately one-third of patients who require a transplant do not have a suitable matched donor, and umbilical cord blood transplants are an increasingly utilized alternative, with over 20,000 performed since 1988. One of the major complications is the increased risk for serious infection due to the prolonged period of time the patient's immune system is suppressed after transplantation. Dr. Dallas and her team have developed a novel method to generate cells that will hasten the time to recovery. Their goal is to translate these findings to pediatric patients and improve their survival.

Based on progress to date, Dr. De Oliveira was awarded a new grant in 2014 to fund an additional year of this Scholar award. New therapeutic approaches are needed for pediatric leukemia and lymphoma, because patients with refractory or relapsed disease still have a survival rate of less than 50% with current therapies. This research involves a novel cancer immunotherapy protocol, transferring a gene into the patient's own blood stem cells, giving rise to immune cells able to directly and specifically target a surface molecule that is present in more than 95% of leukemias and lymphomas. This project evaluates the cancer cell destruction by the modified immune cells, setting a basis for future clinical trials.

Based on progress to date, Dr. Diede was awarded a new grant in 2013 to fund an additional two years of this Scholar award. DNA methylation is a normal process used by cells to allow information to be passed on to successive generations of cells. Cancer cells can exploit this to silence genes that help prevent tumor formation. This has been extensively studied in adult cancers, but not in pediatrics. Given the relatively short time frame in which pediatric cancers develop, aberrant DNA methylation may play a very important role. This research is to better understand how it promotes the formation of pediatric rhabdomyosarcoma, and may open an exciting new area for treatment and provide valuable biomarkers for cancer detection, diagnosis, and risk assessment.

Based on progress to date, Dr. Gamper was awarded a new grant in 2014 to fund an additional year of this Scholar award with generous support from the McKenna Claire Foundation. Chemotherapy and radiation destroy both cancer cells and normal cells, with toxic effects on growing children during treatment and afterwards. Immunotherapy has the potential to destroy only cancer cells, but it has not lived up to its full potential because cancer cells can promote inappropriate immune responses or simply turn immune cells off. This research examines the function of T cells that lack the ability to methylate DNA; such cells may be better at killing tumors. This may help more patients with high-risk pediatric tumors, and decrease the risk of late-effects by reducing the need for more chemotherapy and radiation.

Based on progress to date, Dr. Rabin was awarded a new grant in 2014 to fund an additional year of this Scholar award. Children with Down Syndrome have a 20-fold increased risk of developing acute lymphoblastic leukemia (ALL), and suffer significantly more frequent and severe complications associated with chemotherapy, including life-threatening infections. This research involves abnormal activity of genes called JAK2 and CRLF2 and new drugs. It will also investigate whether gene variants that are associated with severe infection in the general population occur more frequently in those with Down Syndrome and ALL who suffer severe infectious complications. If so, patients identified as high-risk for infection could be identified ahead of time, to receive enhanced supportive care to prevent severe toxicity.

This grant is made with generous support from the “Daniel the Brave Fund" created in memory of Daniel Gomez to honor his bravery and provide hope for those still in the fight.

Based on progress to date, Dr. Singh was awarded a new grant in 2013 to fund an additional two years of this Scholar award. Diamond Blackfan anemia (DBA) is an inherited condition that leads to anemia, birth defects and cancer. Over-expression of the p53 protein, which protects against tumor formation, may actually lead to DBA. One of p53's functions is to cause cell death in damaged or stressed cells. Chronic over-expression of p53 may lead to an environment that leads to cancer transformation and survival. Understanding the conditions that promote the formation and survival of cancer cells is vital to improve early diagnosis and treatment of childhood cancer.

Leukemia is cancer of white blood cells and accounts for about 25% of all childhood cancers. Human chromosomes are normally subjected to various environmental and developmental challenges that might cause breaks, called translocations. While almost all of those breaks are efficiently repaired by the DNA repair machinery, translocations do arise from very rare events when mistakes occur during the repair, increasing the risk for leukemia in children. This study involves basic questions about the cause and process of translocation to better understand the underlying causes of leukemia, potentially leading to the discovery of targets for new therapeutic strategies.

Most cancer therapies have significant toxicity, thus new treatment strategies are needed. Pediatric patients with cancer are excellent candidates for immunotherapy because their immune system is more robust compared to adults. Due to our lack of understanding of how to best activate these specialized anti-cancer cells, progress in pediatric immunotherapy has lagged behind. This research focuses on how we can best activate specific T cells to defend the immune system against tumors, specifically gliomas (brain tumors) and advances the field of immunotherapy as a promising form of treatment for these children.

Rhabdomyosarcoma is the most common cancer that originates in the soft tissue of the body in children. There are two subtypes, embryonal (ERMS) and alveolar (ARMS), and children with ARMS have poorer response to conventional chemotherapy and radiation therapy, and much lower survival rates than those with ERMS. This research aims to discover chemical inhibitors of a gene called PAX3-FKHR and how "knocking down" that gene may help patients respond better to chemotherapy.The goal of this project is to establish a new approach for developing drugs to effectively treat ARMS.

The human body has an ability to detect and eliminate cancer through the immune system, but cancer cells can escape detection. Dr. Curran's research attempts to overcome this tumor escape via gene therapy mediated treatments. Pediatric leukemia is the most common childhood cancer, and patients with recurrent or resistant leukemia have limited options for treatment. Redirecting the immune system to eradicate resistant leukemia cells will provide a new possibility for a cure. Also, by specifically targeting cancer cells, we eliminate the long term complications associated with the conventional treatments of surgery, chemotherapy, and radiation. Dr. Curran was a St. Baldrick's Fellow and now has a faculty position.