Grants Search Results

Doctors have been testing ways to boost the immune system to fight cancer in clinical trials over the last ten years. Although these approaches have led to very impressive results in patients with blood cancers, they have not worked well in patients who have tumors in their solid organs. Solid tumors have specialized cells that act as bodyguards, protecting the cancer cells from the immune system. Dr. Parihar has developed a strategy to selectively remove these 'bodyguard' cells from tumors, which will then allow the immune system to enter tumors and kill the cancer cells. He will test a new and selective nano-medicine he has created to kill 'bodyguard' cells. If successful, the new nano-medicine can help the immune system of patients with a range of childhood solid tumors, including neuroblastoma, one of the most common extra-cranial solid tumors in children where response rates remain low.

Acute lymphoblastic leukemia (ALL) is the most common cancer of children, and although treatment is considered largely successful, in many cases leukemic cells stop responding to chemotherapy and re-emerge. As a consequence, ALL relapse remains a leading cause of childhood cancer-related death. Dr. Aifantis will test the possibility that the bone marrow microenvironment surrounding the leukemia supports the growth of disease and protects leukemia cells from chemotherapy. Together with colleagues he generated the first map of the ALL immune cell microenvironment allowing identification of novel players within the remodeled leukemic bone marrow that promote leukemia survival. They found that high levels of a specific cell type, known as non-classical monocytes, in ALL patient blood and bone marrow correlates with inferior patient survival. They demonstrated that depletion of leukemia-supporting monocytes enhances killing of leukemic cells with specific ALL therapies. In this project Dr. Aifantis will investigate the processes giving rise to monocytes capable of supporting leukemia survival. Further, he will use novel model systems to test whether targeting monocytes enhances responses to a range of existing ALL therapies as well as emerging approaches, such as Chimeric Antigen Receptor (CAR) T-cell therapy, that utilize a patient's own immune system to kill leukemic cells.

Alveolar rhabdomyosarcoma is one of the most aggressive and difficult to treat tumors in children. If not caught early, metastatic disease has a dismal 5-year survival of less than 5%, even after the most intensive chemotherapy possible. Even in the rare circumstances when these children do well, the long-term side effects of the intensive chemotherapy are debilitating. We can, and must, do better. We have known for some time that the cause of alveolar rhabdomyosarcoma in 60% of the most aggressive cases is a specific genetic abnormality. This genetic mistake creates a new gene, and Dr. Hiebert will determine how this new gene causes cancer and determine what would happen to these sarcoma cells if we had a drug specific for this new gene. To do this, he has engineered alveolar sarcoma cells grown in the lab so that this cancer gene can be quickly turned off by an existing drug. This allows, for the first time, the treatment of these sarcoma cells with a specific drug to define all of the events that occur in the first few minutes to several days of drug treatment to establish that inhibition of this new cancer gene is a viable therapeutic strategy.

This grant is generously supported by Rachael Chaffin’s Research Fund, a Hero Fund created in memory of a young girl who loved life. Rachael loved people, animals and the outdoors. It was heartbreaking when she was diagnosed with Rhabdomyosarcoma in the summer of 2013 at the age of 11. With a positive attitude and determination, Rachael began her long battle with cancer. She truly believed she would beat cancer so she could go on to help others. In 2014, Rachael organized a team of family and friends called “Kicking Cancer with Ray Ray” to raise funds for St. Baldrick’s and they continue the tradition today. This Hero Fund honors Rachael’s passion to find a cure for kids’ cancer and carries on her legacy of increasing awareness of childhood cancer to find better treatment options and cures through research.

Dr. Resnick's research project focuses on how to cure one of the deadliest brain tumors in children called diffuse midline gliomas (DMGs), previously also known as diffuse intrinsic pontine gliomas (DIPGs). No available cancer treatments work against DMGs and children die from this lethal disease within 8-11 months of diagnosis. To improve survival and develop better treatment against DMGs, he assessed genes being turned on or off in DMG tumor cells. Together with colleagues, he has identified novel gene products common in multiple DMG tumors that arise when two unrelated genes join and become expressed as one novel protein entity. Here, he will study the role of these gene products, or gene fusions, in DMGs, specifically those involving a known cancer-causing gene called MET. He will test drugs that target the MET gene fusions in DMGs by performing experiments on models that accurately represent human DMG tumors. The results from this project will help identify new drug treatment strategies to target DMG tumors in children. Successful therapy options from this study will be made available to children with DMGs in real-time through our partnership with a clinical trial consortium that brings new treatments to children with brain tumors.

Dr. Rowe is applying stem cell biology to understanding childhood leukemia. Overall, pediatric oncologists have made remarkable progress in treating children with leukemia with chemotherapy, but some children have forms of leukemia that don't respond well. Dr. Rowe is interested in better understanding what makes this subset of leukemias resistant to treatment. To do this, he is developing new models of these unfavorable forms of leukemia so that he can understand precisely how normal blood cells become leukemic blood cells. If Dr. Rowe can achieve this, then researchers can find new ways to more effectively treat these forms of leukemia.

Pediatric cancers are often comprised of mixtures of cells with different characteristics. Some of the most important differences relate to chromosomal changes, with some cells having a normal or nearly normal chromosome profile, others having altered numbers of intact chromosomes, and yet others having extra or missing copies of one or more chromosome segments. Prior studies have shown that cancers with more segmental changes are usually more aggressive and therapy-resistant, but the specific effects associated with the different chromosomal changes are unknown. Here Dr. Cobrinik and colleagues will define the effects of such changes in two pediatric cancers -- retinoblastoma and neuroblastoma -- by isolating individual cells within the tumors that either have or lack specific chromosome changes, comparing their overall gene expression and cell signaling profiles, and identifying the critical changes that increase malignancy. The study involves three investigators with expertise in neuroblastoma, retinoblastoma, and a novel single cell sequencing approach that enables us to distinguish and characterize the chromosomally distinct cells within individual tumors in unmatched detail. This study is expected to reveal the most central features that distinguish more versus less aggressive cancers, as a critical step towards targeting and subduing the more aggressive and lethal cells within individual tumors.

Precise understanding of the basic mechanisms by which childhood cancers develop is essential to design tailored and superior treatments for cancer patients. These treatments are expected to cure and avoid long-term complications in cancer survivors. In many instances, we turn to models to reproduce human cancers, but the success of this strategy depends on how accurately we can unravel the origin of the disease. This project is based on Dr. Dominguez-Sola and colleagues recent findings on the origins and cellular basis of Burkitt lymphoma, a most aggressive form of childhood lymphoma with little treatment alternatives. This project will use unprecedented models of this cancer type to expand our understanding of the mechanisms of disease and identify therapeutic strategies that are less toxic, more effective, and superior to those currently available in the clinic.

This grant is funded by and named for Jack's Pack - We Still Have His Back, a St. Baldrick's Hero Fund. Jack Klein was a ten year old who loved life, laughing and monkeys. During his illness, his community of family and friends near and far rallied around him under the moniker "Jack's Pack". Their slogan was "We have Jack's Back". After Jack succumbed to Burkitt's Lymphoma, his "pack" focused their energy and efforts to funding a cure...just as Jack would have wanted.

Neuroblastoma is a pediatric cancer that originates from mistakes in nerve cell development. Limitations in our mechanistic understanding of disease onset and progression have led to inaccurate patient risk predictions and over-treatment of infants, with long-term side effects. Recently, Dr. Kulesa and colleagues developed a computational model to predict neuroblastoma disease outcome based on a network of six development genes of receptor tyrosine kinase signaling that is more accurate at early disease stages than any current gene list algorithm. What remains to be determined is whether this model can be refined to increase its predictive value and tested to simulate hypothetical treatment strategies with individual patient data. To address these questions, he will include MYCN into the network model, a proto-oncogene gene that is correlated with poor prognosis, and compare model and experiment results of network perturbations that simulate targeted treatments. Dr. Kulesa will take advantage of acquired human neuroblastoma cell lines and our ability to modulate these genes in culture, and patient data from large-scale neuroblastoma genomic databases and published studies. At the conclusion of our study, he will have a better understanding of the mechanistic basis of neuroblastoma disease progression and a refined computational model to more rapidly and accurately predict individual patient disease outcome.

Ewing Sarcoma (EwS) is an aggressive bone and soft tissue tumor occurring in children and young adults. Approximately 25-30% of patients already have metastases at diagnosis and in spite of aggressive treatment, the survival for patients with metastatic disease remains dismal. EwS is considered an immune cold tumor that is largely resistant to conventional immunotherapy. Alternative treatment approaches are sorely needed, particularly in patients with metastatic disease. Dr. Sorensen and colleagues are using three novel strategies for targeting EwS tumors: 1) Inhibiting an EwS specific fusion protein that drives EwS tumor development. 2) Targeting a surface protein called IL1RAP. 3) Recruiting natural killer (NK) immune cells to EwS tumors and priming them to attack the tumor. This grant is the result of a generous anonymous donation to fund Ewing sarcoma research, specifically. It is in honor of a teenager fighting Ewing sarcoma, and is named the St. Baldrick's - Martha's Better Ewing Sarcoma Treatment (BEST) Grant for All.

Acute lymphoblastic leukemia (ALL) remains the most common cancer of children and young adults. Despite intensified treatments that achieved cure rates around 85%, there is a number of children who will relapse and succumb to therapy-resistant disease. One of the revolutions in the treatment of human cancer the last decade was immunotherapy, the ability of our own immune system to fight cancer. Unfortunately, despite its successes in a number of solid tumours, immunotherapy has not really impacted the treatment of leukemia, with the exception of CAR-T cell treatment of pediatric B-ALL. Indeed, some frequent types of pediatric ALL, and specifically T cell ALL (T-ALL) and its subtypes, have no immunotherapy treatment options. We believe that this is because we still don't understand how the cells of the immune system interact with the leukemia. Actually, researchers don't even know what type of immune cells are there available to fight the disease. Dr. Aifantis is applying a number of single cell techniques to create a map of the immune cells in the bone marrow of children with T-ALL. He is doing this at diagnosis of the disease, after treatment (remission) and when the children relapse. These studies will offer the first map of the immune system in pediatric ALL and will enable researchers to propose ways to activate the immune system to fight the tumour.

Acute lymphoblastic leukemia (ALL) is the leading cause of cancer-related death in young people. The high-risk ALL is a subtype of ALL that fare a high rate of relapse and mortality. Intriguingly, high-risk ALLs show increased signaling response to growth factors that results in uncontrolled cell proliferation, a block in normal B cell development, as well as a loss of tumor suppressor genes. Currently, the field is hampered by a lack of models that closely resemble human high-risk B cell leukemia for discovery of novel therapeutic therapies. Dr. Tong has generated novel models that closely resemble human high-risk B cell leukemia that are amenable for downstream applications. She is now using these novel models to perform a genome-wide genetic screen to identify novel targets to eradicate B-ALL proliferation. Furthermore, she is working to discover druggable signaling pathways that confer resistance to existing ineffective therapies. Therefore, this work will likely provide new insights into therapeutic strategies in treating pediatric high-risk B-ALL.

Rhabdomyosarcoma (RMS) is a rare and devastating cancer of childhood. Identifying and characterizing novel genes essential for RMS cancer growth can help improve our understanding of RMS disease process. Novel genes identified can also serve as potential therapeutic drug targets for treating RMS patients. BCOR is among the most frequently mutated genes in RMS. However, the role of BCOR in promoting cancer growth and disease progression remains unexplored. As the recipient of the Glen Parker Bayne Hero Fund St. Baldrick's Research Grant, Dr. Chen is working to characterize the biological function of BCOR in RMS. Completion of the study will not only provide new insights into the role of BCOR in the disease process of RMS, but also therapeutic rationale for targeting BCOR in improving survival outcomes of RMS patients.

This grant is named for the Glen Parker Bayne Hero Fund which was established to honor this little boy's courageous battle with rhabdomyosarcoma and celebrate his survivorship. Glen was diagnosed when he was almost 2 and endured a year of intensive treatment. Today he has no evidence of disease and Glen's Army, a group of family and friends rally to raise funds and awareness for research to find cures.

Altering chemotherapy, including dose intensification, has not improved the survival for osteosarcoma (OS) patients. Genomic analysis has been unsuccessful in identifying consistent targetable options, and there were no responses in relapsed/refractory OS patients treated in numerous Phase I or II trials. Identifying new therapies is imperative. Immunotherapies such as dendritic cell vaccines (DCV) and checkpoint inhibitors have shown activity against adult cancers but there are no studies in children or adolescents (AYA) with OS. Dr. Kleinerman and colleagues demonstrated the efficacy of checkpoint inhibitor therapy against OS lung metastases. They have also showed that the activity of DCV can be improved by checkpoint inhibition. They are investigating whether a unique dendritic cell vaccine that augments T-cells is effective against primary and metastatic OS. This project aims to identify new therapeutic approaches for treating children and AYAs with relapsed/metastatic and primary OS. If efficacy is demonstrated, this approach can be translated into a clinical trial for children with OS lung metastases. Another goal is to combine vaccine therapy with chemotherapy for newly diagnosed patients to improve disease-free survival.

For children with pediatric brain tumors radiation therapy has been the backbone of treatment, in combination with surgery and chemotherapy. Although pediatric brain tumors can be highly responsive to radiation its use needs to be limited since radiation can be damaging to the brain, causing abnormal inflammation and long-term cognitive deficits that will profoundly impact the lives of patients. As the recipient of the Benicio Martinez Fund for Pediatric Cancer Research St. Baldrick's Research Grant, Dr. Sredni and her colleagues have identified a new drug (MW151) that can be given orally to patients receiving radiation therapy and can protect their brains against the cognitive decay caused by radiation. They are about to start a clinical trial, funded by the government (NIH/NCI), associating MW151 to whole brain radiation for the treatment of adults with brain metastases. Her goal is to move this approach to the pediatric population. This project is performing experiments that will test if inhibiting neuroinflammation with MW151 will interfere with brain tumor's response to radiation. This information is crucial to allow them to move forward with the studies necessary to use this protective drug in children. This new drug candidate has the potential to provide a safe and effective new adjunct protective treatment strategy. It can potentially transform the care and significantly improve the quality of life of our young patients and their families. Weeks after being the top fundraiser in his 6th grade class and shaving his head at his school’s event, Benny was diagnosed with medulloblastoma. Despite complications from treatment and setbacks, Benny has an amazing can-do attitude and is battling the cancer with determination.

This grant is funded by the Hero Fund that honors Benny’s fight and supports cures and better treatments for kids like him.

Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer. Although most children and adolescents are cured with modern treatments, relapsed/refractory ALL remains one of the most common causes of death from pediatric cancer. This observation highlights the importance of understanding why the leukemia cells of some children are difficult to kill with modern drugs (this is called intrinsic resistance). Glucocorticoids are a type of drug that have been used to treat ALL for over 50 years and are given to all children with ALL. It is known that it is harder to cure children with ALL when their leukemia cells show intrinsic resistance to glucocorticoids. He is now working to understand how IL7 makes ALL cells resistant to glucocorticoid drugs and to use this knowledge to develop ways to cure more patients. He has identified drugs that appear to suppress the effects of IL7 on ALL cells and that make them more sensitive to glucocorticoids. They believe that combining one of these drugs with glucocorticoids could cure more children with ALL in the future.

Cancer cells grow and divide faster than normal cells and therefore have an increased demand for building blocks compared to normal cells. The metabolic pathways that supply these building blocks are often altered in tumors to meet the increased demand. Because cancer cells rely on these metabolic pathways they can be targeted by chemotherapeutics to block cancer growth. Dr. Sabatini and colleagues recently identified a new group of genes that play an important role in one metabolic pathway that supplies cells with the necessary building blocks. He is testing whether these genes can be used as new drug targets to treat cancer and identify additional genes in the same metabolic pathway that might also serve as drug targets. This work will help the development of new chemotherapeutics with less toxic side effects.

Thanks to advanced diagnosis and treatment, many children now can be treated from cancer and stay alive for a long time; they are called survivors. Some anticancer drugs are harmful to the heart and may cause heart failure in these survivors. High blood pressure increases the risk of heart failure in survivors, but no one knows how this happens. Dr. Zordoky has developed a new model to answer this question. He thinks that anticancer drugs make the hearts age faster leading to a worse response to increased blood pressure. He is looking at a natural compound and a new group of drugs which prevent aging to see if they will protect the hearts from the bad effects of anticancer drugs and make the hearts stronger when hit by high blood pressure. The findings of this research will open the door for testing these compounds in the clinic in order to prevent late side effects of anticancer drugs in survivors.

Childhood leukemia patients diagnosed with MLL rearranged leukemia (MLL-r) have a particularly poor outcome. MLL-r cells are dividing endlessly, due to the constant growth signal sent by a protein located on the cell surface called FLT3. FLT3 signals can be regulated by chemically modifying the protein in a variety of ways. Dr. Li is exploring a novel way to regulate FLT3 by studying how the activity of FLT3 is regulated by PRMT1 mediated methylation, and evaluating whether a PRMT1 inhibitor in combination with the traditional FLT3 inhibitor could completely "turn off" survival signal of MLL-r leukemia.

Cancer associated with different types of lymphocytes is known as lymphoma. Different forms of lymphoma are a common cause of pediatric cancer in the US. Current clinical therapy is based on conventional chemo- and radiation therapy, which is associated with numerous side effects.

As the recipient of the Jack's Pack - We Still Have His Back St. Baldrick's Research Grant, Dr. Bahal is researching an alternative robust therapy against lymphoma by exploring new chemically modified therapeutic molecules and their interaction with novel targets. One of the major challenges associated with current therapies are side effects due to non-targeted delivery of the drug to the normal bystander cells that can result in potential toxicity. Dr. Bahal is using a nanotechnology based approach for targeted delivery. He aims to accomplish two specific goals: a) To optimize the design and synthesis of a new class of bioactive molecules to target pediatric lymphoma; and b) To test the therapeutic effect of synthesized molecules in disease-related models. Investigation of these novel methods will lead to the development of novel drug candidate for pediatric lymphoma. Jack Klein was a 10 year old who loved life, laughing and monkeys. During his illness, his community of family and friends near and far rallied around him under the moniker "Jack's Pack". Their slogan was "We have Jack's Back". After Jack succumbed to Burkitt's Lymphoma, his "pack" focused their energy and efforts to funding a cure...just as Jack would have wanted.

Dr. French is studying one of the most deadly childhood and adolescent cancers known, called NUT midline carcinoma. There is no effective treatment for this cancer, which has a median survival of 6.7 months. Recently, his team discovered a new class of drug, called 'NEO', that in preliminary studies appears promising in models, an unprecedented finding that gives some hope that they may have stumbled across a new effective treatment for this disease. Based on some recent studies, Dr. French thinks that the drug class directly acts against the cancer protein that drives NUT midline carcinoma, called BRD4-NUT. BRD4-NUT is created by a mutation that fuses one gene, BRD4, to another, NUT, which alone don't cause cancer, but when fused together create a very potent cancer protein. He think the drug inhibits both the BRD4 and NUT halves of this fusion in a manner that gives the drug some selectivity for BRD4-NUT. The findings are exciting because the NEO drugs are set for clinical trials to begin in 2019. Dr. French and colleagues are working to 1) validate the findings that the NEO drugs work well in models bearing NUT midline carcinoma to provide rationale to enroll NUT midline carcinoma patients onto these trials, and 2) determine scientifically how the NEO drugs inhibit NUT midline carcinoma growth.