Grants Search Results

All proteins in our bodies are made using assembly instructions contained in messenger RNAs, or mRNA. mRNA molecules themselves are constructed from building blocks called exons. When exons are joined together, or 'spliced', out of order, the resulting protein code is scrambled. This is what causes several types of leukemias in older adults. We have discovered that incorrect splicing also occurs with high frequency in childhood leukemias originating in antibody-producing B-cells. Dr. Thomas-Tikhonenko is testing two ideas. The first is that incorrect splicing is needed to sustain uncontrolled multiplication of leukemic cells. The second is that restoring proper exon assembly with specific drugs would slow down or block cancerous growth. If successful, these studies could pave the way to new clinical trials and improved survival of children with leukemia.

Neuroblastoma is one of the most common childhood cancers. There are different subtypes of Neuroblastoma; some have a very poor prognosis for the patient. Dr. Stockwell's team has identified a new aggressive subtype of Neuroblastoma, called "mesenchymal", and sought new therapies that can specifically target this subtype. Since genetic markers that can identify patients with the mesenchymal subtype are know, a selective therapy will have a greater chance of success in the clinic. They recently discovered that a common type of cholesterol-lowering drug, called statins, are potent and selective killers of mesenchymal neuroblastoma cells in the lab. There are many different statins, and now Dr. Stockwell is determining which is the most potent drug and exploring why the mesenchymal subtype is so sensitive to statins. He is also testing these drugs in models of the disease to show that statins are effective at killing mesenchymal neuroblastoma cells. Since these drugs have a documented safety profile in children and well-studied pharmacological activity, these drugs can be brought through preclinical testing relatively quickly and developed as novel therapies for this aggressive pediatric cancer.

Glucocorticoids, which are sometimes called "steroids", are a type of drug used to treat all children, adolescents, and adults with acute lymphoblastic leukemia (ALL). In fact, there is substantial evidence that glucocorticoids are the single most effective drugs used to treat ALL, and that relapse is frequently due to the fact that they stop working. Although glucocorticoids have been used for over 50 years, we still do not fully understand how they kill ALL cells and why some ALL cells become resistant and cause relapse. Dr. Shannon has developed a novel approach for generating, transplanting, and treating ALL in models that now provides an unprecedented opportunity to uncover mechanisms of drug response and resistance. The purpose of this research project is to study ALL cells that have become resistant to glucocorticoids during treatment in order to identify the underlying reasons and to use this knowledge to develop better ways of treating them.

Brain tumors are the most common solid tumor in children, and diagnostic imaging guides almost every step in the care of children with brain tumors. However, currently available imaging methods have limited accuracy. Dr. McConathy is using an amino acid tagged with radioactivity (FET) to detect abnormal metabolism in tumor tissue using positron emission tomography (PET) in combination with magnetic resonance imaging (MRI). He expects this new imaging technique to improve the ability to see brain tumors before and after surgery to help doctors better plan the treatment of children with brain tumors. In the long term, Dr. McConathy expects FET-PET/MRI to help select and plan the best therapies and increase the chance of achieving cures.

Rhabdomyosarcoma is a deadly cancer when spread through the body. With the Aiden's Army Fund St. Baldrick's Research Grant, Dr. Li is combining drugs already FDA approved for adult cancers in a way that stops rhabdomyosarcoma tumor cells from creating new tumors elsewhere in the body. This approach is unique because Dr. Li not only aims to stop the tumor cells from growing, but will try to convert what is left to non-cancerous cells similar to what is found in normal muscle. This grant is funded by and named for the Aiden's Army Fund, a St. Baldrick's Hero Fund. Aiden Binkley who was diagnosed with Stage IV rhabdomyosarcoma at age 8. This bright, funny and courageous little boy believed he got cancer so he could grow up to find a cure for it. His vision is being carried on by Aiden’s Army through the funding of research. They will march until there is a cure!

Recently the Meshinchi lab discovered that mesothelin, a cancer-specific antigen, is highly expressed in a subset of childhood AML cases, a result that both highlights the distinct genetic differences between adult and pediatric cancers and opens the door for the development of more targeted therapies. Dr. Kolb is developing novel combinations of bispecific T-cell engaging antibodies, called SMITEs (Simultaneous Multiple Interaction T-cell Engagers) that will co-target mesothelin and the AML marker CD33. These T-cell engaging protein pairs physically link cancer cells to cytotoxic T-cells resulting in more potent and selective killing than single agents alone.

Diffuse intrinsic pontine glioma, also referred to as brainstem glioma, is a pediatric cancer that accounts for the majority of deaths from brain tumors in children. Although radiation therapy is the standard of care for brainstem gliomas, the median survival of children with this tumor type is less than one year from diagnosis. In order to improve the treatment of these patients, Dr. Kirsch's team is using a model of brainstem glioma that can be used to evaluate the effectiveness of new therapies. Using this model, they are testing whether removing a protein called ATM, which is the target of drugs now entering clinical trials, will enhance radiation sensitivity in brainstem gliomas. They hypothesize that deleting this target, when given in combination with radiation therapy, will increase the number of tumor cells killed by radiation and will therefore improve survival in brainstem gliomas when they have a specific gene mutation commonly found in this childhood brain tumor. If successful, these studies will inform the design of future clinical trials testing this strategy in children with brainstem gliomas. This grant is named for Hannah’s Heroes, a St. Baldrick’s Hero Fund created in honor of Hannah Meeson and pays tribute to her fight by raising awareness and funding for all childhood cancers because kids like Hannah “are worth fighting for.”

Ewing Sarcoma is an aggressive disease affecting children and young adults. Patients are treated with intensive chemotherapy. This helps some, but not all, with early disease, works poorly in those with advanced disease, and can have serious side effects. Searching for new and better therapies, Dr. Jedlicka's lab has found a new protein that works abnormally in Ewing Sarcoma and that could be a new target for treatment. Dr. Jedlicka is working to understand more about how this protein works and how best to block it, to see if it could be a useful new treatment.

Synovial sarcoma is a soft-tissue cancer in adolescents and young adults. More than half of patients develop metastasis, or spread of the cancer to the lungs. Once it has metastasized, synovial sarcoma is fatal in nearly all patients. Dr. Jones' team has developed a model of synovial sarcoma and found that when the tumor spread to the lungs many white blood cells begin to infiltrate the tumors. He is studying whether these particular white blood cells from the immune system are trying to fight the tumor or are helping the tumor grow and spread to the lungs. This team is testing if the presence of these immune cells in a large panel of human synovial sarcomas are associated with the same patients developing clinical spread of disease.

ALL is the most common blood cancer occurring in children. Great strides have been made in the treatment of this disease, but new less toxic therapies for high risk ALL are needed. A new effective therapy is chimeric antigen receptor T-cells (CAR-T) which involves altering a patient’s own cancer fighting cells (T-cells) to express a protein able to recognize a protein on ALL cells (CD19), thus promoting killing of ALL cells. This form of therapy is much less toxic than traditional chemotherapy, but it is still associated with unwanted side effects. Dr. Falcon is working on ways to eliminate anti-CD19 CAR-T if severe side effects occur. This will greatly enhance the safety of this promising treatment. A portion of this grant is generously supported by the Not All Who Wander Are Lost Fund, a St. Baldrick's Hero Fund which was named after Kiersten Dickson’s favorite quote from J.R.R. Tolkien and honors the memory of a free spirited, courageous young woman who battled a rare, incurable cancer. This fund hopes to advance cutting edge immunotherapy treatments for pediatric cancers.

A new class of drugs called EZH2 inhibitors is currently in clinical trials for the treatment of patients with relapsed B-cell lymphomas, a common subtype of pediatric lymphoma. These drugs suppress the activity of the EZH2 enzyme, which is known to be critical to tumor growth. Over time, however, if the lymphoma cells become resistant to EZH2 inhibitors, they may lose their effectiveness. Dr. Gulati aims to understand the mechanisms through which lymphomas develop resistance to EZH2 inhibitors. This will extend the usefulness of these drugs and will help in the development of methods to overcome the resistance. Awarded at the Memorial Sloan Kettering Cancer Center, and transferred to Baylor College of Medicine.

Based on progress to date, Dr. Iglesias was awarded a new grant in 2019 to fund an additional year of this Fellow award. Neuroblastoma is the second most common pediatric solid tumor. Patients with high-risk disease have only a 50% chance of survival. The immune system can be engineered to efficiently kill cancer cells while sparing healthy tissues. However, neuroblastoma has been shown to evade these treatments by downregulating their target structures and upregulating inhibitory proteins. Dr. Iglesias is developing immune cells that specifically recognize neuroblastoma cells and also circumvent the aforementioned treatment evading mechanisms by restoring the target structures and blocking the inhibitory proteins. Through this work Dr. Iglesias aims to develop a new treatment approach for patients with high-risk neuroblastoma.

Children who have leukemia (a type of blood cancer) that is difficult to treat with just chemotherapy can be treated and even cured with transplants of blood stem cells from a donor. However, even when donor and patient cell types are carefully matched, immune system incompatibilities between a patient's body and cells from a donor can cause many complications including graft-versus-host disease, which can be fatal in extreme cases. Results from this research will hopefully teach us a way to manipulate the immune system using something called "exosomes" so that the child receiving the stem cell transplant is less susceptible to attack from the donor's cells and can have a successful cure. Through this research Dr. Kim hopes to be able to use exosomes to protect the child's body from the donor cells that can cause harm, yet preserve the donor cells that can fight the leukemia.

Based on progress to date, Dr. Pierro was awarded a new grant in 2019 to fund an additional year of this Fellow award. While outcomes for childhood leukemia have improved dramatically, the prognosis for children who relapse remains poor making relapsed leukemia one of the main causes of cancer death in children. Discovering the underlying pathways that lead to chemotherapy resistance and relapsed disease is therefore a top priority. To prevent relapse and improve treatment response, Dr. Pierro's laboratory has focused on discovering genetic mutations responsible for relapse and chemotherapy resistance. Mutations in a gene known as MMSET have been identified as one of the most common mutations in relapsed leukemia in children. This mutation in other cancers imparts a poor prognosis which suggests it has a role in drug resistance. Dr. Pierro's team has developed leukemia cell lines with and without the MMSET mutation and is treating the lines with chemotherapy to test this theory. He is also identifying the pathways controlled by this gene to identify the mechanism by which it protects the cells from the effects of chemotherapy. This information could be used to develop targeted therapy to prevent relapse and restore sensitivity to chemotherapy thereby improving outcomes.

The goal of this study is to develop new therapies for Ewing sarcoma by targeting a protein called EWS-FLI1. Many people believe that the key to improving outcomes for Ewing sarcoma patients is to develop new drugs that block EWS-FLI1. In order for this to be successful, there is a need to understand exactly what happens to the Ewing sarcoma cell when EWS-FLI1 is turned off. Dr. Grohar is using the latest technology to both characterize the consequence of EWS-FLI1 silencing and identify novel compounds that turn EWS-FLI1 off.

Based on progress to date, Dr. Winters was awarded a new grant in 2019 to fund an additional year of this Fellow award. Dr. Winters' research involves developing more effective and more targeted therapies for children with acute myeloid leukemia (AML), a type of leukemia that continues to have poor outcomes. The therapy for pediatric AML has not changed much in 20-30 years, and many children who receive this therapy relapse. There is a protein on many AML cells called CD123, which marks the earliest leukemia cells. In adults there are drugs that target this protein which are being studied in clinical trials. However, no one has studied whether CD123 is a useful target in pediatric AML. Dr. Winters is looking at CD123 protein expression in AML samples from pediatric patients, as well as investigating whether expression of CD123 marks the primitive leukemia cells in these patients - that is, those that give rise to the leukemia and cause relapse. She is also testing some of the same drugs that are being used in adult clinical trials on these pediatric samples in a laboratory setting, to see if they may be useful in pediatric patients. These studies are expected to generate new therapy options for children with difficult-to-treat AML.

Acute myeloid leukemia (AML) is a cancer of the immature cells in the bone marrow. One common chromosomal abnormality found in pediatric AML is the inversion of chromosome 16 (inv(16)). Current treatments for inv(16) AML are associated with significant toxicity, as well as serious long-term chronic effects. Therefore, there is a pressing need to develop new, more targeted treatments for children with inv(16) AML. Inv(16) generates a fusion gene called CBFB-MYH11. CBFB-MYH11 causes changes in gene expression, which are the first step in the development of leukemia. Because Cbfb-MYH11 is expressed in all inv(16) leukemia cells, it makes an attractive drug target. Currently, there are no CBFB-MYH11 inhibitors suitable for use in humans. However, it is possible that other proteins cooperate with CBFB-MYH11, some of which may be better drug targets. One potential co-factor is HDAC1. Dr. Hyde's team found that HDAC1 binds CBFB-MYH11 and is required for its activity. They also found that an HDAC1 inhibitor significantly blocks the growth leukemia cells in culture. In this project, Dr. Hyde is testing whether HDAC1 is an important co-factor of CBFB-MYH11 and if HDAC inhibitors effectively target Cbfb-MYH11+ leukemia cells in vivo. These results will have direct clinical implications for children with inv(16) AML.

Based on progress to date, Dr. Mulama was awarded a new grant in 2020 to fund an additional year of this Scholar grant. Kaposi sarcoma-associated herpesvirus is a virus that causes cancer known as Kaposi sarcoma, which is very common in HIV+ children, especially in Africa and sometimes in individuals who get an organ transplant. Dr. Mulama is designing and testing a vaccine that prevents and treats the viral infection, as well as antibodies to detect infection in people. He will also test the vaccine so that one day it can be used as a treatment to prevent Kaposi sarcoma-associated herpesvirus infection and Kaposi sarcoma in more than 40,000 patients worldwide each year.

Based on progress to date, Dr. Wulff was awarded a new grant in 2019 to fund an additional year of this Fellow award. Ewing sarcoma (ES) is the second most common bone cancer in children. Approximately 25% of children with ES have metastasis, which are tumors that have spread to other parts of the body, such as the lungs. It is especially difficult to treat these children and more than 70% die within 5 years. Therefore, it is important to learn about what it is that allows these tumors to spread and hopefully develop new drugs to treat these patients. Certain proteins are expressed at much higher levels in metastatic lung tumors compared to the primary bone tumor, suggesting that these proteins play a role in allowing the tumor to spread. Dr. Wulff is studying the role of these proteins by increasing or decreasing them, and then testing how this affects the cancer's ability to grow and spread. Dr. Wulff's team thinks that the cancer's ability to spread can be decreased by decreasing a particular set of proteins. In addition, she is testing new drugs that inhibit the function of these proteins, with the hope to identify new therapies that will improve overall survival rates for patients with metastatic ES. This is grant is generously supported by Team Clarkie, a St. Baldrick's Hero Fund. Clarkie Carroll was diagnosed with Ewing sarcoma in his upper right femur in 2013. He endured surgery and treatments with strength, positivity and a sense of humor. Today he has no evidence of disease. A portion of this grant was also funded by this Hero Fund. It was created to honor Clarkie and ensure researchers have the resources to further Ewing’s sarcoma research as well as stimulate greater awareness and inspire others to believe pediatric cancer research can and will lead to a cure.

The seeds of many childhood cancers are likely to be laid during human development before a child is born. Therefore, one may view childhood cancer cells as being stuck in development. Dr. Behjati aims to define at what stage tumour cells are stuck and to find ways of stimulating cancer cells to resume development. He envisions that this will provide a way of maturing cancer cells into harmless, non-cancerous cells. The St. Baldrick's Robert J. Arceci International Innovation Award is given in honor of the late Dr. Robert Arceci. A pioneer in the field, this award reflects Dr. Arceci's values including creativity, collaboration, and commitment to early- to mid-career scientists.