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Cancer is a genetic disease in which a cell learns to take advantage of certain processes that allow that cell to grow and survive unchecked. Bone cancer is an aggressive disease in both children and pet dogs that can be painful and often leads to death of the patient even with aggressive surgery and chemotherapy. Most often these patients die because the tumor has spread to other areas of the body, not from the original bone tumor, which is often removed with surgery. Therefore, in order to better battle this disease, new therapies that target the cells that spread are needed. Preliminary work with a new drug that targets this process has shown promise as just such a therapy. The goal of The Ben's Green Drakkoman St. Baldrick's Research Grant is to more thoroughly investigate this drug for its ability to prevent or delay spread of the tumor cells using both human and dog bone tumor cells.

This grant is named for the Ben's Green Drakkoman Fund, a St. Baldrick's Hero Fund created to honor the memory of Ben Stowell who battled osteosarcoma with an inspiring determination to live life fully. The fund is named after a super hero Ben created named the Green Drakkoman who defeats his enemy, the Evil Alien.

Diffuse intrinsic pontine gliomas (DIPG) are lethal pediatric brain tumors with no treatments. In order to develop cures we need to understand their biology. Cancers survive on fuel to generate energy to support their uncontrolled proliferation. One of the fundamental nutrients that drive the energy production is the amino acid glutamine. How glutamine is taken up and metabolized by DIPG tumor cells is not know. Further it is not known if inhibiting cancer cells from taking up and metabolizing this fuel is therapeutic. To address this significant gap in our knowledge, Dr. Venneti is studying glutamine metabolism in DIPG cancer cells and evaluating inhibition of glutamine metabolism as a potential therapeutic strategy. This grant is made with generous support from the McKenna Claire Foundation established by the Wetzel family in memory of their daughter, McKenna. Their mission is to cure pediatric brain cancer by raising awareness, increasing community involvement and funding research.

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.

Cancer cells are hard to defeat because they are so similar to normal cells. Most current methods that kill cancer cells impose collateral damage on normal cells that lead to immune suppression, hair loss, and gastro-intestinal damage. Dr. Whitehurst's research focuses on identifying therapies that will only kill tumor cells but leave normal cells unharmed. Here, she is focused on a tumor type that impacts adolescents: Ewing Sarcoma. She has identified a pathway, called TNFa, which is “mis-wired” in these cancer cells. Instead of dying when this pathway is activated, the cancer cells keep growing. Importantly, she has identified inhibitors of the pathway that can kill these tumor cells. Dr. Whitehurst is working to understand how this pathway is mis-wired in cancer cells and the consequences of its inhibition. The end goal would be the identification of chemical inhibitors that could be used in the clinic as a less toxic and more effective treatment option.

Adolescent and young adult (AYA) cancer survivors have an elevated risk of medical problems that can impact the quality and length of their lives, but few studies have focused on the occurrence of late medical conditions in this population. Using data on nearly all AYA cancer survivors in California, the Rich and Weissman Family Lymphoma Survivorship Fund St. Baldrick's Research Grant is identifying how often specific late medical conditions occur and how the risk of these medical conditions vary by clinical and patient factors. The results of the study will identify subgroups of young patients at increased risk of serious medical conditions, information critical to improving survivorship care and outcomes. Jared Weissman is a Hodgkin’s lymphoma survivor thanks to a clinical trial made possible by research. This Hero Fund honors his survivorship and his grandparents, Terri and Barry Rich, by funding research for new treatment options for cures and less toxic after effects for survivors.

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.

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.”

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.

Neurons are nerve cells that populate certain regions of the human body and are responsible for transmitting chemical signals back and forth to the brain to regulate critical bodily functions. A deadly form of pediatric cancer, known as neuroblastoma, occurs when a subset of these neurons start to proliferate uncontrollably. These cancer cells can migrate and spread throughout the body, making it very challenging to treat with currently available drugs. This highly aggressive form of neuroblastoma occurs in children who are older than 18 months. At such an early age, this disease can be quite devastating and there is an imperative need to better understand how this form of neuroblastoma develops. Recent work has identified pediatric cancer mutations in distinct specialized proteins that regulate chromatin (the complex of DNA and proteins), known as chromatin remodelers. One such protein, ATRX, was recently found to be mutated frequently in neuroblastoma tumors identified in adolescent and young adults, which have poor overall survival. Dr. Bernstein is exploring a novel therapy for neuroblastoma patients that harbor ATRX mutations thorough innovative and state-of-the-art approaches. Dr. Bernstein's team is comparing the cellular changes that occur in the presence of the drug in models of neuroblastoma.

Many cancer treatments kill both normal and cancer cells. Drugs used in standard cancer treatments have long term effects in children, such as causing developmental delays or second cancers later in life. Dr. Blackburn's team is working to find new drugs that kill cancer cells, but do not affect normal cells. By discovering characteristics that are unique to cancer and finding a drug that recognizes that specific characteristic, they will be able to selectively kill cancer cells. Their research goal is to improve cancer treatments so that children can live long, normal lives after their cancer is cured.

Children with cancer continue to succumb to their disease, many after receiving toxic therapies like chemotherapy and radiation. Also, surviving children face life long negative health consequences ranging from learning disabilities, to more severe effects such as a higher chance of getting another cancer in adulthood. Therefore, additional, rigorous scientific research needs to be performed to develop new and effective treatment options for these kids. Cancer growing inside the body hides in plain sight of the immune system. This is because cancer cells evolve to escape recognition by the immune cells. Therefore reawakening the immune system could be a very effective way of using a patients' own attacker cells to engulf cancer cells and get rid of the disease. Dr. Davare is working to discover and test new ways to reactivate immune cells for attacking cancer cells. For this project, she has developed an innovative method to identify synthetic molecules that will uncloak the cancer cell and make it visible to the immune system for destruction. This research strategy, in the long run, will open new doors and has the potential to not only increase survival of children with cancer, but their long term quality of life as well.

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.”

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.

Childhood cancer survivors can have problems with their lungs due to their cancer treatment. Dr. Kirchhoff is completing the first study to examine how air pollution affects the health of childhood cancer survivors.

Relatively little is currently known about the cellular and molecular mechanisms of medulloblastoma spread throughout the spinal fluid. Dr. Keller's preliminary findings show that medulloblastoma tumor cells actively migrate to the surface of the covering of the brain and spine, rather than arriving passively. Dr. Keller is investigating the efficacy of stopping the tumor cells from migrating to the brain and spine surfaces, which, if successful, will provide a rationale for future clinical trials.

Dr. Wechsler and his team study how normal white blood cells turn into leukemia cells. They have discovered that a protein called CRM1 is directly involved in turning on specific genes that cause leukemia to develop. Dr. Wechsler is studying this previously unrecognized function of CRM1 by identifying other proteins that are required for CRM1 to turn on. This research aims to allow Dr. Wechsler to design new drugs that can selectively target leukemia cells and increase cure rates.

The interaction between two important cancer-related proteins called MDM4 and TOP2A may cause cancer and contribute to disease progression. Dr. Zhou is studying the regulation of MDM4 and TOP2A to identify small-molecule inhibitors (agents) that can block the MDM4-TOP2A interaction, leading to inhibition of these two proteins. The results of these studies will provide important clues to help scientists develop novel methods and drugs to specifically and simultaneously target TOP2A and MDM4 for treatment of pediatric cancer patients.

Treatment of childhood acute lymphoblastic leukemia (ALL) using chemoradiation can be successful, but it is difficult to manage treatment-associated side events and secondary cancers. Furthermore, in relapsed/refractory patients, the overall prognosis remains dismal. Direct inhibition of the main proteins promoting cancer (the 'oncogenes') is not successful in ALL. Dr. Ntziachristos's "Just Do It...and be done with it" St. Baldrick's Research Grant will study certain oncogene-supporting mechanisms that might be specific to a diseased state, and not to a healthy state. Dr. Ntziachristos has selected one of these mechanisms to target in ALL models, and is assessing the anti-cancer activity that results. Such experiments could pave the way for clinical trials for high-risk disease.

This grant is named for the "Just Do It...and be done with it" Hero Fund created in honor of Sara Martorano who doesn''t let anything dim her sparkle and has a compassionate heart and smile. It also celebrates the courage of all cancer kids through treatment and the support of their family and friends.

Diffuse Intrinsic Pontine Glioma is a type of incurable brain tumor that affects young children. Despite treatment with radiation and chemotherapy, the tumor exhibits resistance to current treatments and grows back. Dr. Beroukhim is studying the tumors at a single-cell level to determine how they become resistant to treatments, which will help guide the development of combination therapies to improve outcomes.

This grant is made with generous support from the McKenna Claire Foundation established by the Wetzel family in memory of their daughter, McKenna. Their mission is to cure pediatric brain cancer by raising awareness, increasing community involvement and funding research.