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The shape and function of bone, fat, muscle, and other connective tissues evolve through a carefully orchestrated process that leads mesenchymal stem cells (MSCs) to progressively differentiate into more lineage-restricted tissue-specific phenotypes. As this occurs, MSCs must interpret their surrounding extracellular milieu. When everything works correctly, normal mesenchymal tissues emerge. When disrupted, as tragically occurs with Ewing sarcoma (ES), the aberrant fusion protein (FP) acts as powerful transcription-factor that corrupts the epigenetic program and locks ES in an undifferentiated state unable to interpret or respond to the biophysical cues present in the tumor microenvironment. Attempts to understand the FP’s effect upon tumor-ECM interactions within monolayer culture systems that lack a native tumor microenvironment has contributed, not unexpectedly, to spurious results that overestimate the clinical effectiveness of chemotherapy. To close this gap, Dr. Ludwig's multi-disciplinary team is using an innovative 3D tissue engineered model, pioneered by his laboratory, to assess next-generation EWS-FLI1-targeted therapies within a physiological microenvironment that cannot readily be studied in vivo. This project will shed new light on ES biology and promises to improve the ability to co-target the FP and other proteins that maintain the aggressive, poorly differentiated state of ES.

This grant is generously supported by the Shohet Family Fund for Ewing Sarcoma Research. Noah was diagnosed with Ewing sarcoma in his freshman year in college. After limb salvage surgery and chemotherapy, he was able to return to school. Two years later, Noah relapsed. This Hero Fund honors his courageous fight and hopes to raise funds for Ewing sarcoma research.

Malignant rhabdoid tumor (MRT) and atypical teratoid/rhabdoid tumor (AT/RT) are rare but devastating childhood cancers. Most children diagnosed with MRT and AT/RT are under the age of two, and most will die from their disease despite intensive treatment interventions. New insights into what causes these cancers, and new therapies, are desperately needed. Genetically, MRT and AT/RT are simple cancers, caused by loss of just one gene called SMARCB1. If we are to understand and treat MRT and AT/RT, therefore, we need to understand how loss of SMARCB1 causes cancer.

As the recipient of the Oh Danny Boy I Love You So: The Danny O'Brien Rhabdoid Tumor Research Fund St. Baldrick's Research Grant, Dr. Tansey is working on an innovative molecular mechanism through which loss of SMARCB1 causes MRT and AT/RT. He proposes that these mutations drive cancer by stimulating the activity of a known pro-tumorigenic gene called MYC. Dr. Tansey further proposes that MRT and AT/RT can be effectively treated by drugs that block the actions of MYC, currently being developed by us and others. He is testing this model and exploring its therapeutic implications. Completion of this work has the potential to transform the understanding of how MRT and AT/RT form and how they can be treated. Danny O’Brien was five months old when he was diagnosed with a rare malignant rhabdoid tumor on his liver. Despite treatment to shrink the tumor, he passed away at the tender age of 9 months. Fortunately, he knew nothing but love and affection for all of his short life. This fund honors Danny’s courage and remembers his unconditional love in the midst of his battle with cancer.

We can now manipulate the immune system with remarkable precision and efficacy to fight certain cancers. However, tumors adapt to reduce immunotherapy efficacy. This is true for solid tumors including osteosarcoma. Therapy-refractory metastatic osteosarcoma represents a pressing unmet need, as the outcome has not improved for over 3 decades. This multi-institutional collaborative proposal explores tumor-extrinsic pathways by which pulmonary metastatic osteosarcoma evade immunity. Dr. Huang’s team is focusing on key molecules responsible for such evasion, against which existing or emerging therapeutic agents are available currently or in the very near future. Therefore, uncovering these pathways could realistically offer multiple new clinical trials for pediatric and AYA metastatic osteosarcoma in the next 3 years. This Osteosarcoma Collaborative St. Baldrick's Grant to Cure Osteosarcoma is funded through the generosity of the Osteosarcoma Collaborative.

Despite the use of multimodal treatments and the implementation of several clinical trials worldwide, pediatric cancers survival rate has come to a standstill for the last decade. Moreover, intensive therapies are not devoid of long-term side effects, notably increasing lifetime risk for secondary malignancies. The duty of the pediatric oncologist is to propose the most adequate treatment to cure pediatric patients with the best quality of life for a long time. Therefore, understanding the biological underpinnings of pediatric malignancies is crucial to develop new therapeutic paths adapted to the specificities of a young organism. A major pitfall is the lack of adequate experimental models. To overcome this problem, Dr. Broutier is developing patient-derived 3D-organoid models (mini-tumor growing in a dish) of pediatric cancers. Beside their broad interest for research community, she will use them to identify mechanisms involved in cell death resistance in pediatric cancers, as a key step towards development of new targeted therapies adapted to children and adolescents.

Nearly half of all children diagnosed with Acute Myeloid Leukemia (AML) will suffer a relapse after initially successful treatment. Whereas therapy efficiently clears the bloodstream of leukemia cells, frequent evidence of residual drug resistant disease points to a leukemia protective role of the bone marrow microenvironment. The mechanism by which the bone marrow acquires these protective abilities is not clear. Dr. Kurre recently observed that so called stroma cells, that provide bone marrow structure and support are functionally altered. Pilot studies conducted by Dr. Kurre also identified a new mechanism by which AML changes these stroma cells. In this project Dr. Kurre is studying pediatric AML samples to understand how the altered stroma protects leukemia cells from the effect of drugs commonly used to treat children with AML. The long term goal is to develop treatment approaches that reduce the burden of relapse, by maintaining initial remissions in children with AML, and without further escalating drug toxicity. Awarded at Oregon Health and Science University, and transferred to The Children's Hospital of Philadelphia.

Sarcomas are tumors of the bone and soft tissues that comprise up to 20% of cancer diagnoses in children. Despite dismal outcomes for patients with recurrent or metastatic disease, treatment regimens have remained largely unchanged for decades – intense non-specific chemotherapy combined with surgery or radiation. Dr. Tulpule studies Ewing’s sarcoma (ES), a bone tumor caused by a unique genetic change that creates a tumor-specific protein EWS-FLI1. To date, no drug has been identified to directly block the cancer causing EWS-FLI1 protein. His research takes a different approach to combating ES by asking a fundamental question: can we identify a targetable weakness in ES tumors that is caused by the EWS-FLI1 protein? Using a cutting-edge screening technology called CRISPR interference, Dr. Tulpule's team identified a specific vulnerability in ES cells’ capacity to repair damage to their DNA. Normal cells have many backup systems in place to repair DNA damage, but they have shown that EWS-FLI1 causes ES cells to become overly reliant on a single pathway, known as homologous recombination (HR) repair, such that blocking HR is an effective and specific way to kill ES. Dr. Tulpule is building a detailed understanding of why ES cells are so vulnerable to HR pathway blockade and then applying that knowledge towards developing less toxic and more effective treatments for ES patients.

This award allows Dr. Parsons the freedom to pursue discovery without the restrictions of a normal grant. The questions he is exploring include: What are the biologically and clinically-relevant genomic alterations in high-risk and rare pediatric cancers? What are the most useful and cost-effective clinical sequencing tests for childhood cancer patients? How can clinical genomics/precision oncology be most effectively implemented for diverse patients and families in varied clinical settings? What clinical benefit can precision oncology approaches and the use of molecularly-targeted therapies offer to childhood cancer patients? He is optimistic that a "team science" approach, bringing together investigators from diverse disciplines, departments, and institutions, will continue to yield critical data and discoveries that guide pediatric cancer research and clinical care in the next decade.

Some childhood cancers do not respond to chemotherapy, surgery, or radiation. For these patients, researchers are developing a new set of treatments that use their own immune system to attack the cancer. To turn on these defenses, they need to bolster the DNA in 200 million immune cells, efficiently and safely. Unlike other strategies, these cells do not need to come from the patients, who are already weakened. Dr. Weiss has invented an engineering solution to do so and is testing it so that he can make this treatment widely available to patients and their doctors soon.

This year it is estimated that 800 children will be diagnosed with osteosarcoma. It is thought that sex hormones play a role in the onset of the disease, as more boys than girls get osteosarcoma and the cancer develops at the time of puberty. Dr. Miranda hypothesizes that a key molecule in estrogen signaling is turned off in osteosarcomas, preventing those cells from being normal bone. Her preliminary data shows that she can turn back on that key estrogen signaling protein. These drugs have not been tested in osteosarcoma patients, but are FDA-approved drugs, so they could provide a treatment for osteosarcoma patients in the immediate future.

This grant is generously supported by the Sweet Caroline Fund created to honor the memory of Caroline Richards who was diagnosed with osteosarcoma at age 11. She persevered through rigorous treatments with a giving spirit and a contagious smile, always thinking of how to make others happy or laugh. This fund pays tribute to her compassion for others by supporting osteosarcoma research to help kids with cancer

The lives of children surviving cancer are cut short by life-threatening infections. Most pathogens causing these infections come from the gut. Healthy children have good bacteria in their gut that protect them from pathogens. Chemotherapy and antibiotics harm good bacteria in the gut that protect children from pathogens. Without good bacteria, pathogens increase in the gut. These pathogens can get into the bloodstream and cause serious infections. Prior studies have repeatedly shown that replacing healthy stool with good bacteria in the gut is the best treatment and prevention of gut infections. Dr. Andersen's team is developing a new test that detects the good bacteria and pathogens in the gut using a stool sample. This new test will allow earlier identification of children with cancer at the greatest risk for a serious infection and the children most likely to benefit from replacing healthy stool with good bacteria back in their gut. They believe that replacing good bacteria in the gut can prevent serious infections from pathogens, including those with limited antibiotic treatment options. This new test will also identify the specific good bacteria in the gut that prevent infection for developing new probiotics to prevent serious infections in children with cancer.

Despite recent advances in technology, very little is known about many types of rare and high risk childhood cancers. Since the numbers of these patients are so small, it has been very difficult to study how best to take care of them. Dr. Potter is using technology to look at the genetic code of these rare tumors, in order to learn more about why and how they occur, as well as how they change over time. This knowledge will help to create tests to diagnose these patients, as well as to develop more effective, less toxic treatments.

This grant is generously co-supported by the Invictus Fund and O Danny Boy I Love You So: The Danny O'Brien Rhabdoid Tumor Research Fund. The Invictus Fund was created to honor the memory of Holden Gilkinson who was diagnosed with Stage IV anaplastic Wilms tumor when he was 3 years old. Holden endured intense treatment and surgery, eventually losing both kidneys. He passed away just a few days shy of his 7th birthday. Through it all, Holden’s unconquerable spirit and love for life prevailed and is personified in the poem “Invictus” by William Ernest Henley. Danny O’Brien was just 5 months old when he was diagnosed with a malignant rhabdoid tumor on his liver. This cancer is extremely rare and aggressive. He endured chemotherapy to shrink the tumor for surgery, but the treatment was not effective. At the tender age of 9 months, Danny passed away. Fortunately, he knew nothing but love and affection all of his short life. This fund honors Danny’s courage and his unconditional love even in the midst of his battle with cancer.

Osteosarcoma is the most common primary bone tumor in childhood. The survival rate remains dismal, mainly due to ineffective therapeutic approaches for the relapsed/metastatic patients. One major obstacle of treating osteosarcoma is lack of suitable preclinical models. Dr. He's studies have established the first cultured osteosarcoma tissue model (an organoid). Dr. He aims to establish the first biobank of osteosarcoma organoids from patients as an open resource for the field, and utilize this organoid biobank to evaluate a novel class of therapeutics targeting key signaling pathways in osteosarcoma cells. This study will provide a powerful platform for predicting clinical treatment responses and developing new therapeutics for treating osteosarcoma.

Phthalates are chemicals added to many products that we use every day, including some common medications. Phthalates interfere with hormone systems in our bodies, which might cause cancer. Dr. Ahern wants to know if phthalate exposure while in the womb or during childhood increases the risk of childhood cancer. It would usually be time-consuming and expensive to answer this question scientifically. However, Dr. Ahern's team has developed a way to measure phthalate exposure using electronic pharmacy records that is both fast and inexpensive. This technique works because phthalate exposure from medications dwarfs exposure from other products. He will use this technique on existing pharmacy and cancer data from the entire population of Denmark. Dr. Ahern will measure phthalate exposure in pregnant women and in their children, and calculate whether that exposure increases a child's chances of developing cancer. If he finds that it does, we could prevent childhood cancer cases by limiting the amount of phthalates used in consumer products.

Although many children being treated for cancer initially respond to therapy, cancer cells often become resistant to chemotherapy drugs. Drug resistance is a major cause of cancer relapse, recurrence, and treatment failure. Dr. Gordon's goal is to identify new approaches to block, or reverse, resistance to an important class of cancer drugs. He has already identified one approach to reverse resistance in the laboratory, which he is now testing in models of cancer. Dr. Gordon is also testing a large number of additional drugs for the ability to prevent or reverse resistance.

Cancer cells rely on specific nutrients for growth and survival, rendering nutrient restriction as a potential therapeutic strategy. Along this line, acute lymphoblastic leukemia (ALL) cells have been found to be dependent on exogenous supply of asparagine, a nonessential amino acid, for protein synthesis. As a result, depletion of asparagine in the blood stream by L-asparaginase, a chemo-agent, has been successfully used to treat pediatric ALL for 40 years. However, ALL patients can develop resistance to the continuous application of this chemo-agent. Dr. Zhang is determining how ALL cells become resistant to L-asparaginase treatment, and therefore to provide experimental evidence of novel therapeutic targets that can potentially improve the outcome in pediatric ALL patients.

Leukemia is a blood cell cancer that frequently affects children. Despite the advances in treatment options, children with certain subtypes of leukemia are resistant to current therapy. Novel therapy for childhood leukemia is urgently needed. Dr. Fang's team recently found a protein, whose name is GPR68. They found that the levels of GPR68 were increased in blood cells of leukemia patients. When they decreased GPR68 levels, leukemia cells died, suggesting that increased GPR68 helped leukemia cells survive. Interestingly, normal blood cells with reduced levels of GPR68 were normal, suggesting that only leukemia cells need GPR68. Dr. Fang's findings suggest that lowering GPR68 levels or limiting its function may help cure leukemia without injuring normal blood cells. As the recipient of the Emily Beazley's Kures for Kids Fund St. Baldrick's Research Grant, she will be working to understand the function of GPR68 in leukemia cells and normal blood cells, and test drugs that could cure leukemia by inhibiting GPR68 function.

This grant is funded by and named for Emily Beazley's Kures for Kids Fund, a St. Baldrick's Hero Fund. At the age of 8, Emily was diagnosed with Stage III T-cell lymphoblastic non-Hodgkin’s lymphoma and battled through three relapses. Her family prayed for a miracle but discovered Emily herself was the miracle, inspiring a community to come together to show love and change lives. She had a dream of starting a foundation to fund research and named it “Kures for Kids”. Today, Emily's family and friends carry on her dream and her mission in her memory.

NUT midline carcinoma (NMC) is a deadly cancer that affects children and young adults, with a survival of less than 7 months. NMC is caused by a protein called BRD4-NUT that changes the structure of DNA in such a way that the DNA drives expression of cancer-associated genes that promote growth of NMC. Dr. French proposes to determine what is actually happening to the structure of the DNA that allows it to express the cancer-driving genes. There are two protein types he suspects are helping BRD4-NUT distort the DNA conformation; these are called HDACs and HATs. Dr. French's team will use state-of-the-art inhibitors that target specific HDACs and HATs to determine their respective roles and help identify novel therapeutics to treat this incurable disease.

The immune system acts as the body's defense against cancer by recognizing and attacking cancer cells. However, cancer cells have devised strategies collectively called "immune evasion," to thwart these protective mechanisms, making it difficult for immunotherapies to be fully effective.

As the recipient of the Emily Beazley Kures for Kids Research Grant, Dr. George aims to understand how the MYCN gene, which is abnormal in over half of patients with high-risk neuroblastoma, can cause tumor growth by shutting off protective immune mechanisms. In her preliminary studies, she has observed that MYCN amplification is associated with genes that evade the immune response, but exactly how MYCN does this is not known. Dr. George will use a novel model to understand how abnormal MYCN enables tumor cells to evade the immune system. At the age of 8, Emily was diagnosed with Stage III T-cell lymphoblastic non-Hodgkin’s lymphoma and battled through three relapses. Her family prayed for a miracle but discovered Emily herself was the miracle, inspiring a community to come together to show love and change lives. She had a dream of starting a foundation to fund research and named it “Kures for Kids”. Today, Emily's family and friends carry on her dream and her mission in her memory.

Radiation therapy is an important tool in the treatment of childhood cancer. Radiotherapy not only makes tumors shrink, it also causes inflammation of the tumor and can make immune cells attack the cancer. However, tumor cells can secrete substances that prevent immune cells from killing cancer cells. In addition, certain immune cells, called regulatory T cells (Treg) and myeloid derived suppressor cells (MDSC), exist to prevent an overshooting immune response. These cells are recruited to inflamed tumor tissue and dampen the anti-cancer immune response. To overcome this problem, Dr. Otto is testing a drug in combination with radiotherapy that has shown to reduce or deplete immunosuppressive cells from tumors, and lead to increased numbers of cancer killing immune cells in the cancer tissue. In models of pediatric cancer, he is combining this drug with a particular form of radiotherapy, called radionuclide therapy that uses radioactive substances which are injected into the bloodstream to carry their radioactive load directly to tumor cells. Dr. Otto hopes that this combination therapy will lead to robust and long-lasting anti-cancer effects.

This grant is made with generous support from the Team Campbell Foundation, established in memory of Campbell Hoyt, who courageously battled anaplastic ependymoma, a rare cancer of the brain and spine for five years. Its mission is to improve the lives of families facing a childhood cancer diagnosis through raising awareness, funding research and providing psycho-social enrichment opportunities.

Based on progress to date, Dr. Peltier was awarded a new grant in 2020 to fund an additional year of this Fellow award. Bone marrow transplantation (BMT) is required to cure many childhood cancers. However, bone marrow transplantation is often complicated by severe and often fatal side effects. Both the beneficial anti-cancer effects and harmful side effects of bone marrow transplantation are due in part to the new immune system that the patient receives. Unfortunately, we do not know how to precisely fine tune this new immune system to make BMT safer for more children. As the Hope for Harper St. Baldrick's Fellow, Dr. Peltier seeks to further understand in his work how a component of this new immune system is controlled by a recently identified class of genes called non-coding RNAs (ncRNA). These ncRNA genes do not make proteins like classic genes, but instead regulate the production and function of proteins made by classical genes. His early data shows that unique ncRNA genes from multiple classes of ncRNAs are turned on and off following BMT. However, it is not known if or how these unique ncRNA genes influence the new immune system after BMT. Dr. Peltier seeks to further understand the function of these ncRNAs following BMT, which may suggest ways of developing medicines to improve BMT.

This grant is named for and generously supported by the Hope from Harper Fund created to honor Harper Wehneman who was diagnosed with Wilms tumor just before her 8th birthday. She fought valiantly throughout her cancer journey and is remembered for inspiring people to choose joy no matter the circumstance. This fund continues her legacy by giving hope to kids fighting cancer through research for stem cell transplant survival.