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Whilst it is well known that damage to our DNA can cause cancer, is is still not fully understand what causes such DNA damage in many childhood cancers. Dr. Wang and colleagues recently made a breakthrough by discovering that our own body produces a natural toxin called formaldehyde that causes DNA damage and an aggressive blood cancer in children. This was a shocking discovery as it had previously been thought that formaldehyde mainly came from industrial chemicals found in factories. Dr. Wang's overall aim in this research proposal is to unravel exactly where formaldehyde toxin is made in our body. This knowledge can help to identify children at risk of developing blood cancers, and to develop strategies to modulate the production of formaldehyde as novel therapies against blood cancers. The first year of this grant is is generously supported by RowOn 4 A Cure, a St. Baldrick's Hero Fund. Rowan was a happy, spunky, funny, smart, and smiley little girl. With that same tenacity, she faced her cancer diagnosis of a rare form of acute myeloid leukemia when she was three. Despite intense chemotherapy and radiation and a successful cord blood transfusion, Rowan relapsed after a brief remission. The family relocated in search of another treatment option but before one could be found, Rowan sadly passed away. RowOn 4 A Cure was established to honor Rowan and continue her fight against AML by raising awareness and funds for research to find better options for treatment of relapsed AML and ultimately, a cure for the disease. Her family remembers Rowan’s perseverance during tough treatment days and intend to make an impact as they “Row On” to find a cure.

Acute myeloid leukemia (AML) is the second most common type of leukemia in children. Despite treatment advancements, over 30% of children with AML cannot be cured. In AML cell populations, the leukemia stem cells (LSCs) make up a small part of the total, but are specially important: they provide a steady supply of new AML cells and are unfortunately very resistant to killing with drugs. Dr. Sui and colleagues believe that if they are able to kill the LSCs, they could cure patients with AML. Dr. Su has found that an enzyme called METTL1 is important in allowing LSCs to safely stay anchored in the bone marrow and identified a drug that inhibits METTL1 and eliminates LSCs. Dr. Su's study explores why METTL1 is important for LSCs and investigates how Dr. Su and team could best use their in-house developed METTL1 inhibitor to treat childhood AML using model systems. If successful, this research could pave the way for a clinical trial, offering hope for improved outcomes for childhood AML patients. This grant is generously supported by Double Deckers Destroy AML, a St. Baldrick's Hero Fund. Joel and Seth were not only identical twins but best friends. In an ironic twist of fate, both boys were diagnosed with Acute Myeloid Leukemia just three months apart. With the overlapping diagnoses and treatments, the family was separated for months at a time and looked forward to days when they could be together at home. Joel and Seth both received bone marrow transplants and endured complications from the procedures. Sadly, both boys relapsed. Surrounded by their loving family, Joel died in November 2017 at the age of three, followed by Seth in May, 2019 when he was four years old. The twins were named as 2020 Ambassadors for St. Baldrick's so their story can continue to inspire many. The Double Deckers Destroy AML Hero Fund was established because the Decker family strongly believes more research is needed for AML, especially when the disease has relapsed. They want to support research so other families won’t have to say goodbye too soon.

Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer with more than 3000 children/adolescents under the age of 20 diagnosed with ALL each year in USA. ALL affects a type of white blood cells called lymphocytes that help the body fight infection and disease. ALL can be broadly divided into either B-ALL or T-ALL. B-ALL affects a type of lymphocytes called B-lymphocytes whereas T-ALL affects T lymphocytes. Historically children with T-ALL have worse prognosis than B-ALL. B-ALL also have better therapeutic options whereas children with T-ALL are limited to therapies with well documented long-term negative effects like chemotherapy, radiation therapy. In this proposal, Dr. Thansapani and colleagues aim to evaluate a new therapeutic approach of nutrient deprivation to treat T-ALL grounded on their strong preliminary finding that T-ALL cells need high levels of the nutrient valine for their growth and survival. Dr. Thandapani's project investigates different avenues exploiting this vulnerability.

Children everywhere in the world get cancer but their chances of surviving differ based on where they live. Disparities in childhood cancer diagnoses and survival have been described by sex and age, but there are gaps in this literature from countries with limited resources. The first goal of Dr. Force's project is to analyze how childhood cancer diagnoses and survival differ by sex, age, and world region, using data from the most comprehensive international collection of hospital cancer registries, and to assess potential underlying drivers of these disparities, which would be beneficial in identifying interventions to improve equity in childhood cancer outcomes. The second goal of Dr. Force's project is to compare childhood cancer data from hospitals and population-based cancer registries, to determine whether hospital data could be used to supplement information on childhood cancer burden where data is currently lacking in global models, better illuminating the disparities that exist globally.

Diffuse midline glioma (DMG), previously known as diffuse intrinsic pontine glioma (DIPG), is a deadly childhood tumor with no effective treatments. Dr. Li's project seeks to understand the genetic and epigenetic dysregulation of DMGs. Through cutting-edge single-cell analyses and advanced AI models, researchers aim to map the tumor's epigenetic landscape, identify key regulatory elements, and predict the function of risk mutations. This knowledge could pave the way for new targeted therapies and improve DMG outcomes. This grant is funded by and named for #Joe Strong 71, a St. Baldrick’s Hero Fund created in memory of Joe Purdue. Joe was a talented football player and cherished friend and son. He was diagnosed with DIPG shortly after graduating from high school, cutting short his plans to attend college. He is remembered for determination as he battled the most lethal form of brain cancer. #Joe Strong 71 carries on Joe's legacy by funding research for DIPG.

Despite remarkable improvements in treatment for children with some types of cancer, pediatric brain tumors remain an area that desperately require more effective and low toxic therapy solutions. Dr. Jun Qi has formed a multi-disciplinary team to identify novel targets for pediatric brain tumors and develop new strategies to suppress the targets for patient treatment. Using a chemical strategy, Dr. Qi and his team aim to disrupt the functions of these targets to effectively inhibit brain tumor cell growth and block tumor progression in the models that resemble the real disease. The study focuses on improving on-target effect and, more importantly, on getting these potential drug candidates into the brain. The proposed study will translate from bench to bedside for patient care and result in a novel therapeutic strategy with significant improvements in survival and reduced morbidity for pediatric brain tumor patients to fulfill the mission of St. Baldrick’s Foundation.

The study of genetic disease of cancer predisposition has served as a model for understanding cancer in general. Fanconi anemia is a rare genetic disease of failed blood production and cancer proneness, including leukemia and head and neck cancer. The genes and encoded proteins participate in DNA repair. However, an examination of cancer databases of DNA sequence shows that Fanconi genes are mutated in up to 30% of all head and neck cancers in non-Fanconi patients. Dr. Kupfer and colleagues have studied one particular mutation that resides in the Fanconi FANCD2 gene that interrupts its protein binding to another important gene BLM, which also participates in DNA repair. This proposal will seek to study the normal function of the FANCD2-BLM interaction in the cell and the consequences of its disruption. Dr. Kupfer also seeks to identify ways disruption of the normal pathway will render cancers vulnerable to molecular targeting to improve therapeutics.

Cancer patients take life-saving drugs that, unfortunately, can result in peripheral nerve damage. For example, many patients receiving cisplatin experience permanent hearing loss. There is one therapy that has been approved to mitigate cisplatin-induced hearing loss, however, the reduction in hearing loss is modest (< 30%) and this mitigating treatment is associated with poorer overall survival rates due to inhibition of cisplatin's cancer-fighting properties. Thus, it is approved for low-risk pediatric patients only. To develop a better alternative, Dr. Rutherford and colleagues are testing novel compounds they have developed at Washington University, which have shown to protect the ear from noise trauma. With hearing tests and with anatomical measurements of the cochlea, Dr. Rutherford will attempt to prevent hearing loss following cisplatin treatment in models. After this innovative project proves successful, subsequent model studies will determine if Dr. Rutherford's therapy inhibits cisplatin's cancer-fighting role.

Hepatoblastoma is the most common liver tumor diagnosed in early childhood, and new therapies are urgently needed to improve survival and reduce treatment related morbidity. Immunotherapy is a type of cancer treatment that harnesses the body's own immune system to target and attack cancer cells. While some immunotherapies have been very successful against certain tumor types in adult patients, they have been largely unsuccessful in treating pediatric tumors. This demonstrates how little we know about how the pediatric immune system responds to tumors. Using samples and models of hepatoblastoma, Dr. Cabric's research aims to identify the key immune cells involved in recognizing and responding to hepatoblastoma. Identifying the key immune cells involved in tumor immunity, and mechanisms that allow tumors to escape detection and deletion by the immune system, will allow us to find novel targets for future immunotherapies that work in children. This grant is funded by Allied World, a global provider of insurance and reinsurance solutions.

Children, adolescents and young adults with recurrent or refractory Osteosarcoma have a very poor prognosis, with a dismal 6mo overall survival of less than 5%. Presumably, this poor prognosis is in large part secondary to the development of resistance to chemotherapy and radiation. More recent studies employing therapies that release and activate the patients’ immune cells, called T-cells, and even targeted T-cells have not improved this poor prognosis. Dr. Cairo proposes to investigate novel and innovative methods of combinatorial immunotherapy to circumvent known mechanisms of resistance. Together with colleagues, he proposes to investigate at the bench (in the laboratory) and in models with osteosarcoma alternative methods of combination immunotherapy including natural killer cells (NK) that we have been engineered in the laboratory to also circumvent mechanisms of resistance and to additionally express a single or dual target that are present on the osteosarcoma cells. They further plan to investigate the efficacy of adding other immunotherapies to enhance the function and persistence of these targeted NK cells with antibodies, and two different NK activating cytokines. They will also investigate the optimal combination of this immunotherapy in children, adolescents and young adults with recurrent or refractory osteosarcoma to determine the safety and efficacy of this approach. Finally, Dr. Cario and team will determine what are the genetic and immune mechanisms of resistance after these novel combinatorial immunotherapy approaches utilizing state-of-the-art laboratory techniques. The goal of this grant is to develop novel combinatorial immunotherapy that will significantly increase the overall survival in children and adolescents with poor risk osteosarcoma. To make a significant impact for kids fighting osteosarcoma, five funders have banded together with St. Baldrick’s to support this grant – The Helping Osteosarcoma Patients Everywhere (HOPE) Super grant supported by Battle Osteosarcoma, the Faris Foundation, the Zach Sobiech Osteosarcoma Fund of Children’s Cancer Research Fund, the Children’s Cancer Fund NY (supporting the Maria Fareri Children’s Hospital and New York Medical College) and Nationwide Children’s Hospital.

Chimeric Antigen Receptor (CAR)-T cells have been clinically effective in patients with leukemias and lymphomas. Dr. Venkataraman’s goal is to bring similar success in treating a fatal brain tumor in children called DIPG (Diffuse Intrinsic Pontine Glioma). A major obstacle in treating brain tumors with CAR-T cell therapy is a lack of antigens which are tumor specific, or which are absent on normal vital tissues that can lead to off-target toxicities. To overcome this risk, Dr. Venkataraman and colleagues have successfully generated and tested the functionality of a novel “logic-gated” CAR-T cells targeting two distinct antigens, CD99 AND B7H3 that are highly expressed on DIPG but present singly on certain normal cells. This gated “AND” CAR-Ts will have full-activation against DIPG cells having both the antigens while sparing the single antigen expressing normal cells and will now investigate the safety, preclinical efficacy of these CAR-T cells against DIPG and evaluate its translational relevance to DIPG patients.

CAR-T cell immunotherapies, treatments that use T cells constructed to recognize tumors and kill them, revolutionized how doctors treat children with B cell leukemia (B-ALL). These killer T cells recognize a specific protein expressed on the surface of the leukemic cells. Unfortunately, leukemia frequently relapses and often finds ways to "switch off" the expression of this protein, making T cells unable to track and kill them. This notion is called "antigen escape," as the tumor finds a way to escape the immune treatment. Dr. Aifantis plans to identify ways to avoid antigen escape by boosting the expression of the surface recognition protein. The study aims to validate such mechanisms in an organism using CAR-T cell models and sequencing patient cells. At the same time, Dr. Aifantis will design screens that will help identify surface antigen-specific regulators, so researchers can one day create combinatorial protocols using CAR-T cells and targeting specific antigen surface expression regulators.

Ewing sarcoma (EwS) is a malignant cancer of bone and soft tissues that occurs mainly in children, adolescents and young adults. If the tumors spread, fewer than 1/3 will survive. For some pediatric cancers, recent progress has led to new treatments that use one's own immune system to target cancer cells. However, immunotherapy has not been successful for EwS because we don't know enough about how EwS tumor cells evade the immune system. The tumor microenvironment (TME) is an intricate ecosystem consists of cancer cells and the host's immune system. Dr. Kuo's project will focus on dissecting the TME of EwS, to understand how tumors develop. Using EwS tumors removed from pediatric patients during their cancer diagnosis and treatment, Dr. Kuo will use newly-developed techniques to map the TME and use a genetic model of EwS developed at CHLA to examine tumor/immune cell interactions in living tissue. The long-term goal of this work is to identify new treatment options for children with EwS. This grant is funded by and named for The Shohet Family Fund for Ewing Sarcoma Research. In his freshman year of college, Noah was diagnosed with Ewing sarcoma. He endured many months of chemotherapy and had limb salvage surgery. Able to return to school, Noah had no evidence of disease for 2½ years until April 2018 when routine scans revealed he had relapsed. He passed away in May 2021 at the age of 25. Noah and his family were always passionate about the need for curative treatments for diseases of the AYA population. The Shohet family intends to raise funds for this Hero Fund in Noah's memory to find cures for Ewing sarcoma and to carry on his legacy of possibilities and hope.

Pediatric Burkitt Lymphoma (BL) arises from errors during immune (B cell) development. Treatment failure is associated with dismal outcomes, and many pediatric BL survivors will suffer long-term toxicities from therapy, highlighting the need to explore opportunities to identify patients who may be cured with less intense therapies. Little is currently known about the biology of pediatric BL and clinical implications of specific mutations. Therefore, systematic analysis of tissue from children treated on clinical trials represents a unique opportunity to gain insights from valuable specimens to inform biologic risk-based chemotherapy and identify potential targeted therapeutic strategies. Dr. Allen will characterize intrinsic and acquired genetic factors that underlie pathogenesis and predict response to therapy in patients with pediatric BL who have completed treatment on COG clinical trials. 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.

Each year, approximately 1000 Americans aged 20 years or younger are diagnosed with acute myeloid leukemia (AML). Currently, even the most effective targeted drug BCL2 inhibitor-venetoclax (VEN) cannot eradicate all leukemia cells. The remaining cells cause disease recurrence and result in a very low overall survival rate for AML patients. In preliminary studies, Dr. Li found that targeting an enzyme called ADSS2 promotes pediatric AML cells sensitivity to VEN induced mitochondrial apoptosis, resulting in a synthetic lethality. This study will ask how ADSS2 preserves AML cells fitness and test the effectiveness of a first-in-class ADSS2 inhibitor combined with VEN or other BCL2 family protein MCL1 inhibitor in models of AML. If successful, this could lead to a clinical trial with potential impact for childhood AML patients.

Cancer cells compete with the body for food. Some cancer cells use fat to grow, spread, and hide in the brain. When cancer cells hide in the brain, it is hard for chemotherapy reach them due to the blood brain barrier, which allows cancers to come back when they come out of hiding. Dr. Wang and colleagues are investigating how childhood leukemia uses fat to survive in the brain and how drugs that starve leukemia of fat can kill leukemia cells hiding in the brain. The second year of this grant is generously supported by Rhys’ Pieces of the Cure, a Hero Fund created to honor Rhys Goldman and his journey with cancer. He was diagnosed with pre-B acute lymphoblastic leukemia just 2 weeks before his 6th birthday and endured treatment for three years. Rhys missed a lot of school and life during those years but since marking the end of treatment in July 2018, he has been enjoying swimming, singing in a boys’ choir, chess tournaments, playing with his dogs and going to school. Rhys’ Pieces for the Cure was created to ensure more research is funded for the treatment of pediatric cancer that is specifically focused on less toxic cures for kids.

Children with the brain tumor ependymoma have high relapse rates and poor long-term survival. Treatment options for ependymoma are limited and there is no known effective chemotherapy. Dr. Lindquist is working to make a new model of this tumor, to study how the tumor forms and grows, and to test new therapies in this model and patient-derived tumors. The ultimate goal is to identify new therapies that will extend the lives of children with ependymoma.

The goal of this project is to engineer immune cells to target cancer, particularly a type of pediatric cancer called acute myeloid leukemia (AML). AML cells develop strategies to escape surveillance by the immune system. Despite current therapies, cancer cells are able to survive and progress. Natural killer (NK) cells play an important role in the immune response to cancer by recognizing and killing tumor cells. NK cell activity is regulated by activating and inhibitory receptors. Tumor cells express proteins that provide inhibitory signals to NK cells, blocking NK cell anti-tumor functions and allowing for tumor escape. Dr. Campbell and colleagues propose to tip the balance in favor of immune cell activation by knocking out a key NK cell inhibitory receptor, TIGIT. Dr. Campbell hypothesizes that eliminating NK cell TIGIT expression will remove inhibitory "brakes" on NK cell activation and enhance anti-tumor activity. The purpose of this study is to develop an effective cellular therapy for pediatric AML.

Acute Myeloid Leukemia (AML) is a blood cancer that sadly takes the lives of many children each year, and major efforts are being made to save these lives. One idea has been to teach the patient's body to fight off the AML like it would fight off an infection. This strategy alters the patient's immune system by making CAR-T cells, which are cells that fight cancer. CAR-T cells have been successful in curing patients with another similar type of blood cancer, but when it was tried in patients with AML, the approach was less successful. Dr. Anand's project is to understand why it didn't work as well so that further improvements that lead to cures for kids with AML can be made. This grant is generously supported by the JJ's Angels Hero Fund which honors the memory of Juliana LaMonica and her courageous battle with AML. Diagnosed at the age of two, Juliana underwent a bone marrow transplant but passed away shortly after turning three. Her sweet spirit and charismatic personality continue to inspire people to support the funding of pediatric cancer research through Team JJ’s Angels.

Acute Lymphoblastic Leukemia (ALL) are aggressive cancers of B- and T- immune cells. ALL is most common in children but also affects adolescents and young adults. 90% of childhood ALL is curable. However, ~10% of children and ~30% of adolescents and young adults with ALL are not cured. To combat hard-to-treat ALL, Dr. Swaminathan will harness the body’s natural anti-cancer defense mechanism: a type of immune cell called a natural killer (NK) cell. He will also find defective NK cells in children with ALL. Those with fewer defective NK cells tend to survive longer and spend more of their lives free from disease compared to patients with high levels of abnormal NK cells. These findings will inform the development of NK cells as affordable therapies to cure pediatric ALL.