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.

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.

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.

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.

Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors of infancy. Standard therapies lead to severe toxicities and poor overall survival. Dr. Raabe aims to identify novel therapies to reduce toxicities and improve survival. Dr. Raabe and colleagues found that cancer cells rely on activation of the integrative stress response (ISR) to maintain cell equilibrium and survival. However, if the ISR is activated too intensely or for too long, cells undergo apoptosis and die. Paxalisib and gemcitabine are medications that induce considerable cell stress, further activating the integrative stress response, and extending survival in models of AT/RT. Dr. Raabe is investigating how these medications act together to target cell stress pathways and their impact on survival in models of AT/RT. The findings will translate directly through the International Pacific Pediatric Neuro-Oncology Consortium (PNOC) into a new clinical trial treating children with relapsed or refractory AT/RT.

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.”

Dr. Kabanov and colleagues propose an entirely new way to treat medulloblastoma, the most common malignant pediatric brain tumor. Current treatment requires radiation followed by a year of chemotherapy, fails almost half the patients, and can leave survivors with lifelong brain injury. Tiny extracellular vesicles called exosomes produced by a type of immune cell called macrophages were discovered to travel from the bloodstream into brain tumors. Dr. Kabanov will load exosomes with an agonist of Toll-like receptor to reprogram medulloblastoma tumor associated myeloid cells and enhance their tumoricidal properties. If successful, the therapy will improve medulloblastoma treatment by replacing the current radiation and chemotherapy with the one that is less toxic and more effective.

The first year of this grant is funded by and named for the Strong & Courageous Hero Fund, established in honor of Jonah. It celebrates his survivorship from medulloblastoma and his goofy, loving, inclusive personality. This fund was inspired by Jonah’s desire to help other kids with cancer and supports research of brain tumors and the multitude of challenges facing survivors post treatment.

Children receiving bone marrow transplant can have serious complication such as bloodstream infections and graft versus host disease and some children die of these complications. Alteration of the bacteria in the gut by treatments including antibiotics is an important cause of these complications. In a previous study Dr. Davies and colleagues have tested the use of human milk to help keep gut bacteria healthy in very young children and found that this treatment worked. They are now studying a purified sugar from human milk, 2-FL that can be given easily as a medicine. Dr. Davies will also test a novel rapid urine test and a blood test to assess health of the gut bacteria during the study. Current tests require a stool sample and can take a long time. This trial will generate the data needed to perform a large-scale multi-center randomized clinical trial that will best prove how well this treatment works.

This grant is generously supported by the Rays of Hope Hero Fund which honors the memory of Rayanna Marrero. She was a happy 3-year-old when she was diagnosed with Acute Lymphoblastic Leukemia (ALL). She successfully battled ALL, but a treatment induced secondary cancer claimed her life at age eight. Rayanna had an amazing attitude and loved life. She, like so many kids facing childhood cancer, did not allow it to define who she was. This Hero Fund aspires to give hope to kids fighting cancer through research.

There is an urgent need for novel targeted therapy for osteosarcoma (OS). Molecular targeted therapy has yielded stunning response rates of >90% for specific targets such as NTRK gene fusions. In contrast, the mainstay of therapy for osteosarcoma has remained the same for more than 30 years and few targeted agents have successfully translated to the clinic for OS patients.

The challenge to develop targeted therapies for osteosarcoma is that the tumor has different driver mutations in different patients. However, 12-39% of tumors share a common amplification in a gene called MYC. In this project, Dr. Grohar and colleagues will consider this subset of osteosarcoma as a distinct entity. They are characterizing the role of MYC in the pathogenesis of osteosarcoma and determining how MYC makes osteosarcoma aggressive. Ultimately, they will identify compounds that will serve as clinical candidates for MYC-driven osteosarcoma. They will then determine if they are best translated to the clinic as single agents, in combination with chemotherapy, or as metastasis-targeted therapy.

Dr. Grohar has assembled a team with the necessary expertise. Chand Khanna is a disease expert in osteosarcoma, the Grohar lab has expertise in drug development for bone sarcomas, the Neamati and O'Keefe labs are experts in drug discovery/chemical biology/natural products. Filemon Dela Cruz is an expert in preclinical drug modeling, Ted Laetsch and Rashmi Chugh are experts in sarcoma clinical trial design, and Ethos (led by Chand Khanna) and Vuja De (led by David Warshawsky) are companies that will aid in the development of these compounds for the clinic. Together they will identify compounds that are specific and effective for MYC amplified osteosarcoma.

To make a significant impact for kids fighting osteosarcoma, five funding partners have banded together with St. Baldrick’s to support this grant – The Fight Osteosarcoma Together (FOT) Super Grant supported by Battle Osteosarcoma, CureSearch for Children’s Cancer, Michael and April Egge, The Osteosarcoma Collaborative, and the Zach Sobiech Osteosarcoma Fund of Children’s Cancer Research Fund.

Beckwith-Wiedemann Syndrome (BWS) is a cancer predisposition syndrome and patients with BWS have a significantly increased risk of developing hepatoblastomas. The same genetic changes on chromosome 11 that cause BWS are found in 40% of hepatoblastomas. Dr. Kalish has previously shown that noncancerous liver and HB tissue from patients with BWS have distinct molecular signatures, suggesting the events that set up patients with BWS for HB are due to these changes on chromosome 11. Using the largest BWS collection of tissues worldwide, Dr. Kalish and colleagues will study the specific features of BWS and nonBWS liver cells and HB cells to determine how the changes of chromosome 11 lead to HB. Cell models derived from liver tissue will be used to test how these changes cause the transition from normal liver to HB. This work is a critical step in developing targeted therapies for patients with HB.

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.

Burkitt lymphoma (BL) is the fastest growing, most aggressive pediatric tumor. In the 1960s, it was universally fatal. Over the past decades, clinical trials identified very high dose chemotherapy therapies as effective. Over 95% of children with BL in the US now survive. However, over 80% of cases of BL arise in children in sub-Saharan Africa (SSA) and other lower income regions where high dose chemotherapy is not currently feasible and in these settings BL is typically fatal. In the study, Dr. Allen builds on the observation that BL tumors from US and SSA are largely indistinguishable, but surprisingly tonsils from children in SSA and US have vastly different gene expression patterns. He therefore hypothesizes that the much higher rate of BL in SSA may not be due to intrinsic cancer cell factors, rather due to the nature of lymphoid tissues out of which the cancer cells grow. If Dr. Allen and colleagues can identify factors that lead to BL, they hope to create opportunities to prevent and treat BL in SSA.

This proposal introduces four groundbreaking advancements in the treatment of Ewing sarcoma (EwS), a rare and aggressive cancer. Firstly, Dr. Li and colleagues aim to optimize and assess the effectiveness of cutting-edge anti-IL1RAP ADCs in treating EwS. Secondly, they seek to uncover new insights into the diversity and heterogeneity of targets within EwS tumors. Thirdly, will explore the potential of innovative bispecific ADCs to target a wider range of EwS cells, enhancing treatment efficacy and reducing the risk of relapse and spread. Lastly, Dr. Li will explore the possibility of applying these advancements to other IL1RAP+CD276+ cancers like acute myeloid leukemia (AML). Overall, this research holds promise for improving outcomes and broadening treatment options for patients with these challenging cancers.

This grant is funded by and named for the D-Feet Cancer - The Dalton Fox Foundation. D-Feet Cancer - The Dalton Fox Foundation was established to honor and remember Dalton’s contagious smile and sense of humor, even on his toughest days with Ewing Sarcoma. He is an inspiration and the reason for the mission and interest in finding targeted therapies and treatments for Ewing Sarcoma, a pediatric bone cancer.

There has been little recent progress in treating Ewing sarcoma, a pediatric tumor involving bone. Dr. Stegmaier and colleagues have used a technology called CRISPR to identify urgently needed, new therapeutic targets for this disease. They prioritized a class of targets which are expressed in immature but not mature tissues. These proteins are often abnormally re-expressed in cancers such as Ewing sarcoma. Thus, drugs targeting these proteins would be expected to have minimal toxicity. The Stegmaier lab identified the target IGF2BP1 as a top selective gene dependency in Ewing sarcoma; deletion of IGF2BP1 was more deleterious to Ewing sarcoma than all other cancer types screened. Importantly, IGF2BP1 is not expressed in most normal human cells. Dr. Stegmaier will validate IGF2BP1 as a therapeutic target in Ewing and will determine the mechanisms by which Ewing sarcoma cells rely on IGF2BP1 for growth. With IGF2BP1 chemical inhibitors in development, this project has exciting translational potential for patients with Ewing sarcoma.

This grant is funded by and named for The Ben Brandenburg Fund for Ewing Sarcoma Research. Ben passed away at the age of 15. He is remembered for his quick wit, indomitable spirit and bravery. This fund is his lasting legacy and ensures that research is funded so fewer children will have to suffer from Ewing Sarcoma.

The majority of children with newly diagnosed Burkitt lymphoma (BL) are cured. Unfortunately, the outcome is poor for patients whose disease returns (relapse). The relapse is caused by multiple reasons but mainly is due to drug resistance and suppression by the tumor surroundings. Novel therapeutic approaches are urgently needed. Natural killer (NK) cells can attack cancer cells. Dr. Cairo is developing immunotherapeutic agents to enhance the functions of NK cells to kill BL. Expanded NK cells will be modified by genetic techniques to specifically target CD20 and a special protein will be developed to bind to another surface protein CD19 on BL. A virus will be created to secrete IL21 to enhance NK persistence and function. If successful, the combinatorial therapies will become available to pediatric BL patients in the clinical setting and would offer a potentially more effective and less toxic therapeutic approach, ultimately leading to improved survival.

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.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk type of B-ALL. Children and adolescents/young adults with Ph-like ALL have greater than 60% relapse risk and experience significant mortality with best-available chemotherapy. Emerging data suggest that patients with Ph-like ALL are more likely to develop immunotherapeutic resistance to treatments. Dr. Tasian, and Dr. Terry Fry at the University of Colorado, and their colleagues are testing whether a new CAR T cell immunotherapy that they developed will decrease the risk of relapse for patients with Ph-like ALL. This work will be the groundwork to translate findings into a phase 1 clinical trial.

This grant is supported by The Ty Louis Campbell (TLC) Foundation. TLC was created in memory of Ty, who lost his 2-year battle with brain cancer just days after his fifth birthday. TLC funds innovative research and clinical trials specifically geared toward the treatment of the deadliest childhood cancers (including brain and spinal cord tumors). TLC seeks less toxic, more effective treatments that are specifically designed for children fighting cancer. Their ultimate mission is to help fund the intelligence and technology that will uncover new ways to cure children with cancer.

Adoptive immunotherapy has demonstrated unprecedented success in the treatment of pediatric leukemia. Extending its therapeutic potential to other pediatric malignancies such as glioblastoma (GBM) has proved challenging. In this therapy, T cells are isolated from a patient, expanded outside of the body, and genetically modified prior to reinfusion. The ability of these T cells to recognize and eliminate cancer cells is improved by expressing a protein (CAR) on the T cell surface. An important challenge is to minimize the manipulation of patients' T cells outside the body. Prolonged culture compromises their efficacy. Dr. Ghassemi developed approaches to generate CAR T cells in 1 day. These cells have increased potency. She is combining this recent development with a metabolic strategy to overcome the metabolic nature of tumor environment. This synthetic advancement combined with the production of CAR T cells in 1 day will lead to superior CAR T cells for cellular immunotherapies against pediatric GBM.

This grant is funded by and named for the Be Brooks Brave Fund. Despite his diagnosis at age 5 with inoperable brain and spinal tumors, Brooks taught so many people what life is truly about--love. He was BRAVE beyond his years with an inspiring “faith over fear” attitude. This Hero Fund hopes to raise money for high-grade glioma research so no other family will hear the words, “there is no cure”.

Ewing sarcoma, an aggressive bone cancer that occurs in children and young adults, is caused by an abnormal chimeric protein (EWS-FLI1) that prevents cells from maturing into normal connective tissues through a process known as cell differentiation. How EWS-FLI1 acts to stop differentiation, however, remains an enigma. To solve this problem, Dr. Ludwig uses powerful gene editing tools to systematically turn the EWS-FLI1 protein up or down, then measures whether such changes allow cancer cells to behave more normally. The information gained from this research is expected to lead to new anti-cancer treatments for adolescents and young adults battling Ewing sarcoma.

This grant is named for 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 and sadly passed away. This Hero Fund honors his courageous fight and hopes to raise funds for Ewing sarcoma research.

The AACR-St. Baldrick's Foundation Award for Outstanding Achievement in Pediatric Cancer Research has been established to bring attention to major research discoveries to the pediatric cancer research community and to honor an individual in any sector who has significantly contributed to any area of pediatric cancer research, resulting in the fundamental improvement of the understanding and/or treatment of pediatric cancer. The recipient will nominate an emerging leader conducting research in the academic sector to receive a research grant.

The 2022 SBF-AACR Award for Outstanding Achievement in Pediatric Cancer Research went to Dr. David Malkin at The Hospital for Sick Children (SickKids). Dr. Alanna Church at Boston Children's Hospital received the 2022 research grant. Dr. Church's research interests are in bringing molecular testing to the clinical care of children with cancer to improve diagnoses and treatments.

Childhood Hodgkin lymphoma (a cancer of white blood cells) is highly curable. Modern chemotherapy regimens effect a cure in over 95% of children diagnosed, however, about 15-20% will suffer a recurrence of their lymphoma and need additional highly intensive chemotherapy and bone marrow transplantation. These intensive regimens have many serious chemotherapy-related side effects (infections, mouth sores, etc.). Dr. Wadhwa’s study will investigate a novel predictor of cancer relapse and serious chemotherapy-related side effects by studying the role of body composition at Hodgkin lymphoma diagnosis in cancer-free survival and chemotherapy toxicities. Body composition has already been shown to be a significant predictor of cancer relapse and chemotherapy toxicities in adults with cancer. Dr. Wadhwa’s team will examine the body composition of children at cancer diagnosis, its association with cancer-free survival and serious chemotherapy related toxicities, how body composition changes during cancer treatment, and whether changes in body composition during cancer treatment impacts survival.

This grant is funded through a partnership between the St. Baldrick’s Foundation and the American Cancer Society.

More children die from brain tumors than any other type of cancer. Pediatric high-grade gliomas are the type of childhood brain tumor that is the hardest to treat and the most likely to result in death. Researchers have learned that pediatric high-grade glioma is actually several different types of tumors that are driven to grow by different genetic changes in the tumor cells. Almost all clinical trials have shown that chemotherapy doesn’t cure more kids and just leads to more side effects, however a clinical trial completed almost 10 years ago, used two chemotherapy medicines, in addition to surgery and radiation, and cured significantly more patients than previous therapy combinations. Dr. Green will use modern pathology tests to figure out the pediatric high-grade glioma subtype for all of the patients from that previous trial. Dr. Green and colleagues will look at the survival on each trial by subgroup to know which subgroup(s) showed better survival with the addition of one of the chemotherapy medicines to their treatment. Answering this crucial question will change the future of pediatric high-grade glioma treatment. With these results, current pediatric high-grade glioma patients will be able to be given the right standard treatment to maximize their chance of survival and minimize side effects.

This grant is funded through a partnership between the St. Baldrick’s Foundation and the American Cancer Society.