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Medulloblastoma is the most common malignant brain tumor in children. While multimodal therapy for medulloblastoma at diagnosis has resulted in improved outcomes, there are very few options at the time of relapse, with overall poor survival. Preclinical data have shown anti-tumor activity with liothyronine (T3, activated thyroid hormone) in medulloblastoma models. T3 has safety data and dosing which are available for children. Dr. Ronsley and colleagues will translate these preclinical findings into a clinical trial, which will treat children and adolescents with relapsed medulloblastoma with T3 in combination with chemotherapy and evaluate both safety and efficacy and the role for monitoring with liquid biopsy.

This grant is named for Hannah’s Heroes, a Hero Fund established to honor Hannah Meeson. At age 6 she was diagnosed with anaplastic medulloblastoma. After a relapse and additional treatment, Hannah currently shows no evidence of disease. Throughout her treatments, Hannah never complained and remained positive and happy. This fund pays tribute to her fight by raising awareness and funding for all childhood cancers because kids like Hannah “are worth fighting for.”

The most difficult cases of Ewing sarcoma to treat are when it comes back after completing initial treatment. Dr. Brian Ladle and colleagues at Johns Hopkins University and the National Cancer Institute believe the immune system is capable of mounting a powerful immune response against Ewing sarcoma as an effective treatment. Dr. Ladle and team will identify the best immune targets in Ewing sarcoma and discover ways to activate the immune system against the most promising targets. These targets will be tested in their lab using models.

To make a significant impact for kids fighting Ewing sarcoma, five funding partners have banded together with St. Baldrick’s to support this grant – Advancing Cures for Ewing Sarcoma (ACES) award supported by the Sam Day Foundation, The Faris Foundation, Rutledge Cancer Foundation, The Shohet Family Fund for Ewing Sarcoma Research (a St. Baldrick’s Foundation Hero Fund), and Alan B. Slifka Foundation.

Mixed Phenotype Acute Leukemia (MPAL) is a subtype of leukemia that shares features of the 2 most common types of leukemia: acute myeloblastic leukemia and acute lymphoblastic leukemia. Unfortunately, it is really hard to cure with no consensus treatment. When cells divide, chromosomes can break and the pieces can re-attach to the wrong place resulting in a chromosomal translocation. This new abnormal chromosome can result in the expression of a new gene and a new protein, called a "fusion protein". In MPAL, a common translocation involves the ZNF384 gene that can be fused to over 20 new genes, but the consequences are not well understood. Dr Libbrecht has identified that a novel drug that inhibits BRM/BRG1, essential proteins that maintain the DNA structure, and can kill MPAL cells in vitro. Her studies aim to better understand how BRM/BRG1 inhibition affects the ZNF384 fusion proteins and MPAL cells to validate it as novel therapy for MPAL.

Vincristine is a chemotherapy drug commonly used to treat cancer in children and young adults, but it can cause vincristine-induced peripheral neuropathy (VIPN), a side effect that leads to numbness, pain, weakness, and difficulty with balance. These symptoms can severely impact daily life and may require chemotherapy dose reductions or discontinuation, potentially affecting cancer treatment outcomes. Currently, doctors use a grading system to assess VIPN severity, but this method is not sensitive enough to detect early symptoms and is difficult to implement consistently. Therefore, there is a need for a more reliable and accessible way to identify VIPN early. Dr. Belsky will utilize a potential solution of a blood test to measure neurofilament light chain (NfL), a substance released during nerve damage. Dr. Belsky and colleagues will explore whether NfL levels can detect VIPN in children and young adults to improve the ability to monitor nerve damage, enabling doctors to adjust treatments earlier, optimizing cancer care.

Teens with leukemia go through tough treatments that make them feel tired and weak, so they spend a lot of time sitting and lying down, which can make side effects worse and put them at risk for chronic diseases like diabetes. Dr. Ivory is testing ReSeT, a program she developed for teenagers getting leukemia treatment to interrupt sitting time with short exercise breaks that will likely improve their lifestyles, heart health, and quality of life. Over 10 weeks, each teenager will use a Fitbit, health coaching, and an app-based support group to slowly increase their activity. After testing ReSeT in 30 teenagers to see if they can do it and what they think, she will fine-tune ReSeT and test it again in 10 more teenagers and compare how they do with 10 teenagers who didn't get the program to see if the program works. The goal is to use small behavior changes to help teenagers with cancer be more active during and after treatment to improve their lifelong health.

Acute myeloid leukemia (AML) is harder to cure than most other types of childhood leukemia and lymphoma. Treatments are toxic and require patients and their families to spend up to a year in the hospital. Childhood AML survivors often have serious side effects later in life from their treatment. We need new treatments for AML that are less toxic and more effective. AML is often caused by mutations in a protein called N-Ras that tell the leukemia to grow and divide much more quickly than healthy tissue. If we could shut down this abnormal N-Ras signaling, it would stop the leukemia from growing. Unfortunately, no approved drugs exist that target mutant N-Ras proteins. Dr. Decker and his colleagues are testing a new drug called ABD778 that selectively blocks the growth of AML cells with mutant N-Ras. The results of this research could move drugs like ABD778 closer to the clinic and pave the way for new treatments for childhood AML.

This grant is named for the Cody Thompson Memorial Hero Fund. Cody spent much of his childhood in the hospital. As an adult he embraced the health and happiness of children and was an avid St. Baldrick's volunteer. This grant is a tribute to the compassion he carried throughout his life.

Dr. Lerman is studying the connection between how aggressive childhood brain tumors called diffuse midline gliomas (DMGs) look on MRI scans and the DNA of the tumors themselves. Tumors that look different from each other on MRI scans and have different changes in their DNA grow in different ways. What is not known is how the appearance of the tumor on the MRI scan is related to the changes in the tumor's DNA. By studying this connection, Dr. Lerman hopes to predict how a tumor might grow based only on an MRI scan, which would help patients and families who either cannot or choose not to have a surgical procedure called a biopsy to test the tumor's DNA. Right now, there is no treatment that cures DMG and all patients are treated the same way: with radiation. Dr. Lerman plans to identify groups of tumors that behave similarly, which will help future clinical trials test the right medicine for the right patient.

Dr. Dionysiou and team are studying a small molecule naturally found in the body called miR-21. This molecule could make a treatment called allogeneic hematopoietic cell transplantation (allo-HCT), which cures children with aggressive leukemia, safer and more effective. This treatment uses immune cells from a donor, but it can cause a serious problem called graft-versus-host disease (GVHD), where the donor cells attack the patient's healthy tissues. The challenge is to stop this attack without weakening the donor cells' ability to fight the cancer. By understanding how miR-21 controls the immune response, Dr. Dionysiou hopes to find ways to prevent GVHD while allowing the donor cells to attack the cancer, making this life-saving treatment safer and more effective.

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.

In the past decade, new therapies that train the immune system to recognize and kill cancer cells have revolutionized cancer care. Unfortunately, cancers arising from connective tissue like bone have not responded to these immunotherapies. Despite almost four decades of trialing/testing progressively more intensive chemotherapy, outcomes for osteosarcoma (the most common bone tumor) remain dismal once it has spread beyond the initial site. Dr. Smith wants to understand why these immunotherapies have failed by studying a model closely resembling human osteosarcoma. Based on his findings, Dr. Smith will test novel immunotherapies to prioritize the next generation of osteosarcoma human clinical trials.

This grant funds a student to complete work in pediatric oncology research for the summer. Dr. Satake and colleagues are studying a rare and aggressive childhood kidney cancer called malignant rhabdoid tumor of the kidney (RTK). Children with RTK have extremely poor outcomes (survival rate 25%) despite lots of different treatments since tumors continue to grow even with treatment and tend to relapse. They believe that the investigational drug called OTS964 may be a new potential treatment. They also believe that OTS964 may be even more effective when used with navitoclax, a drug which has a different mechanism of killing cancer cells. In this project They plan to test the new treatment using these drugs in a human RTK mouse model, and to study the mechanism of actions, with the goal of finding a new treatment for RTK patients. This work is being completed under the mentorship of Dr. Noriko Satake.

High-grade glioma (HGG) is an aggressive brain tumor treated with surgery and radiation/chemotherapy. With such aggressive treatment, most children are not cured. Infant-Type Hemispheric Glioma (IHG) has a better cure rate than other types of HGGs. Commonly diagnosed in patients younger than 1, IHGs are large tumors and occupy half of a baby's brain. Surgery is often complicated with life-threatening bleeding in the brain with severe adverse effects further compounded by chemotherapy. Therefore, though IHGs have favorable cure rates, they require more effective and less toxic therapy. IHGs have genetic defects called receptor tyrosine kinase fusion, which are targetable by medicines called tyrosine kinase inhibitors (TKI), commonly used in adults. When used in IHG, tumor size is reduced without surgery or chemotherapy. Dr. Bagchi's clinical trial will treat based on the tumor's genetic defects using TKI and integrate quality of life measures so children survive & thrive.

Osteosarcoma is a bone cancer that affects children and adolescents. Unfortunately, its treatment has remained the same since the 1980's, and once the cancer spreads to other organs, less than 40% of the patients survive despite treatment. Dr. Aquino Lopez and colleagues will use the immune system to eliminate tumor cells. During an illness with a virus, immune cells called virus specific T cells (VSTs) eliminate infected cells by recognizing "viral signals". Dr. Aquino Lopez will use an artificial virus combination called CAdVEC to modify cancer cells and make them look like they are infected with a virus. Doing so, will trigger immune cells to eliminate the cancer cells.

Ewing sarcoma is an aggressive bone tumor in children, adolescents, and young adults. New therapies with greater efficacy and less toxicity are urgently needed to save the lives of these young patients. Dr. Theisen and colleagues will identify a new vulnerability in the mitochondria (i.e. the powerhouse) of Ewing sarcoma cells as well as several possible drugs that target this pathway. Dr. Theisen and team will determine both the reason that Ewing sarcoma cells have this unique vulnerability and how best to target this pathway therapeutically. In the long term, this will lead to better ways to treat Ewing sarcoma.

This grant is named for Julia's Legacy of Hope, a Hero Fund that honors Julia's positive and courageous spirit and carries out her last wish: "no child should have to go through what I have experienced". Diagnosed at age 16 with Ewing sarcoma, Julia fought cancer and survived only to be stricken in college with acute myeloid leukemia, a secondary cancer as a result of treatment. Through this Hero Fund, her family hopes to raise awareness and funds for childhood cancer research especially for Adolescent and Young Adult (AYA) patients.

Brain tumors are the deadliest type of cancer that afflicts children. The ability of brain tumor cells to spread (metastasize) outside of the original tumor along the leptomeninges, the covering of the brain and spinal cord, is responsible for making many brain tumors so hard to treat. How cancer cells embedded in the leptomeninges survive, thrive, and resist best treatments is poorly understood. A better understanding of leptomeningeal metastasis is required to make new therapies that can meaningfully increase survival for children diagnosed with aggressive brain cancers. Dr. Reinecke and colleagues will create a way that can identify and screen potential therapies in a cell culture dish, thereby streamlining interventions they take to models of pediatric brain tumors. Dr. Reinecke and colleagues believe that establishing this preclinical platform has the potential to identify therapies that have a chance to positively impact the lives of children diagnosed with metastatic brain tumors.

Ewing sarcoma is a devastating childhood bone cancer. Doctors treat these pediatric patients with toxic chemotherapies, radiation, and surgery. Dr. Langdon and colleagues will develop targeted combination therapies to safely and effectively kill Ewing sarcoma cells. Dr. Langdon finds changing where proteins are normally found in cancer cells create potential new targetable vulnerabilities for Ewing sarcomas. Each vulnerability is thought of as a new "Achilles heel" for these cancers. Dr. Langdon and colleagues believe that combining two drugs - one which changes where proteins are normally found and one which targets the new vulnerability - will kill Ewing sarcomas. Dr. Langdon's team will look to why these drugs work so well against Ewing sarcomas and determine if they are truly safe and effective.

The most common source of pain when treating children is needles. Avoiding painful procedures is a cause of stopping treatment for children with cancer in Low and Middle-Income Countries (LMICs). Dr. McNeil and colleagues will utilize an evidence-based care bundle to reduce needle pain based off of past results used in hospitals with LMICs with high patient and parent satisfaction which reduced pain by a significant amount. Keeping in mind the large differences in resources and cultures between the different hospitals, Dr. McNeil and colleagues will be able to understand the key features of using the care bundle in different hospitals. Dr. McNeil's team will identify different adaptations each hospital uses and study the ability of a hospital to continue to implement care.

Neuroblastoma (NB) is a deadly childhood cancer. Children with NB are classified as high-risk (HR) due to genetics or metastatic disease. Metastatic disease occurs when tumor cells (TC) leave the original tumor and travel to distant organs and develop into new tumors by a complex set of steps. Before tumor cells can form metastasis, they often go through a long period of dormancy (rest) to evade therapy. In NB, the bone marrow is the most common site of metastasis and relapse. The MYCN_TT is a unique model of NB, that spontaneously metastasizes to distant sites such as kidney marrow (equivalent to bone marrow). Dr. Anderson and colleagues will utilize the MYCN_TT model in understanding the molecular and cellular mechanisms underlying metastasis and dormancy, which will inform the development of novel therapeutic strategies for HR-NB.

Children diagnosed with a brain tumor called diffuse midline glioma (DMG) have no options for a cure. Dr. Ramakrishna and team at Stanford Medicine have developed a new treatment, called CAR T cells, for these children by training their immune system to find and kill cancer cells. Excitingly, children treated on a clinical trial with these CAR T cells have improved symptoms and reduced tumor sizes. Unfortunately, for some patients, tumors grew after treatment, suggesting a need to understand how to improve the treatment. An immune cell, called a myeloid cell, was identified surrounding treatment of the first patients. Dr. Ramakrishna and colleagues will seek to understand these myeloid cells in the context of CAR T cell activity in patients. Modeling these myeloid cells in the lab, Dr. Ramakrishna and team will test approaches to improve CAR T cell activity against DMG cells. This project will improve understanding of CAR T cells in patients and develop new treatments for children with these devastating brain tumors.

Sneha Ramakrishna, MD, is a pediatric hematology-oncologist at Stanford Medicine Children’s Health and an assistant professor - University Medical Line in Pediatrics - Hematology & Oncology at Stanford Medicine.

This grant is named for the Pray for Dominic Hero Fund. The fund was established in honor of Dominic Liples who lived with joy. He is remembered for compassion and determination while he faced his own difficult battle with a rare and aggressive brain cancer. The Pray for Dominic fund carries on Dominic's legacy of joy and hope by funding research for high-grade gliomas.

One in three children with newly diagnosed cancer has unmet resource needs such as food, housing, transportation, or utilities. These social needs increase during cancer care and are linked to worse outcomes for children and their parents. Government benefits such as the Supplemental Nutritional Assistance Program (SNAP or food stamps) improve child and maternal health outcomes. Dr. Umaretiya will conduct a pilot study using ASSIST, (a benefits navigator intervention to help families enroll and stay on government benefits such as SNAP) among 40 families of children with newly diagnosed cancer and test whether it is feasible and acceptable to families, allowing to identify barriers and facilitators to use ASSIST intervention.

Modern pediatric cancer diagnosis requires the ability to perform and interpret molecular studies including gene-specific assays as well as sequencing studies to capture mutations specific to pediatric cancer that are important for diagnosis and treatment stratification. Such assays are widely available in developed countries and most hospitals have trained molecular pathologists who can carry out and interpret these studies. These are highly technical skills that require at least a year of hands-on training. In many Low and Medium Income Countries (LMIC) including Mexico, there are very few trained molecular pathologists, limiting the ability to provide adequate diagnosis for cancer patients. Dr. Ramirez-Ristori will obtain this training at the University of California, San Francisco and return to Mexico to become the very first fully trained molecular pediatric pathologist in the entire country.