Genes instruct cells to do their jobs through making specific proteins. In our body, all cells store this what-to-do manual in a set of higher-order structures called chromosomes. When chromosomes break off, the broken pieces sometimes exchange their places to build new chromosomes. These errors, known as translocations, could have no effect on our bodies, but in many cases they might cause problems as severe as cancer. Dr. Su's research focuses on learning how chromosomal translocations promote tumor formation in children and young adults, as well as looking for clinically useful approaches to correct their pathogenic activities and cure these deadly diseases.

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.

Diffuse intrinsic pontine glioma (DIPG) is a deadly pediatric brain cancer, and there is a dire need to develop new therapeutic strategies to improve the terrible outcomes for these patients. Looking at genes that are turned on or off in a cancer can be helpful to figure out what is causing cancer growth. While looking at genes that are turned on in DIPG, Dr. Tsai found a gene called FOXR2 that is turned on at very high levels in a subset of DIPGs. FOXR2 is usually turned off, and turning on FOXR2 makes tumors grow very quickly. FOXR2 is actually capable of turning on an entire set of genes that are called ETS transcription factors (TFs). This is surprising as these genes have never been shown to be activated in DIPGs. Others have shown that ETS TFs can turn on the MAPK signaling pathway. Dr. Tsai also has found that FOXR2 is able to activate MAPK signaling. The goal is to determine exactly how FOXR2 and ETS TFs cooperate together to turn on MAPK signaling to make DIPGs grow. This grant was awarded at Dana-Farber Cancer Institute and transferred to Children's Hospital of Los Angeles.

A portion of this grant is generously supported by Griffin's Guardians, a St. Baldrick's partner. Griffin's Guardians was created by the Engles in memory of their son, Griffin. Their mission is to provide support and financial assistance to children battling cancer in Central New York, raise awareness about pediatric cancer and provide funding for research.

Anthracycline chemotherapies are important, lifesaving medicines given to a majority of children with cancer. However, they can injure the heart and cause heart failure in up to 10% of children years later, during cancer survivorship. Unfortunately, with the current available tools, there is not much known about which children will develop heart failure and what treatments would work best for them, and by the time the problem is identified it may be too late to help them. Dr. Narayan seeks to address this problem by using state-of-the-art, in-depth imaging techniques in adolescent and young adult survivors of childhood cancer to detect early changes in the heart. The goal is to develop new tools to provide early, personalized treatments to prevent heart failure.

This grant is named for TEAM ABBY Gives, a St. Baldrick's Hero Fund. Abby was diagnosed with Pre-B ALL when she was almost five years old. She had a successful bone marrow transplant, but battle battled graft vs. host disease (GVHD) and heart disease for years. Abby and her treatment team worked hard over many years to keep the GVHD in check. Sadly, Abby passed away on October 19, 2021. This fund unites the incredible support of family and friends in Abby's memory and inspires others to join the fight for cures and better treatments.

Leukemia, a cancer of the blood and bone marrow, is the most common cancer in kids. Over the last 60 years, great strides have been made in treating children with leukemia, and today, most leukemias are curable. However, certain leukemias are difficult to treat and have a poor prognosis. In order to better treat cancers, researchers seek to better understand the pathways by which cancer cells develop in order to identify medicines that target proteins in these pathways. Dr. Aumann and colleagues study the fusion protein CALM-AF10 which is found in some leukemias, and found that these leukemias have increased expression of a protein called SIX1. Dr. Aumann is studying how the SIX1 protein makes blood cells turn into leukemia cells, and is using two small molecule inhibitors in combination with other chemotherapy as potential new treatments for this and other leukemias. The hope is that the these studies will clarify the role of SIX1 in CALM-AF10 and other leukemias.

Though most children with cancer are able to be cured, some children are more likely to be cured than others, even with the best available treatments. Childhood cancer treatment is a long and difficult process for children and their families, and most families need support from those around them including community support and resources. Adults with cancer living in disadvantaged communities are much more likely to die from their cancer, though much less is known about how the characteristics of the community impact outcomes for children with cancer. Dr. Hoppmann uses a large national cancer database, coupled with measures of social determinants of health (measures of poverty, healthcare access, educational attainment, social and physical environment) to determine how these community vulnerabilities impact children with cancer. Results will help ensure gains made in pediatric cancer are shared equitably among all children, including those from disadvantaged areas.

Infant leukemia is an aggressive cancer with a very poor prognosis. The leukemia cells in most of these patients have a genetic change in which a gene (KMT2A) is broken and combined with other genes that typically do not interact with one another (this is called "rearranged"). A drug named SNDX-5613 has been developed that directly targets the changes that occur in a cell with a KMT2A rearrangement to specifically kill these leukemia cells, and it has shown promise in treating adult leukemia patients with a KMT2A rearrangement. An upcoming clinical trial will combine SNDX-5613 with traditional chemotherapy for children with leukemia with a KMT2A rearrangement that has come back (relapsed) or proven resistant to typical treatment (refractory). In addition to testing the safety and efficacy of SNDX-5613, studies will be done on patients’ blood and bone marrow samples to better understand how the drug functions in fighting leukemia. This trial represents the next step in evaluating this promising new targeted drug for these deserving patients, and the associated studies are key to helping us understand more about the biology of this leukemia and how to best target it.

This grant is named for the Oh Danny Boy, I Love You So: The Danny O'Brien Rhabdoid Tumor Research Fund. 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.

Dr. Sykes is developing new therapies for childhood leukemia and lymphoma. Specifically, he is looking at a type of leukemia that develops from abnormal T-cells and is named acute lymphoblastic leukemia (T-ALL). T ALL is a particularly deadly disease if it does not respond to therapy (refractory) or if it responds initially and then comes back (relapsed). When a normal T cell becomes a leukemia cell, it develops certain advantages and certain disadvantages. Therefore, one way to kill a leukemia cell is to identify these disadvantages and to exploit those using specific drugs. This research focuses on how leukemia cells make DNA and RNA building blocks called nucleotides. An enzyme called DHODH is essential to the process of making nucleotides within the leukemia cell. Drugs that inhibit this enzyme rapidly kill the leukemia cells and spare the life of normal cells. Researchers call this approach 'nucleotide starvation' because it starves the leukemia cells of these DNA and RNA building blocks. Normal cells have back-up systems to deal with periods of nucleotide starvation. Dr. Sykes believes that leukemia cells have lost these back-up systems and that is why they are so sensitive to starvation. So far his research has shown that this nucleotide starvation approach works extremely well in leukemia cells outside of the body and in leukemia cells in laboratory mouse leukemia models. The fact that many DHODH inhibitor drugs are already available and have already been tested in humans suggests that clinical trials are feasible and could begin in a timely manner. Dr. Sykes hopes that DHODH inhibitor therapy will be effective treatment for children with T ALL, especially those children who have run out of other good treatment options.

High-risk medulloblastoma is a devastating childhood brain cancer that results in death in nearly 50% of patients. To improve future treatments for this disease, Dr. Prensner is studying a category of newly-discovered "dark proteins", which have been excluded from prior work due to their small size and unconventional locations in the human genome. He has found that a group of these dark proteins are critical for medulloblastoma cells to survive. This research will reveal how these dark proteins may point toward new approaches to treat medulloblastoma, which may be critical to define the next generation of anti-cancer therapies in this disease. This grant was awarded at Dana Farber Cancer Institute and transferred to the University of Michigan.

Dr. Nguyen uses the patient's own immune T cells and armors them in the laboratory with a chimeric antigen receptor (CAR) to recognize neuroblastoma cells and kill them. Although she has demonstrated a robust anti-tumor effect of CAR T cells in models of neuroblastoma, she noticed that they can be overwhelmed by too many tumor cells and work less effectively. However, the CAR T cell function was restored when the cells were engineered to express tethered IL15 and -21 on their surface. Though these cytokines activated the CAR T cells and improved their function, models also showed signs of toxicity, which she hypothesizes to be caused by cytokine-driven CAR T cells. Therefore, this project will describe the manifestation and understand the cause of CAR T cell-associated toxicities in our neuroblastoma model. Furthermore, Dr. Nguyen and colleagues propose to reduce the side effects by engineering tethered cytokines that are predominantly expressed in the vicinity of tumor cells (conditional expression). The completion of this project will forge a new direction for the use of cytokines in CAR T cell therapy and render a new fourth-generation CAR T cell therapy safer for translation into the clinic. This honor award is without funding.

Hepatoblastoma is a very rare liver tumor diagnosed mainly among children younger than five years of age. Since it is hard to collect enough cases to study, researchers have not fully evaluated germline risk factor, i.e., the genetic information inherited from parents. Dr. Yang and colleagues have generated the largest germline genetic dataset for hepatoblastoma in the world, with which they can study the genetic causes of both onset and survival. They aim to better understand these genetic mechanisms to facilitate early detection and possibly identify targets of therapy for hepatoblastoma.

Limited progress has been made over the last 30 years against kid brain tumors, especially those in the thalamus and the pons (Diffuse Intrinsic Pontine Glioma, DIPG), a specific location in the brain. Radiotherapy (RT) is the only treatment available that can prolong the life of children with the most aggressive form of brain tumors. Recently, RT is recognized to activate the immune system against multiple tumors. However irradiated kid brain cancers always regrow which suggest that RT is not activating immunity against these tumors. Understanding why this phenomenon is happening is critical to develop strategies that will exploit the immune stimulation from RT to control and cure brain cancer. The activation of cancer-associated fibroblasts (CAFs) by RT can be responsible for treatment resistance and the lack of immune stimulation of kids brain cancers. Dr. Vanpouille-Box's initial results show that stopping the immunosuppression of CAFs with a fibroblast activating protein alpha (FAP) blocker re-activates the immune system against irradiated pediatric brain tumors. Thus, blocking CAF emerges as a novel approach to prevent brain cancer regrow and to activate immunity in irradiated brain cancer. She proposes to: 1) Define the role of CAF in mice models of pediatric brain cancer 2) Determine the efficacy of CAF and EGFR blockade in irradiated pediatric brain cancer. Dr. Vanpouille-Box and colleagues hope to find that: - CAF stop the immune stimulation of irradiated pediatric brain tumors - blocking CAF immunosuppression works well to reactivate immunity against irradiated brain cancer, especially on the context of epidermal growth factor receptor therapy.

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.

Brain and spine tumors are the leading cause of cancer-related death in children and adolescents. While cure can sometimes be achieved with conventional chemotherapy, surgery, and/or radiation, prognosis is dismal for patients whose aggressive brain/spine tumors progress despite these treatments. There is a critical need to develop new effective, well-tolerated therapies for children, adolescents, and young adults with refractory high-grade brain/spine tumors. Lutathera is a targeted radiotherapy which binds to tumor cells that express somatostatin receptors, causing tumor cell death through localized release of radiation, with minimal side effects. Many pediatric and young adult high-grade brain/spine tumors express somatostatin receptors, making them ideal targets for this therapy. Dr. Lazow is conducting a clinical trial to assess the safety and effectiveness of Lutathera in children and young adults with recurrent high-grade brain/spine tumors. Within this trial, she will also 1) evaluate how somatostatin receptor expression varies across different brain/spine tumors and determine clinical, imaging, pathology, and genetic characteristics which correlate with that expression, 2) identify imaging and molecular biomarkers predictive of response to Lutathera and/or disease recurrence, and 3) perform radiation dosimetry to establish optimal dosing of Lutathera in children and young adults, ensuring adequate tumor penetration while minimizing toxicity. If Lutathera proves safe and effective in treating children and young adults with refractory brain tumors, further studies will be planned to expand to a larger patient population and eventually incorporate Lutathera into upfront treatment backbones for these aggressive diseases.

This grant is funded by and named for the Miracles for Michael Fund, a St. Baldrick's Hero Fund created in memory of Michael Orbany who was diagnosed with medulloblastoma when he was 6 years old. After completing initial treatment, his cancer relapsed within a year and he passed away at the age of nine. Michael had unwavering faith and perseverance, wanting most of all to make others happy. This fund honors his tremendous strength to never ever give up.

Based on progress to date, Dr. Moghimi was awarded a new grant in 2023 to fund an additional year of this Scholar grant. In recent years, a very successful immunotherapy strategy to modify a patient's immune cells (called T-cells) to attack cancer has been developed for children with leukemia (cancer of blood cells). These modified immune cells are called Chimeric Antigen Receptor T cells (CAR-T cells). These CAR-T cells are very potent and do a better job than any chemotherapy at killing cancer. However, this life-saving tool has been available only to a small group of patients and for a handful of cancers. This is because most cancers don't have the targets those CAR-T cells aim for, or they have a target that can also be found on normal organs. As a result, these CAR-T cells could harm normal organs as collateral damage, a significant adverse effect of treatment that clinicians would want to avoid. In this proposal, Dr. Moghimi is striving to build the next generation of CAR-T cells that solely react to a combination of targets. These cells recognize a tumor only if they have both targets in sight and will not otherwise attack normal organs. CAR-T cells that operate based on a combination of two targets are more accurate than other targeting cells. Using this new generation of CAR-T cells, researchers would be able to significantly expand the availability of this powerful treatment to many more patients. Dr. Moghimi and colleagues will develop these special CAR-T cells for patients with Acute Myeloid Leukemia (AML), another common form of leukemia with a higher mortality rate for children. These results will provide pre-clinical evidence that could quickly translate to new clinical trials for children with relapsed AML through the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) consortium, an international collaboration headquartered at CHLA.

Based on progress to date, Dr. Wu was awarded a new grant in 2023 to fund an additional year of this Scholar grant. Diffuse midline glioma (DMG) is a fatal brain cancer in children and there are no effective treatments. The brain's natural barrier prevents drugs from reaching the tumor. Focused ultrasound (FUS) uses sound waves to temporarily open the blood brain barrier to increase drug delivery to the protected tumor cells in the brain. As the Hannah's Heroes St. Baldrick's Scholar, Dr. Wu will be using panobinostat, a promising drug tested in cancer cells in the laboratory to examine if FUS can increase its delivery and whether the addition of radiation can further improve the outcomes.

The 2023 year of this grant is co-funded by the Focused Ultrasound Foundation.

The 2021 and 2022 years of this grant are funded by and named for Hannah’s Heroes, a St. Baldrick's Hero Fund established to honor Hannah Meeson. At age six she was diagnosed with anaplastic medulloblastoma. After a relapse and several additional months of 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.”

Based on progress to date, Dr. Jones was awarded a new grant in 2023 to fund an additional year of this Scholar grant. Acute myeloid leukemia (AML) is a difficult to treat cancer that is associated with death in nearly 4 out of 10 children who are diagnosed with this disease. We know that there are multiple factors that contribute to poor outcomes in these patients, however, researchers don't fully understand all of them. Dr. Jones will gain a greater understanding of the resistance associated with a specific type of AML that is particularly difficult to treat. She hopes to gain clarity about this type of disease to find more specific therapies to target those resistance mechanisms in the cancer cells.

Based on progress to date, Dr. Chavez was awarded a new grant in 2022 to fund an additional year of this Scholar grant. Researchers have found that some very aggressive cancers produce extra pieces of DNA that are located outside of our 23 chromosomes and form circles. This is why we call them circular extrachromosomal DNA, or ecDNA. These ecDNAs are thought to be a fundamental driver of cancer growth. However, very little is known about ecDNA in childhood brain tumors. This is why researchers have now looked for ecDNA in medulloblastoma- a cancerous brain tumor that starts in the lower back part of the brain, called the cerebellum. Medulloblastoma can occur at any age, but most often occurs in young children. Though medulloblastoma is rare, it's the most common cancerous brain tumor in children. And indeed, we have observed that there are very specific types of ecDNA in medulloblastoma tumors, especially in those tumors that are very aggressive and difficult to treat. As the Hannah's Heroes St. Baldrick's Scholar, Dr. Chavez would like to learn more about ecDNAs in medulloblastoma and hopes that this will lead to a scientific revolution in how some of the most difficult-to-treat childhood brain tumors are understood and treated.

This grant is named for Hannah’s Heroes, a Hero Fund established to honor Hannah Meeson. At age six she was diagnosed with anaplastic medulloblastoma. After a relapse and several additional months of 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.”

This grant was awarded at the University of California, San Diego, and transferred to Sanford Burnham Medical Research Institute.

Acute myeloid leukemia (AML) is an aggressive pediatric cancer associated with poor outcomes. Current therapies are toxic and result in a high incidence of late effects; including infertility, heart failure, and second cancers. Therefore, distinguishing who will be cured with chemotherapy alone from those who require more intensive therapies is critical to improving cure rates in AML while limiting treatment related late effects. The presence of small numbers of persisting leukemia cells after chemotherapy has become an important predictor of leukemia relapse. However, current assays used to detect residual leukemia have limited sensitivity and many patients with "no detectable leukemia" still go on to relapse. This underscores the need to identify and develop more accurate and sensitive leukemia detection assays for AML. This project aims to develop a novel assay that harnesses "best in class" technologies to enable detection of one leukemia cell for every one million normal cells -- a sensitivity that eclipses the current standard of care by more than one hundred-fold. Additionally, unlike many other novel methods for detecting leukemia, this assay will be universally applicable to every patient diagnosed with AML. Finally, this assay will reveal not simply whether or not leukemia cells are present, but the exact genetic code comprising the remaining leukemia cells. Successful validation of Dr. Huang's assay will therefore fill a critical unmet need in the field of AML, and the resulting product will be an optimized test ready for clinical use.

A portion of this grant 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.

Although rates of cure for childhood cancer have greatly improved in recent years, thousands of children continue to suffer from advanced, incurable cancer. Healthcare professionals bear a responsibility to ensure that the care of children with advanced cancer meets the goals and wishes of patients and their families. However, we do not know whether we fulfill this aim in pediatric cancer care. Dr. Ananth's prior research reveals intensive healthcare use near the end of life for children with advanced, incurable cancer. This includes lengthy stays in the intensive care unit and common use of interventions like breathing tubes. Yet, healthcare professionals worry that intense care toward the end of life for children with cancer may increase child and family suffering. In adults with cancer, quality measures have been developed to evaluate where care is most intense, or poor quality. This has consequently allowed researchers to develop interventions to improve the quality of care for adults with incurable cancer. Unfortunately, there are no comparable measures or standards for what constitutes good, or high quality, end-of-life care for children with cancer. Dr. Ananth seeks to address this problem. The overall objectives of this research are to (1) refine a list of potential measures of high quality end of life for children with cancer, and (2) develop an innovative questionnaire to systematically evaluate whether patients are receiving high quality end-of-life care. She hopes that, through this work that is distinctly family-centered, she can develop interventions to enable healthcare teams to provide optimal, compassionate care for children who have incurable cancer.

Based on progress to date, Dr. Hoang-Minh was awarded a new grant in 2022 to fund an additional year of this Scholar grant. Brain tumors are the most common cause of cancer-related deaths in children. The current treatments are often associated with lifelong mental and motor deficits, and the tumors often recur. Therapies that specifically and efficiently target the tumors and minimize toxicity to the body are critical to improve clinical outcomes for children affected by these deadly diseases. As the Pray for Dominic St. Baldrick's Scholar, Dr. Hoang-Minh's research is exploring a powerful method that uses the children's own immune system to destroy their brain tumors, known as immune cell therapy. This therapy has emerged as a very effective and safe treatment for blood cancers and several types of solid tumors. It uses powerful immune cells, called T cells, to specifically kill the brain cancer cells and has already shown promising results in preclinical and clinical studies conducted at our institution. This project investigates novel approaches to make this immune therapy even more effective and safer. Dr. Hoang-Minh will also follow the fate of therapeutic T cells using a new, non-invasive imaging technology called magnetic particle imaging. The results of these studies are important as they could improve clinical protocols using immune cell therapies for childhood brain tumors and extend or save the lives of children afflicted with those very aggressive cancers.

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.