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

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

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

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

Adoptive immunotherapy has demonstrated unprecedented clinical success in the treatment of leukemia. 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. This protein increases "specificity," the ability to recognize cancer cells, and "function," the ability to destroy those cancer cells. An important challenge in cellular immunotherapy is to minimize the manipulation of patients' T cells outside the body. Prolonged culture protocols trigger functional exhaustion and compromises their efficacy upon return to the body. A critical issue involves the pre-requisite "activation" step necessary for CAR expression on the cell surface of T cells. By optimizing culture conditions, Dr. Ghassemi developed approaches to express CAR in dormant T cells without the need for activation. Importantly, her preliminary findings show that elimination of this activation step retains effector function and potency of CAR T cells in models of the pediatric cancer ALL. This project is providing insight into the regulatory components influencing CAR expression in dormant T cells which will lead to superior CAR T cells for cellular immunotherapies against ALL.

This grant is supported by 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) 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.

In the U.S., children with a blood cancer called Hodgkin lymphoma (HL) are usually treated successfully. Some of these children will suffer health problems several years later because of the treatment they received. Because of this, doctors use powerful imaging tools to identify patients who are likely to do well or not. Those who are likely to do well require less treatment and those who are less likely to do well can receive more treatment. But in low-income countries like Malawi, these tools are unavailable, and the children there often receive treatment that may be unnecessary. Scientists have found unique abnormalities in adults with HL that can tell us who is less likely to do well. Here, Dr. Ozuah is testing whether these abnormalities are present in children and could be used to decide how best to treat children with HL in low-middle income countries

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

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

Ewing sarcomas are bone cancers that impact many adolescents and young adults. Despite the use of intensive traditional chemotherapy combined with advanced surgical techniques, 30-40% of patients still die after the disease eventually spreads to other organs, such as the lungs and bone marrow. Dr. Hayashi's team believes the key to overcoming this problem lies in the identification of “Circulating Tumor Cells (CTC)”. These are cells that break away from the original tumor and travel through the blood stream, eventually taking root in another organ to form what is called metastatic disease, meaning the cancer has spread from where it started into different areas of the body. These cells undergo multiple changes in order to leave the original tumor and survive in the harsh environment of the blood stream, eventually leaving the blood stream to invade another organ where they multiply and grow. This project aims to dissect each of these complicated steps with the goal of unveiling which element of this devastating process can be targeted to disrupt it.

Despite improvements in outcome for patients with acute lymphoblastic leukemia (ALL), up to 25% of children and 40% of adults fail frontline therapy and their prognosis is dismal, especially for high-risk and relapsed leukemia. Cure rates for ALL patients that are relapsing on therapy is approximately 20% and currently there are no targeted therapies. Dr. Tsirigos' goal is to address this significant clinical need by studying how DNA, our genetic material, is organized inside the nucleus of the cells, i.e. how it is folded in three-dimensional space. Over the past decade, seminal studies have demonstrated that DNA folding is of fundamental importance in that it allows the cell to properly perform its function and retain its identity (e.g. a liver cell versus a blood cell). Very recent studies have demonstrated that disruptions of DNA folding may cause various diseases, such as developmental defects and cancer. However, no study has addressed the question of disruptions of DNA folding on the genome-wide scale in cancer or how such disruptions may be exploited for more effective treatments. Dr. Tsirigos is attempting to answer two key questions. First, are cancer-promoting genes (“oncogenes) capable of disrupting normal DNA folding to transform normal cells into malignant ones? And, second, can drug treatment restore DNA folding and thereby also restore normal cell function?

This grant is made with generous support from the Rally for Ryan Fund. Ryan was diagnosed with high risk ALL when he was 7 years old. He endured 3½ years of treatments with a brave acceptance that this was his fight to win. He recently relapsed and is in the fight again. This fund honors Ryan’s perseverance and his commitment to make a difference for kids with cancer by shaving for St. Baldrick’s and raising funds for research.

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

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

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

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

In the U.S., children with a blood cancer called Hodgkin lymphoma (HL) are usually treated successfully. Some of these children will suffer health problems several years later because of the treatment they received. Because of this, doctors use powerful imaging tools to identify patients who are likely to do well or not. Those who are likely to do well require less treatment and those who are less likely to do well can receive more treatment. But in low-income countries like Malawi, these tools are unavailable, and the children there often receive treatment that may be unnecessary. Scientists have found unique abnormalities in adults with HL that can tell us who is less likely to do well. Here, Dr. Ozuah is testing whether these abnormalities are present in children and could be used to decide how best to treat children with HL in low-middle income countries

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

The goal of Dr. Riehle's research is to find a cure for a rare form of liver cancer that occurs in children and young adults, called fibrolamellar hepatocellular carcinoma (FL-HCC). Unfortunately, surgery is currently the only effective treatment option for these patients, and once the disease has spread outside of the liver there is no chance for cure. Dr. Riehle's laboratory has spent the last few years trying to understand what changes within the liver cause healthy kids to get this cancer, and has developed a couple of new models of FL-HCC that can be used for drug screening. In this project she is using these models to test new treatment options and to try to understand how this cancer develops.

As the recipient of the Rosa and Francesco Romanello St. Baldrick's Research Grant, Dr. Lawlor is studying an aggressive tumor called Ewing sarcoma that occurs most often in teenagers. It usually starts in a bone and then can spread or metastasize throughout the body. Once it has spread, the chances of cure are very poor. She is studying how the tumor cells change the surrounding normal tissues to allow the tumor cells to leave the bone and spread to other sites in the body. Results so far have shown that the tumor cells and the normal tissues "talk to each other" and that this crosstalk is likely to be essential for the growth and spread of the tumor, both within the bone as well as in other tissues. Dr. Lawlor will decipher these messages, and the instructions they convey, so that new therapies can be developed that will intercept them and block tumor spread.

This grant is named in recognition of Salvatore Romanello for his decade of service as pro bono general counsel to the St. Baldrick's Foundation. He has chosen to name the grant in honor of his parents who instilled in him the values of generosity and caring for a greater cause.

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

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

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

Do you ever get a cold sore on your lip, or know someone who does? That sore is caused by a virus that destroys the cells in your lip. As the virus spreads, the sore gets bigger. Viruses are great at killing cells and spreading. But, the sore eventually goes away because the immune system attacks the infected cells, killing them and stopping the viral infection, allowing your lip to heal. Imagine if we could get both the virus and the immune system to kill cancer cells instead of lip cells! Previously Dr. Haworth's team used a safe version of the cold sore virus to infect a common type of hard-to-treat childhood cancer cells. The virus directly killed cancer cells and caused the immune system to attack the cancer cells that the virus missed. Dr. Haworth's team is testing ways to make the virus and immune system work better together. Dr. Haworth is infecting model tumors with the virus, and giving immune cells designed to attack the tumor, hypothesizing that giving both virus and immune cells will cure the tumor. Awarded at The Research Institute at Nationwide and transferred to St. Jude Children's Research Hospital.

This institution is a member of a research consortium which is being funded by St. Baldrick's: Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium. For a description of this project, see the consortium grant made to the lead institution: Baylor College of Medicine, Houston, TX.