Funding Childhood Cancer Research

Clinical Trial Decision Aid (DECIDES) for Adolescents and Young Adults with Cancer and their Caregivers

Adolescents and young adults (AYA) with cancer have lower rates of participation in therapeutic clinical trials; they have limited involvement in decision-making, do not fully understand clinical trials, and are vulnerable to acute distress undermining their decision processes. We developed a decision support tool (DECIDES = AYA Deciding about Enrolling on a Clinical Intervention Trial: Decision Aid for Education and Support) to increase collaboration among AYA, primary caregivers, and providers in clinical trial decision-making. DECIDES is based on decision theory, findings from our qualitative studies of AYA decision-making, evidence-based decision tools in adult oncology, and feedback from CHOP AYA Patient Steering Committee, caregivers, and Scientific Advisory Committee. Content/format includes information on cancer clinical trials and a value clarification exercise in a web-based format with written information, games, video, and animation. We will use a hybrid design to pilot test and identify implementation strategies with newly diagnosed or relapsed AYA: DECIDES alone (n=20), DECIDES+coach (n=20), and Usual Care (n=10). Hypotheses: (1) DECIDES will be acceptable and feasible; (2) DECIDES groups will have more knowledge about cancer clinical trials, open clinical trial attitudes, positive decision processes, and collaborative decision-making than the usual care group. Interviews with participants will provide feedback on DECIDES for future, larger scale implementation.

Overcoming Resistance of CAR T Cells Immunotherapy with CBP/ß-catenin Antagonists in Pediatric Glioma and Ependymoma

Brain tumors are the second most common cancer in children, accounting for 20% of all pediatric cancers. Our research aims to improve treatment for two types of deadly brain tumors: ependymoma and glioma. While some young patients can be successfully treated using radiation and surgery, far too many children fail to respond to therapy or relapse.  The emerging field of immunotherapy has shown great promise in treating various cancers, and one type in particular uses cells from the patient’s own immune system to fight cancer. The method entails isolating a patient’s immune cells (T cells) and genetically engineering them to recognize and kill brain tumor cells using a chimeric antigen receptor (CAR). By infusing these CAR T cells back into the patient, the engineered cells seek out and eliminate malignant cells. Two previous first-in-human clinical trials by our team at City of Hope demonstrated the safety and feasibility of this approach and suggested that it could be effective against brain tumors, provided barriers presented by the tumor can be overcome. One common therapeutic barrier is that the tumors typically present an environment that suppresses the immune response. We postulate that resistance to chimeric antigen receptor T (CAR T) cell therapy involves activation of the Wnt/ß-catenin signaling pathway. We hypothesize that the Wnt/CBP/ß-catenin pathway selective inhibitor ICG-001 can safely overcome tumor resistance and synergize with CAR T cell treatment via two mec.

Stimulating Macrophages to Eat Pediatric Brain Cancer: Combining Anti-CD47 and Irradiation to Enhance the Treatment of Group 3 Medulloblastoma

We devolved a therapy that allows macrophages (a type of white blood cell) to specifically “eat” tumor cells by a process called phagocytosis. The therapy, anti-CD47 treatment, blocks a signal on tumor cells called a “Don’t Eat Me” signal. There are also signals on tumor cells that promote phagocytosis of tumor cells called “Eat Me” signals. We know that increasing “Eat Me” signals (when the “Don’t Eat Me” signal is being suppressed by anti-CD47) greatly enhances the ability of macrophages to “eat” tumor cells. Irradiation is well known to enhance the expression of “Eat Me” signals on tumor cells, and we have preliminary data show that the combination of anti-CD47 and irradiation can enhance eating of malignant brain tumor by macrophages in the test tube, as well as in a live animal. Here, we propose to use this combination (anti-CD47 + irradiation) to kill the deadly pediatric brain tumor, Group 3 Medulloblastoma. We will determine the dose of irradiation needed to enhance anti-CD47 meditated eating of Group 3 Medulloblastoma cells by macrophages in test tubes and live animals. In addition, we will determine how irradiation with anti-CD47 can impact the levels of “Eat Me” and “Don’t Eat Me” signals on Group 3 medulloblastoma tumor cells. Our goal is to utilize this combination to dial down the amount of irradiation needed to treat the children with Group 3 medulloblastoma. This will allow for a more effective therapy that is also safer.

Development of anti-KIT antibodies and immunotoxins as therapeutics and HSCT conditioning agents for pediatric acute myeloid leukemia

Acute myeloid leukemia (AML) is a frequent and devastating type of cancer that affects thousands of children worldwide. Patients diagnosed with AML are generally treated with harsh conventional chemotherapy and/or blood-forming (hematopoietic) stem cell transplantation (HSCT). Unfortunately, regardless of the therapy used, most children have sub-optimal outcomes: overall survival is only ~60% and children who do survive have many severe co-morbidities from the toxic treatments used. Thus, better therapeutic options for these patients are desperately needed. We have pioneered several new antibodies that could become very powerful therapies to safely cure AML. These antibodies target a specific protein, KIT (CD117), which is found on bone marrow stem cells and cells that are thought to start and maintain AML. These anti-KIT therapies may kill the leukemic cells by: 1) depriving the cells of key nutrient stem cell factor (SCF) needed for cell growth and survival, or 2) delivering an additional toxin to kill the cells directly. We propose to test these therapies as stand-alone drugs and in combination with HSCT in models of pediatric AML. If our results are promising, we believe these antibodies could rapidly turn into important drugs for both pediatric and later adult AML treatment. In addition, such work could encourage broader exploration of an entire new class of therapies that target both stem cells and AML cells, which could further improve safety and efficacy of HSCT.

Artificial Intelligence for Pediatric Cancer Imaging

Imaging tests are essential for diagnosing cancers in children and for monitoring tumor response to therapy. By combining magnetic resonance imaging (MRI) and positron emission tomography (PET), pediatric cancers can be imaged with 80% reduced radiation exposure compared to traditional imaging tests. However, the acquisition of combined MRI and PET scans takes about 3-4 times longer (60-90 minutes) compared to traditional combined PET and computed tomography (CT) scans (20-30 minutes). These long acquisition times are a major bottleneck for clinical translation of PET/MRI technologies. To achieve faster diagnoses and higher throughput, we propose to develop novel deep convolutional neural networks (Deep-CNN) that can accelerate PET/MR image data acquisition and interpretation. The goal of our project is to develop Deep-CNNs for accelerated PET and MR image data acquisition of children with cancer. We will accomplish this goal by using deep convolutional neural networks (Deep-CNN) to reconstruct high resolution MR and PET images from low resolution inputs. In addition, we will train our Deep-CNN to classify responders and non-responders based on the image data. To the best of our knowledge, this is the first attempt to apply Deep-CNN to pediatric oncology applications. Results will be readily translatable to the clinic and thereby, will have major and broad health care impact.

Boosting Immunovirotherapy with Tumor Vaccination to Treat Pediatric Malignant Brain Tumors

Medulloblastoma, the most common pediatric brain tumor, is a leading cause of cancer-related death and injury. New, improved treatments are greatly needed. We are currently conducting a clinical trial of a cold-sore virus that has been altered to target and kill brain tumor cells while not harming normal brain cells and to stimulate the child’s own immune system to attack the tumor. Results of the trial have been very promising. In the trial, we have learned that a critical obstacle to achieving more long-term responses from the virus therapy is maintaining an immune system attack on the tumor.  We will overcome this obstacle by combining a new, improved altered cold-sore virus with a unique tumor vaccine.  The new virus produces a substance that attracts more immune cells to the tumor, stimulates an even greater attack on the tumor and is currently in an adult clinical trial at UAB. The novel vaccine, which greatly improves on current technologies, is designed to increase the immune attack against the tumor and increase the amount of tumor cell killing by the  virus. We plan to rapidly translate this research from the lab to the clinic, and we anticipate that we will see even better outcomes in children with brain cancer using these exciting therapies. Importantly, this combination treatment can be applied to treat other pediatric brain tumors and solid tumors outside the brain, increasing the overall potential impact for children with cancer and their families.

Arginine methylation as a potential therapeutic target in high-risk neuroblastoma

Neuroblastoma, an embryonal malignancy of the developing sympathetic nervous system, remains a leading cause of childhood cancer deaths. The goal of this project is to develop novel targeted therapies for high-risk neuroblastoma based on specific, rational molecular vulnerabilities we have uncovered. We have recently discovered a novel regulatory pathway involved in the cancerous properties of neuroblastoma cells. Our preliminary studies have further confirmed the therapeutic potential of using drugs to inhibit this pathway’s role in neuroblastoma cancer cells. In this project, we propose a paradigm-shift approach to determine the role of this pathway in the development of sympathetic nervous system and neuroblastoma tumorigenesis. By better understanding this regulatory pathway, we ultimately aim to improve the treatment of patients with neuroblastoma and other malignancies.

Polycomb inhibition sensitizes AML to anthracycline therapy

Childhood acute myeloid leukemia (AML) is an aggressive blood cancer driven from undifferentiated populations of myeloid cells that inappropriately proliferate and fail to differentiate. The major genetic drivers of childhood AML include mutations to epigenetic machinery, which functions to organize the DNA inside of the cell. Undifferentiated tumors, including subtypes of childhood AML with stem-like characteristics, are associated with high expression levels of Polycomb genes, encoding proteins which can epigenetically silence regions of DNA. This proposal builds on my hypothesis that drugs targeting Polycomb/EZH2 can help lower the dose of co-administered anthracyclines which are a toxic therapy for childhood AML. My preliminary data indicates that across cell models for several AML subtypes, inhibiting EZH2 enables lowering the effective dose of anthracycline by more than 5-fold. This proposed study aims to understand why we are observing this effect, to connect basic questions about the organization of DNA inside the leukemia cells to translational studies with patient-derived samples at Nationwide Children’s Hospital. This proposal will build on a collaboration with AML clinicians and physican-scientists, including Dr. Terri Guinipero, Dr. Huifei Liu and Dr. Ryan Roberts. We will define how DNA accessibility affects the function of anthracyclines in childhood AML.

Pediatric Cancer Data Commons

Worldwide, about 300,000 young people are diagnosed with cancer each year. Thanks to decades of medical research, about 80% will survive. A major roadblock to better outcomes for the remaining 20% is the siloed nature of research’s best hope: data. Data from clinical trials are difficult to collect and share across research groups because each group collects data according to their own preferences and definitions. This limits researchers’ ability to analyze patients’ clinical data and to pair it with data from new techniques, like genomic testing, to make discoveries.

The Pediatric Cancer Data Commons (PCDC) designs better ways to collect and store clinical data (and connect clinical data to other types, such as imaging and genomic data) by developing consensus among researchers to develop a common data language and sharing those standards widely. The PCDC is dedicated to gathering as much data as possible from around the world into a “data commons”—a single place where researchers everywhere can go to access and explore uniform data in pursuit of their research questions.

Funding from The Andrew McDonough B+ Foundation will allow the PCDC to build the tools and systems necessary for collecting, storing, analyzing, and sharing these data. Your funding will supplement work supported by the St. Baldrick’s Foundation and your investment will be maximized by generous matching funds provided by an anonymous foundation.

Understanding the role of SMARCD1(BAF60A) in malignant rhabdoid tumors

SWI/SNF chromatin remodeling complexes are groups of proteins with numerous roles in the organization and activation of DNA. These complexes are vital to the health and development of our cells, and disruption of their activity can lead to a range of diseases. Nearly 20% of all human cancers are thought to arise from mutations in the compositional subunits of SWI/SNF complexes. Malignant rhabdoid tumors (RTs) and atypical teratoid rhabdoid tumors (ATRT) are aggressive forms of pediatric cancer that typically stem from inactivating mutations in a prominent SWI/SNF chromatin remodeling complex subunit known as SMARCB1. It is widely accepted that SMARCB1 acts as a tumor suppressor when functional, but less clear how mutations in the subunit might fuel the growth of cancer cells. Unearthing the molecular mechanisms that are responsible for tumor growth in SMARCB1-mutant cancers could yield new therapies for patients suffering from rhabdoid tumors. We hypothesize that one subunit in particular, SMARCD1, is essential for maintaining the functionality of the residual complex. Further characterizing this interaction could open doors to cancer treatments targeting the residual complex via SMARCD1. We hope to identify the specific genes or features of the genome that SMARCD1 and the residual complex are targeting in cancer cells, with the ultimate goal of finding new ways to eliminate these tumors and generate better treatments for this pediatric cancer.