Project: Pediatric Cancer Foundation Developmental Therapeutics Program (PCFDTP) at Columbia University Irving Medical Center (CUIMC)
“On behalf of the Columbia team, we are deeply indebted to PCF for the more than 10 years of generous support, which has allowed us to grow in regional and national stature, and more importantly, to offer new therapies and genomic technologies to children in need.”
Pediatric Cancer Foundation Developmental Therapeutics Program (PCFDTP) is a keystone of innovative care and clinical research within the Division of Pediatric Hematology, Oncology and Stem Cell Transplantation at Columbia University Irving Medical Center (CUIMC). “Our longstanding partnership with PCF embodies their credo of ‘coming together for a cure.’ This coming together has given us the tremendous opportunity to establish a robust translational research program to bring cutting-edge treatments directly to patients.” To that end, the mission of the PCFDTP at CUIMC is to develop and test novel treatment strategies for children with incurable cancer, resistant to conventional therapies. This program allows them to advance new treatments through basic science research to define novel therapeutic targets, translational research to adapt observations from the laboratory to patients, and clinical trials participation to bring innovative therapies directly to patients. The PCFDTP also serves as the local home for their Precision in Pediatric Sequencing (PIPseq) Program, which uses next-generation sequencing technologies to perform CLIA-compliant and New York State approved whole exome sequencing of patient-matched tumor-normal samples and RNA sequencing of tumor to identify molecular drivers of each patient’s cancer. This helps them to make personalized, genetically informed treatment recommendations, including selection and recruitment to early phase clinical trials. Furthermore, the PIPseq program is a platform for laboratory investigations to elucidate the various abnormal molecular pathways underlying cancer growth and other molecular changes that may represent novel therapeutic targets for pediatric cancer drug development.
Project: Strengthening bench-to-bedside research initiatives at the Comprehensive Neurofibromatosis Center at Columbia University
Phase 0/1 study examining the use of non-invasive focused ultrasound (FUS) with oral selumetinib administration in children with progressive inoperable plexiform neurofibroma
Neurofibromatosis type 1 (NF1) is a rare and under-researched cancer predisposition syndrome that affects 1 in 3,000 people worldwide. Patients with NF1 require monitoring for the development of skin, peripheral, and central nervous system tumors. Plexiform neurofibroma (PNF) is a benign tumor that can grow within a nerve anywhere in the body and seen in about 30-50% of NF1 patients with an approximately 10-15% chance to develop into a malignant peripheral nerve sheath tumor (MPNST), a type of sarcoma. Selumetinib, a MEK-inhibitor is FDA-approved for patients with progressively growing PNFs which can’t be safely removed by surgery. Focused Ultrasound (FUS) has been successfully used to open the blood-brain barrier allowing drugs entering the brain in higher concentrations. We plan to combine FUS with selumetinib to achieve better drug penetration into the PNF which could decrease the systemic side effects of selumetinib and improve quality of life by alleviating the need for surgery.
Project: Delivering RNA Therapeutics for the Treatment of Pediatric Sarcomas
Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma. Fortunately, most children with localized tumors can be cured through current treatment. However, survival rates for children with metastatic disease at the time of diagnosis or who relapse after treatment are a grim 20% to 30%. Despite substantial improvements in the comprehension of the genetic systems governing this pediatric disease, the last forty years have seen few advances in medical outcomes for advanced and metastatic RMS patients. Compounding the roadblocks to new therapy development is the lack of understanding mechanisms that contribute to the treatment resistance of these tumors. Their lab is trying to understand how tumors become metastatic and resistant to drug treatment to interfere and destroy these cancer cells. The research they perform is centered on understanding the regulation of a process termed alternative pre-mRNA splicing. Sections of a gene are differentially excluded to create new proteins with varying functions. Alternative splicing plays a vital role in generating the biological workings of all humans. It significantly affects numerous functions, from cellular processes to disease conditions, and increases our genes’ instructional diversity and functional capacity. Their work has shown explicitly that MDM2, a gene responsible for controlling the critical tumor suppressor gene p53, is alternatively spliced to make MDM2-ALT1 to prevent the inactivation of p53. They are testing the idea that activating alternative splicing of MDM2 will preserve the protective function of p53 and will prevent cancer growth and progression to a novel therapy for Rhabdomyosarcoma.
Project: The role of ZMIZ1 somatic alterations in driving relapse in childhood B acute lymphoblastic leukemia
While the prognosis for children with acute lymphoblastic leukemia (ALL) has improved dramatically, up to 20% of children relapse and their prognosis remains poor. To discover pathways that lead to drug resistance and relapse in ALL, they have focused on the discovery of mutations (relapse-specific somatic variants (SV)). Their previous work has led to important clinical discoveries of genes mutated at relapse that directly impact drug sensitivity. Motivated by this, in collaboration with St. Jude, 178 new pediatric relapse B-ALL cases have been sequenced using whole genome sequencing in an effort to identify novel, rare, but important variants associated with relapse. Some of the genes have not been implicated in chemoresistance, thus they could be novel targets for therapeutic interventions The team will examine the role of a newly discovered mutation in ZMIZ1 in resistance using preclinical models and determine the pathways that drive resistance by determining differences in gene expression in tumor cell lines with and without the mutation.
Project: Development of bone and blood cancers in mouse models of Diamond Blackfan anemia
The focus of this ambitious project remains to be understood as to how cancer develops in patients with the rare genetic disease, Diamond Blackfan anemia (DBA). Patients with DBA have an over 40-fold increased rate of bone cancer (osteogenic sarcoma), 29 for acute myeloid leukemia and 352 for myelodysplastic syndrome. In DBA, there is a mutation in a gene that codes for proteins that are an essential part of the ribosome (ribosomal proteins, RP). The ribosome is the cellular machine that makes proteins (a process called translation) from a message (mRNA) encoded by DNA (a process called transcription). As cancer is recognized as a disease of decreased differentiation/maturation and uncontrolled proliferation, their findings imply that defective ribosome formation contributes to the development of osteosarcoma in DBA. The mouse model, supported by PCF has been fully characterized. This is a long-term ongoing study that has resulted in the creation of a well characterized osteosarcoma –prone mouse and the development of a likely MDS/AML prone counterpart. For the first time, they have a model that recapitulates the clinical scenario, in terms of poor skeletal growth and birth defects in bone. This work supported by PCF allows them to move forward towards studies of osteosarcomagenesis (development of bone cancer) in this model. Importantly, the defect they have engineered into mouse bone is identical to a human mutation that causes DBA and the bone defects in the mouse model that mimic human patients with DBA.
Project: Infrastructure Support for Pediatric Graft-versus-Host Disease Research
Bone marrow transplants can cure leukemia, but there is a risk of graft-vs-host disease (GVHD), a complication where immune system cells from the donor attack the healthy tissue of the patient. GVHD does not always respond to treatment with immune suppressing medications and, after relapse, is the leading cause of death after a bone marrow transplant. The Mount Sinai Acute GVHD International Consortium (MAGIC) collects clinical data and research samples for a multicenter natural history study of graft-vs-host disease (GVHD). The goal of this study is to increase their understanding of GVHD in children and use the knowledge learned to design innovative clinical trials to improve GVHD outcomes in this vulnerable population. Research funding supports the MAGIC Data Coordinating Center (DCC) which oversees the enrollment and monitoring of children across 12 international study sites, improving outcomes for children worldwide that have undergone bone marrow transplant.
Project: Reducing the Burden of Oncologic Chemotherapy And Radiation Exposure Utilizing Targeted Immunotherapy in Children, Adolescents and Young Adults with Lymphoma
As Chief of Pediatric Hematology, Oncology and Stem Cell Transplantation at Maria Fareri Children’s Hospital, Dr. Mitchell Cairo leads a multidisciplinary team of researchers developing treatments to battle Hematologic Malignancies in children and adolescents through targeted immunotherapies, reduced intensity conditioning and allogeneic stem cell transplantation, novel chemotherapy for reinduction therapy, Human Derived Placental Stem Cell (HDPSC) therapy, haplo identical stem cell transplantation, and single or double umbilical cord blood transplantation in children and adolescents who are at a high risk of Hematological Malignancies. The promise of unlocking treatments by harnessing the power of the patient’s immune system renews the efforts of Dr. Cairo’s team to lead advances that save lives while minimizing unwanted side effects both now and in the future. Overall, the program is equipped to design and deliver customized and personalized therapy for each child and adolescent in the cancer center diagnosed with a hematological malignancy.
Project: Improving efficacy and reducing toxicity of childhood neuroblastoma therapy
Neuroblastomas are highly aggressive pediatric cancers, currently causing 15% of cancer-related childhood mortality. They are the most common solid tumor of the abdomen in children. Despite the best available treatments, 50-60% of children with neuroblastoma develop recurrent disease, highlighting the critical need for better therapy. However, the ability to treat children with chemotherapy is limited by its severe toxicity; even the fortunate survivors who respond to intensive therapy have a high risk of long-term toxic effects. For example, these individuals may develop impaired immune systems, with a decreased ability to resist infection, and manifest infertility, hearing loss, and heart failure as adults. Thus, they seek to improve the current methods of delivering chemotherapy, with the goals of simultaneously enhancing treatment and reducing toxicity. In our studies, they are investigating what is termed “targeted chemotherapy” – novel systems which “home” treatment drugs selectively to the tumor, reducing exposure of normal tissues to toxic chemicals. These new strategies leverage cutting-edge biochemical and bioengineering techniques. The approach that they have employed involves design and synthesis of special microbubbles, which act as packaging for chemotherapy, and which can be detected and guided by ultrasound waves to penetrate tumor tissue. To explore this strategy, they have used doxorubicin, an effective but toxic molecule used to treat neuroblastoma, in a model of the disease. They also plan to test whether this same method can be applied to increase tumor uptake of other drugs, since children with neuroblastoma are typically treated with a multi-drug cocktail.
Project: Clinical Translation of an Exportin 1 (XPO1) Dependency in Select Pediatric Solid Tumors
Utilizing a novel tumor RNA analysis pipeline, we recently discovered that Wilms and rhabdoid tumors, two childhood kidney tumors, are unexpectedly dependent upon XPO1, a nuclear pore that pumps tumor suppressors out of the nucleus thereby inhibiting their function. We further showed that blocking XPO1, with a drug called Selinexor, was an effective strategy to shrink Wilms and rhabdoid tumors that we had established in mice. Selinexor had already completed a phase 1 study in children so we know the pediatric safety profile but a liquid formulation had not yet been available so younger children such as those with Wilms and rhabdoid tumors were not able to be evaluated. This project supports a phase 2 clinical trial in which we are evaluating how effective that the liquid suspension form of Selinexor is in patients with relapsed Wilms tumor, rhabdoid tumor, and other tumors for which XPO1 inhibition appears promising including a rare sarcoma called Malignant Peripheral Nerve Sheath Tumors (MPNST). We will enroll up to 9 young children as part of a safety assessment as well as up to 21 patients with Wilms tumor and up to 15 patients with other tumors as part of this study. Support from this grant will enable us to open the trial at 8 sites across the United States.
Project: FLT3 Killer T Cell Immunotherapy for High-Risk Pediatric Leukemias
PCF is excited to announce that our grant will help to fund a planned first-in-human phase 1 clinical trial led by Sarah K. Tasian, MD, which will use a new immunotherapy to target the FLT3 receptor protein in high-risk pediatric leukemias.
Chemotherapy fails many patients with high-risk leukemias, particularly infants with acute lymphoblastic leukemia (ALL) and children with acute myeloid leukemia (AML) with high-risk genetic alterations who have poor long-term survival. Recent CAR T-cell therapies targeting the CD19 protein on ALL cells have been very effective in overcoming chemotherapy resistance and can now cure many children with relapsed ALL. However, some leukemias have learned to outsmart these therapies in various ways. One problem is that infant and childhood ALL with KMT2A genetic rearrangements are more likely to change into AML after CD19 CAR T-cell immunotherapy, which usually makes them incurable.
To date, it has been challenging to develop successful immunotherapies for pediatric AML. To address this problem, CHOP’s collaborative research team, led by Dr. Tasian and her colleague Dr. Terry Fry at Children’s Hospital Colorado, developed and tested a new CAR T-cell immunotherapy targeting an alternative protein called FLT3 that occurs at high levels in a type of AML and in infant ALL. In the laboratory, FLT3 CAR T cells were very effective at attacking and killing both AML and ALL cells in both in vitro and in vivo models of the disease. Remarkably, FLT3 CAR T cells eradicated both KMT2A-rearragned ALL and ALL that had turned into fatal AML after CD19 CAR T-cell treatment of the patient.
“Based upon our promising lab results, we aim to test FLT3 CAR T cells in pediatric patients through a first-in-human/child phase 1 clinical trial,” said Sarah K. Tasian, MD, a pediatric oncologist and Chief of the Hematologic Malignancies Program at CHOP. “Our research team has a strong track record of bench-to-bedside translation of CAR T cells for high-risk pediatric leukemias and is uniquely poised to undertake this challenge. Because of the funding provided by Pediatric Cancer Foundation, we can now work to translate our FLT3 CAR T-cell immunotherapy from promising results in the laboratory to the clinic. We hope that this clinical trial will have significant potential to credential a promising new immunotherapy against a shared target in two major types of high-risk childhood leukemias.”
The Cancer Immunotherapy Program at CHOP has revolutionized the care and the cure of children with relapsed/refractory B-cell ALL via its pioneering investigation of CD19-targeted killer T cells (CART19) that led to first-in-child FDA approval of the tisagenlecleucel cell therapy product in 2017. The program has continued to change and set new paradigms through investigation of additional CAR T cell therapies for children with B-cell ALL or lymphoma, AML, T-ALL, and neuroblastoma.
To find out more information visit: chop.edu/centers-programs/cancer-immunotherapy-program.
Project: Expansion of the Pediatric Early Phase Clinical Trials Program at Montefiore Medical Center
The Pediatric Oncology Early Phase Clinical Trials Program (PEPCTP) at the Children’s Hospital at Montefiore (CHAM) was created approximately 3 years ago after there was a realization that many of our pediatric oncology patients with relapsed/refractory disease were not able to access novel oncology therapies. This lack of access existed for two main reasons: a paucity of early phase trials at CHAM, and an incredibly underserved and under-resourced patient population that was unable to travel to other institutions where novel treatment options were available. CHAM is located in the Bronx, the most economically disadvantaged of the 5 boroughs of New York City. CHAM has a very active program, seeing approximately 120 new cancer patients each year. We know that depending on the tumor type, anywhere from 15-50% of these patients will not respond to initial treatment or will have their cancer recur following treatment. Outcomes in these patients remain very poor. The goal of the PEPCTP has been to provide a home for studies of new anti-cancer agents emanating from various consortiums and collaborative networks, pharmaceutical companies, and from basic science research within Montefiore Medical Center. We hope to continue to develop and maintain an extensive portfolio of clinical trials for our patients whose cancer has not responded to or has come back after standard therapy. These clinical trials of new agents and drug combinations provide immense hope to patients and families, as well as providing incredible data and knowledge to help advance the field of pediatric oncology. We are extremely proud of the progress we have made over the past 3 years and look forward to continuing our growth with the support of Pediatric Cancer Foundation
Project: ALPHA-PARTICLE RADIO-IMMUNOTHERAPY FOR PEDIATRIC GLIOBLASTOMA
Glioblastoma in children is an aggressive disease with a tragically short survival of a few months after diagnosis, despite treatment with multi-modal therapies. This is mainly due to the tumor location, that makes it difficult to treat aggressively without affecting the peripheral brain, as well as to the development of tumor resistance to approved therapies.
Dr. Sofou and her team propose to use an internal form of radiation, injected in the blood, that emits alpha-particles from a radioactive nucleus, to selectively target and kill tumors in the brain. Alpha-particle radiation has two key properties that makes it ideal for treatment of glioblastoma. First, it is impervious to resistance: alpha-particles act like bullets and, as they traverse tissue, they cause double strand breaks in DNA that overwhelm cellular repair, killing cancer cells independent of resistance to any other agents. Second, alpha-particles have limited penetration in tissue (short travel distance up to 4-to-5 cell diameters), limiting damage to the neighboring brain. However, cells not being hit by alpha-particles will likely not be killed. Unlike other alpha-particle radiotherapies, they engineered a therapeutic intervention that selectively delivers alpha-particle radiation in brain tumors, and effectively spreads it within the tumor volume so as to hit (and kill) almost every cancer cell. Importantly, they have strong indications that by simultaneously activating the immune tumor microenvironment, they are a step closer to completely eradicating cancer cells in the brain. If successful, their intervention will provide long-lasting remission, improve the quality of life with an excellent safety profile, and prolong survival.
Project: Enhancing CAR T Cell Persistence Through Memory Reprogramming
Dr. Weber’s research is focused on developing methods to enhance human CAR-T cell therapies for pediatric cancer by endowing T cells with improved durability and exhaustion resistance. His laboratory specializes in modeling and interrogating CAR-T cell exhaustion, a biological process that limits CAR-T cell efficacy in patients. Dr. Weber’s research will uncover molecular programs that drive human CAR-T cell dysfunction, identify targets for therapeutic intervention, and inform universal strategies that improve CAR-T cell efficacy in cancer patients. Poor CAR-T cell persistence is a major barrier to progress for CAR-T Cell therapy and limits clinical responses in children. The overall goals of his research are to identify the molecular mechanisms that govern CAR-T cell behavior – both good and bad – and leverage those insights to enhance T cell fitness for CAR-T cell therapy targeting pediatric malignancies.
Since our inception, we have contributed over $25 million to the fight against childhood cancer. Thanks in part to this support, the cure rate has risen from 50% in 1970 to over 80% today. Yet, tragically, 20% of children still do not survive! This stark reality drives our mission, and fuels our reliance on corporations, family foundations, and individual donors.
These children are our future!
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