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Project: The Initiative for Drug Delivery Innovation is developing novel methods to improve drug delivery methods so that targeted therapies and immunotherapy become more effective.
Brain tumors remain the leading cause of death in children with cancer. Children with newly diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) and glioblastoma, or relapsed malignant brain tumors (medulloblastoma, ependymoma, high-grade glioma), have an extremely poor prognosis. Despite advances in the treatment of adult cancers, researchers have failed to make significant progress in treating children with brain cancer. Therefore, as a team at Columbia University Medical Center, they have focused their efforts to discovering better methods of drug delivery that would ensure a more precise and targeted delivery while reducing systemic long-term effects for patients. Convection Enhanced Delivery (CED) is a method by which medicine can be infused directly into the brain tumor under controlled pressure so that maximum diffusion of the drug is achieved. And Focused Ultrasound with microbubbles (FUS) is a non-invasive method of “opening” the blood brain barrier with ultrasound micro-waves, allowing medicines to enter in sufficient concentrations.
Project: Pediatric Cancer Foundation Developmental Therapeutics Program (PCFDTP) at Columbia University Irving Medical Center (CUIMC)
Pediatric Cancer Foundation Developmental Therapeutics Program (PCFDTP) is to develop and test cutting-edge treatment strategies for children with incurable cancer, resistant to conventional therapies. The PCFDTP also serves as an incubator for precision cancer medicine to provide individually tailored therapies based on a patient’s molecular and genetic characteristics while also serving as a platform for laboratory investigations to identify the various abnormal molecular pathways underlying cancer growth and other molecular changes that may represent novel therapeutic targets for pediatric drug development. Columbia University Irving Medical Center is one of only 21 institutions in North America, and the only institution in the NY, NJ, CT tristate region, approved to offer early drug development trials from the National Cancer to children with relapsed/refractory cancer. PCFDTP provides oversight for Phase I/II trials sponsored by the TACL consortia for childhood leukemia/lymphoma as well as investigator-initiated and pharmaceutical-sponsored studies. This program also provides patient-centered services for children whose cancers are resistant to conventional therapies by providing disease directed treatment, ideally on an early phase investigational clinical trial. Approximately 75% of our patients receive treatment for solid tumors while the remaining 25% receive treatment for leukemia and lymphoma.
In addition, the Division is leading the way in the development of precision cancer medicine at CUIMC and nationally since 2013 when the Precision in Pediatric Sequencing (PIPseq) program was established within the Division. As one of only four pediatric oncology programs worldwide to use comprehensive sequencing approaches for relapsed/refractory and high-risk pediatric cancers, they are the first program to use these sequencing approaches to make informed real time treatment decisions.
Project: Development of immunologic therapy for the treatment of pediatric solid organ malignancies, with a focus on Wilms tumor
Outcomes for childhood cancers have improved substantially over the past four decades due to dose intense multimodality and multi-agent interventions. This effect, however, remains largely restricted to localized tumors, leaving a vast treatment gap for advanced tumors as well as refractory and relapsed malignancies. Wilms tumor is the most common primary renal tumor and the third most common solid malignancy in children. Long-term survival now exceeds 90% yet despite favorable histology, tumor recurrence is observed in 15% of patients and survival rates are substantially lower. Approximately 50% of patients with anaplastic histology experience recurrence and/or advancement of disease, and with advanced disease, only 50% survive to adulthood. Studies are focused on further identification of RNA expression patterns (through bulk and single-cell sequencing) and differential gene expression of additional patients, with the goal of developing targeted immunotherapy treatment options for patients with Wilms tumor. Ongoing and future work are focused on evaluating the tissue immune responses of pediatric solids tumors, including protective immunity, and investigating mechanisms of disease, immunoregulation, and tumor surveillance.
Project: Precision Rabbit Anti-Thymocyte Globulin Dosing to Improve the Survival Chances after Hematopoietic Cell Transplantation
Allogeneic Hematopoietic Cell Transplantation (HCT) or Bone Marrow Transplantation is used to potentially cure chemotherapy refractory (hard-to-treat) childhood hematological cancers like leukemia or lymphoma. Relapse of disease and non-relapse mortality (NRM; defined as death without relapse), are major causes of failure and decrease life expectancy after HCT. Sufficient immune reconstitution of CD4+ T cells (essential host cells for fighting infections and controlling disease) after HCT was recently found to be the driver of improved survival in patients undergoing HCT. The agent used in the preparative regimen prior to HCT that has the greatest impact on the CD4+ T cell reconstitution is called rabbit anti-thymocyte globulin (rATG). This agent has an unpredictable clearance in individual patients when the dose is based on weight of the patient, as it typically is. By understanding the optimum rATG exposure (Area under the Curve: AUC) in blood-levels, they can develop individualized dosing nomograms that will help deliver the best dose for each patient. Strategies to personalize dosing of rATG or precision dosing may have dramatic effects on the immune reconstitution and subsequently survival chances. The goal of this study is to find the optimum rATG exposure that is required for predictable adequate CD4+ immune reconstitution to increase survival chances. They have access to the clinical data and biospecimens of a unique, large cohort of pediatric and young adult patients (343) treated for hematological malignancies. This unique project will provide valuable information towards our goal.
Project: The Role of S100A8/9 Driven Clonal Evolution in Childhood B Acute Lymphoblastic Leukemia
While the prognosis for children with acute lymphoblastic leukemia has improved dramatically, up to 20% of children relapse and their prognosis remains poor. Their lab has focused on understanding how leukemia cells evade therapy leading to the discovery of relapse-specific mutations that drive relapse. However, these mutations can explain only a minority of relapses. Recently, they made the startling discovery that a majority of relapsed blasts contain three novel super enhancers. These are broad regions of highly active DNA-protein networks that drive expression of genes. One such SE guides expression of two proteins, S100A8 and S100A9 that are well known to be secreted by inflammatory cells to augment immunity. A role in cancer has been suggested but never proven. The preliminary data leads them to hypothesize that leukemia cells secrete these proteins to remodel surrounding normal cells to form a protective niche shielding them from therapy. They will test this hypothesis in two aims: genetically engineered cell lines with and without S100A8/9 expression will be tested for growth and response to chemotherapy in two different preclinical mouse models and they will examine changes in the immune microenvironment in response to S100A8/9 in preclinical models and in diagnosis/relapse paired leukemia samples. These results offer the possibility of targeting the microenvironment to prevent relapse. This is the first study showing that the majority of relapses might be due to changes in the microenvironment. Most importantly there are agents that can block the receptors to which S100A8/9 proteins bind thereby enhancing the therapeutic relevance of their findings.
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 the 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 mimic that seen in human patients with DBA.
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: Phase II Study Combining Cryoablation Therapy and Dual Checkpoint Inhibition in Relapsed/Refractory Pediatric Solid Tumors
Many children with bone and soft tissue cancers are not cured and will die. Immune checkpoint inhibitors are medications that cause white blood cells in a patient (called T-cells) to kill cancer cells. They are safe in children but have not been shown to kill pediatric solid tumors when given alone, because these tumors do not have a lot of T-cells. In order to improve the action of checkpoint inhibitors against pediatric solid tumors, another treatment needs to be added to increase the number of T-cells in the tumor. Cryoablation therapy involves inserting a needle into a tumor to freeze and kill tumor cells. It causes T-cells to enter tumors and may help checkpoint inhibitors kill tumors. In this study, patients with pediatric solid tumors that come back after treatment will receive checkpoint inhibitors nivolumab and ipilimumab and undergo cryoablation therapy to one tumor target. They will follow the tumors over time to see if they shrink. They believe the cryoablation will help checkpoint inhibitors kill the tumor that received cryoablation as well as other tumors due to the immune system’s response. They will test tumor tissue and blood from patients before and during treatment to examine how the treatment affects white blood cells in the body. Although cryoablation and checkpoint inhibitors have been found to be a safe therapy individually for children, this is the first known clinical trial studying this combination in children. They expect that this combination will be safe and effective in children with solid tumors.
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 our 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: 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.