Cancer and Blood Disorders Research

Our clinical and translational researchers are investigating:

• Alternative donor transplants for sickle cell disease using novel cell and immunotherapy to improve outcomes
• Transplants for adults with sickle cell disease (STRIDE-II)
• The late effects of transplant for sickle cell disease
• An online decision aid about treatments for sickle cell disease
• Novel cell and immunotherapy to treat or reduce the risk of graft-versus-host disease (GVHD)

Additionally, we:

• Are one of a select group of centers offering gene therapy for sickle cell disease.
• Have expertise in using CAR-T cell therapy for relapsed and refractory acute lymphoblastic leukemia (ALL).
• Have membership in the Primary Immune Deficiency Treatment Consortium (PIDTC), Pediatric Blood and Marrow Transplant Consortium (PBMTC), Blood and Marrow Transplant Clinical Trials Network (BMT CTN), Sickle Transplant Alliance for Research (STAR) and Mount Sinai Acute GVHD International Consortium (MAGIC).
• Offer haploidentical transplant with gene-modified T-cells post-transplant to aid immune recovery (Bellicum).

The focus of our basic research is to:

• Identify the molecular pathways linked to the development and evolution of acute and chronic GVHD.
• Develop novel, nongenotoxic targeted conditioning for hematopoietic cell transplantation (HCT).
• Develop immunobiology of immune dysregulation.
• Develop gene therapy for hemophagocytic lymphohistiocytosis (HLH).

Our researchers are investigating safer, less toxic and more effective methods of treatment for children with brain and spinal cord tumors.

We are members of the NIH-sponsored Pediatric Brain Tumor Consortium (PBTC) and Children’s Oncology Group (COG) Pediatric Early Phase-Clinical Trial Network (PEP-CTN), as well as the Department of Defense (DOD) Neurofibromatosis Clinical Trials Consortium. Our participation in the PBTC, COG and DOD consortia enables us to offer all of the available cutting-edge, government-sponsored national clinical trials for children with difficult-to-treat brain and spinal cord tumors. Jason Fangusaro, MD, serves as the national co-chair for PBTC and is the leader of the Aflac Cancer and Blood Disorders Center Developmental Therapeutics Program. He currently leads numerous national clinical trials through COG and PBTC. His research within pediatric brain tumors focuses mainly on low-grade gliomas and central nervous system germ cell tumors.

Within the Aflac Cancer and Blood Disorders Center, our researchers are also studying aberrant signaling pathways and novel medicines, technologies, and therapeutic combinations with the goal of improving survival and the quality of life and long-term outcomes of our patients. These studies have led directly to additional innovative clinical trials offered locally at Children’s and collaborating institutions.

Their research includes:

STAT3-targeted therapies: The lab of Tobey J. MacDonald, MD, focuses on understanding the role of the cancer stem cell survival factor STAT3 in childhood brain tumors. His lab is developing and optimizing drug combinations to target STAT3 in tumor cells and the immune system. In collaboration with Waldemar Priebe, PhD, at MD Anderson Cancer Center, the team has successfully tested the efficacy of the drug WP-1066 (Moleculin Inc.), a STAT3-selective inhibitor, in models of pediatric brain cancer. Dr. MacDonald is preparing to lead the first-in-child investigation of WP-1066 in a Phase 1 clinical trial at Children’s for children with relapsed malignant brain tumors. The CURE Childhood Cancer Foundation supported these investigations.

Infant high-risk embryonal brain tumors and childhood medulloblastoma: Claire Mazewski, MD, and Anna J. Janss, MD, PhD, have each led the two most recent COG national clinical trials for these aggressive tumors (COG studies ACNS0334 and ACNS0331, respectively). Dr. Mazewski has a long-standing interest in the treatment of infants with malignant brain tumors. The goal of these studies is to use high-dose chemotherapy and stem cell transplant in place of radiation. The focus of Dr. Janss’ research is the treatment of childhood brain cancers, particularly medulloblastoma, in a way that maximizes chances for survival but preserves quality of life and minimizes the acute and long-term toxic side effects.

Immunotherapy: Dolly Aguilera, MD, leads several clinical trials, initiated by the Aflac Cancer and Blood Disorders Center, of immunotherapy for pediatric brain tumors. Her clinical trials with interferon-modulating drugs (polyICLC and pegylated interferon) have shown some early evidence of efficacy for children with progressive low-grade glial tumors. The therapy appears to have very little, if any, toxicity. She hopes to confirm this activity and low toxicity in a national trial of polyICLC for children with NF1 and progressive low-grade gliomas that have not responded to standard therapies. In addition, she is collaborating with investigators at Augusta University in a Phase 2 trial of the immunotherapy indoximod for children with relapsed aggressive malignant brain tumors.

Experimental  therapeutics for WIP1-associated brain tumors: The lab of Robert “Craig” Castellino, MD, studies the role of the Ser/Thr protein phosphatase PPM1D (aka WIP1) in high-grade pediatric brain tumors. PPM1D amplification or overexpression occurs in medulloblastoma. Dr. Castellino has shown high PPM1D expression in Grp3/4 medulloblastoma and PPM1D amplification in a subset of Sonic hedgehog (SHH) medulloblastoma. High PPM1D expression enhances the growth of TP53 wild-type medulloblastoma, in part due to increased expression of the major p53 regulator HDM2. Dr. Castellino also recently demonstrated important cross-talk between PPM1D and SHH signaling that promotes medulloblastoma and that may be targetable using small molecule inhibitors of SHH and PPM1D.

Molecular mechanisms of medulloblastoma progression and treatment resistance: The lab of Anna Marie Kenney, PhD, is investigating molecular mechanisms driving therapeutic resistance in medulloblastoma. Using mouse models for medulloblastoma, her group has identified proteins and signaling pathways that contribute to resistance and may drive tumor recurrence. The team’s goal is to carry out preclinical studies in mouse models to determine whether manipulating these pathways may be a way to increase the effectiveness of current radiation and chemotherapies or may enable dose de-escalation to improve survivors’ quality of life. A related interest in Dr. Kenney’s lab is exploring the microenvironment in medulloblastoma, including the immune component, to determine how these cells may contribute to or impair medulloblastoma growth in manners that may be specific to the genetics of the tumors. Such findings could have future implications for prioritizing patients rel="noopener noreferrer" for immune-targeting or -enhancing therapies.

Outcomes in children with brain tumors: Lisa Ingerski, PhD, is leading critical investigations into the neurobehavioral and quality-of-life (QOL) outcomes of children with brain tumors. More specifically, in collaboration with Dr. MacDonald and investigators at Augusta University, Dr. Ingerski is evaluating QOL outcomes in children with brain tumors treated with precision medicine-based treatments and immunotherapeutics. Drs. Ingerski, Mazewski and Janss are also investigating long-term outcomes of survivors of childhood brain tumors. Together with Dr. MacDonald and investigators at Georgia State University, the group is examining the influence of genetic predispositions on long-term survivor cognitive outcomes. Dr. Janss also conducts clinical work in the Neuro-Oncology Long-Term Brain Tumor Survivor Clinic and facilitates evaluation of the medical, cognitive and neurological late effects of brain tumor treatments. Drs. Janss and Mazewski are studying the impact of genetics, diet and the gut biome on the severity of late effects of brain tumor therapy, hoping to find ways to reduce them and increase the quality of life in survivors. They are also interested in the ongoing care of adult survivors of childhood brain tumors and work with colleagues to create guidelines and pathways to support and monitor individuals as they transition from pediatric to adult neuro-oncology care.

Nanotechnology: In collaboration with researchers at the Georgia Institute of Technology, we are exploring new bioengineering strategies to improve the delivery of therapies across the blood-brain barrier (BBB) and to target the brain tumor. These investigations include the use of focused ultrasound to disrupt the BBB and nanoparticle drug carriers that hone to brain tumors. As part of our precision medicine program for brain tumors, we are also employing uniquely designed microfluidic “chips” to investigate the properties of circulating cancer cells captured from the blood of brain tumor patients and screen in real time the efficacy of new drugs and drug combinations directly on the tumors obtained from patients.

Our grant-funded clinical research studies aim to better understand, detect and manage late effects of cancer therapy. Additionally, we aim to improve our ability to educate, empower and promote health in survivors.

Health-related outcomes

Our researchers are exploring:

• Patient-reported outcomes and quality of life
• Type and severity of late effects most commonly seen in survivors
• Cardiac late effects and models of coordinated care with cardiologists
• Ovarian and testicular late effects and how they relate to delayed puberty and infertility
• Skin cancer and the genetics of skin cancer
• The impact of treatment on body mass index (BMI), both underweight and overweight
• Physical activity and its impact on adolescent survivors’ health and quality of life using technology (smartphones, Fitbit Flex) and community-based exercise programs (local YMCAs)
• Survivor- and family-related barriers to participation in survivor healthcare
• Risky health behaviors in adolescent and young adult survivors and how to encourage a healthy lifestyle
• How to prevent late effects through early interventions (medications or physical therapy)
• Research methodology and statistical applications around clinical outcomes research

Our researchers also have leadership roles in the Children’s Oncology Group Long-Term Follow-Up Guidelines Task Force and the International Late Effects of Childhood Cancer Guideline Harmonization Group. These groups include national and international experts in survivorship who develop the guidelines used to help detect and prevent late effects in survivors.

Communication

We’re seeking new ways to inform and educate survivors about their health risks and improve their health and quality of life by:

• Tailoring evidence-based communication strategies to increase survivors’ knowledge about their care and adherence to long-term follow up healthcare.
• Developing methods of communicating infertility risk to adolescent and young adult survivors.
• Educating Georgia primary healthcare providers about survivor care.
• Using social media to improve adolescent and young adult transition of care.

Cancer SurvivorLink

Cancer SurvivorLink is an online resource designed to supporting continuing care for survivors of childhood cancer. It provides educational materials to improve awareness of survivorship issues, best practices in survivor care, and a secure way to electronically store and share health documents.

Our researchers are studying how SurvivorLink can improve access to survivor care and patient knowledge about important survivor issues. We are:

• Evaluating the abilities of young adult patients (18 to 21 years old) to use SurvivorLink to manage their health records.
• Assessing the impact of SurvivorLink on adherence to cancer survivor care and late-effects visits and screening.
• Using iterative feedback to continuously enhance and improve SurvivorLink.

Survivor health self-management and transition to adult care

COG recommends that survivors receive ongoing survivor-specific care throughout their lives. When pediatric survivors grow up and become young adults, they need to be ready to manage their survivor care and the transfer of care from Children’s and the Aflac Cancer and Blood Disorders Center to adult doctors. Our team is conducting research to understand how we can best help survivors get ready for these responsibilities. Our projects focused on survivor health self-management and transition include:

• Adapting and validating the Readiness to Transition Questionnaire, a survey that measures transition readiness and that assesses shifts in healthcare responsibility from parents to adolescents.
• Characterizing barriers to the transition of survivor care and the subpopulations of survivors at risk for nonadherence post-transfer.
• Evaluating the impact of transition clinics and the introduction of adult providers on successful transition to adult care.
• Establishing a network of college health providers who are knowledgeable of the needs of survivors at colleges and universities throughout Georgia.

Partnerships

• Childhood Cancer Survivor Study: This National Cancer Institute–funded study explores health problems that develop later in life as a result of cancer treatment, also known as late effects.
• Consortium for Pediatric Intervention Research: Consortium to support the feasibility of delivering intervention and to develop opportunities for definitive clinical trials.

Gene therapy is a technique that uses genes to treat or prevent disease. Using this therapy, researchers insert one or more corrective genes, which have been designed in the lab, into the genetic material of a patient’s cells to correct the effects of a disease-causing mutation.

Our basic research in gene therapy focuses on inherited diseases, such as hemophilia, sickle cell disease and hemophagocytic lymphohistiocytosis (HLH), and cancer.

Inherited diseases

Our researchers are focusing on introducing corrective genes into bone marrow stem cells to treat several diseases caused by single-gene defects.

Recombinant viral vectors, which are used to deliver genetic materials into cells, have the potential to be a cure for hemophilia A, sickle cell disease and HLH.

Using high-expression elements and optimized gene sequences can enhance protein expression and enable the use of several gene-transfer platforms. For example, enhanced expression of factor VIII (fVIII, the protein mutated in hemophilia A) can reduce the cost of recombinant fVIII production. Approximately 70% of patients with hemophilia A aren’t treated due to cost constraints, so a reduction in the cost of producing fVIII will increase access to the protein.

Cancer

Our researchers are pioneering an approach to treat cancer using novel immunotherapies—treatments that use the patient’s own immune cells to kill cancer.

• One strategy that is being developed has been termed drug resistance immunotherapy. Our scientists are exploring whether immunocompetent cells (those with a normal immune response) can be genetically engineered to withstand the toxic effects of chemotherapy and, if so, whether the genetic modification makes it possible to use both chemotherapy and cell-based immunotherapy. The ability to use both types of treatment, rather than a single approach, could improve survival rates.
• A second approach is to genetically engineer immunocompetent cells with genes that direct the cellular-killing mechanisms to the cancer. This approach, termed chimeric antigen receptor technologies (CAR-T) modified T-cells, has been successfully used to treat cancers originating in the blood. Our researchers are focused on cancers that affect children, such as neuroblastoma and leukemia.

The focus of our clinical research on hemostasis (stoppage of bleeding or hemorrhage) and thrombosis (blood clotting) includes hemophilia and von Willebrand disease or low von Willebrand factor (VWF), rare bleeding disorders, qualitative platelet disorders, blood clots and pulmonary emboli (blood clots in the lungs).

Hemophilia

Hemophilia is a rare bleeding disorder in which the blood doesn’t clot normally due to defective or deficient factor VIII or factor IX that may lead to internal bleeding into muscles and joints. We are involved in a variety of clinical trials and basic science research:

• Treatment of severe hemophilia A with primary and secondary prophylaxis, which involves the infusion of new clotting factors to prevent bleeding
• Risk factors due to low bone density in hemophilia patients
• Mechanisms of development of factor VIII inhibitors (antibodies against factor VIII), which prevent blood from clotting normally
• Liver-directed gene therapy and stem cell–based gene therapy for hemophilia A
• Clinical trial evaluating a new subcutaneous nonfactor product in babies with severe hemophilia A
• Clinical trial evaluating a new regimen (Atlanta protocol) for treating inhibitors in hemophilia A
• Variation in bleed control of extended half-life factor IX products and extravascular distribution
• Bleeding patterns and overall clinical management of children and adults with moderate to severe hemophilia A in Mexico City

In addition, researchers are studying:

• Risk factors for the development of thrombosis (blood clots) in young children
• The optimal duration of anticoagulation therapy in children with newly developed blood clots
• Presentation and bleeding tendency in children and adults with severe von Willebrand disease
• Treatment of patients on emicizumab with low-dose activated prothrombin complex concentrate (aPCC)

Our basic and translational research focus includes:

• Mechanisms of factor VIII inhibitor formation and its ability to cause disease
• Regulation of factor VIII expression
• Development of factor VIII products, which prevent bleeding
• Mechanisms of platelet activation and clearance and of VWF

Our team is investigating safer, less toxic and more effective methods of treatment for children with leukemia (cancer of the blood) and lymphoma (cancer of the lymphatic tissues). We also apply precision medicine. Our physicians are leaders in multiple national consortia and are committed to personalized approaches for children, adolescents and young adults with leukemia and lymphoma.

The Aflac Cancer and Blood Disorders Center Leukemia Biorepository is led by Sharon Castellino, MD, MSc, and Deb DeRyckere, PhD, and is a resource for the study of rare leukemia.

Our researchers are studying aberrant signaling pathways, novel medicines and combinations. Their research includes: 

• MERTK-targeted therapies: The lab of Douglas K. Graham, MD, PhD, and Dr. DeRyckere focuses on understanding roles for the MERTK protein in leukemia and other cancers. They are developing and optimizing drugs to target MERTK in tumor cells and the immune system. MRX-2843, a first-in-class MERTK-selective inhibitor resulting from this effort, is currently in Phase 1 clinical trials.
• CALM-AF10 biology in leukemia: The lab of Daniel S. Wechsler, MD, PhD, and Waitman Aumann, MD, studies the role of CALM-AF10 in the development of leukemia. The lab is focusing on novel therapeutic interventions for aggressive CRM1- and HOXA-dependent leukemias. 
• Tyrosine kinase inhibitor (TKI) therapies: Dr. Sharon Castellino and Himalee Sabnis, MD, MSc, are studying the late effects of TKI therapy on growth in children and how these therapies may impact immune function and long-term cardiovascular health in pediatric patients.
• Outcomes in patients with leukemia and lymphoma: Dr. Sharon Castellino and her team use epidemiological methods and patient-reported outcomes to evaluate side effects of therapy and long-term health for populations with leukemia or Hodgkin lymphoma. She also studies late effects on the heart in childhood cancer survivors to finding biomarkers for cardiovascular late effects.
• Cancer control and supportive care during leukemia therapy: Tamara Miller, MD, MSCE, is focused on understanding side effects of treatment for pediatric leukemia during therapy. She is using electronic medical record data and bioinformatics to develop novel approaches for reporting on clinical trials. This will improve our understanding of the rates of side effects and enhance epidemiological approaches to studying the benefits of therapy for pediatric leukemia.
• Experimental therapeutics for PTPN11-associated leukemia: The lab of Cheng-Kui Qu, MD, PhD, studies molecular mechanisms by which activating mutations of PTPN11 (SHP2) cause childhood juvenile myelomonocytic leukemia and other leukemia. Research in his lab is focused on understanding cell signaling and metabolic regulation of cell development and leukemogenesis with a focus on tyrosine and lipid phosphatases in normal hematopoietic stem cells and leukemic stem cells.
• Chronic inflammation, immunity and leukemia development: Curtis Henry, PhD, studies the role of chronic inflammation, aging and obesity on leukemogenesis, immunity and therapeutic responses. Identified modulators that induce resistance to chemotherapies or immunotherapies are being examined to determine their therapeutic potential in high-risk populations.
• Molecular mechanisms of leukemogenesis and treatment resistance: The lab of Christopher Porter, MD, studies WEE1 as a chemosensitizing target in acute myeloid leukemia. The lab is also studying the transcription factor ETV6 for its role in leukemogenesis. 
• Targeting MDM2 in cancer treatment: Muxiang Zhou, MD, and Lubing Gu, MD, are searching for small-molecule compounds that can induce degradation of MDM2 oncoprotein and thereby lead to novel targeted therapies.
• Normal and leukemic cytokine signaling: Kevin Bunting, PhD, is studying the biology of signal transducer and activator of transcription 5 (STAT5) and its role in normal production of blood cells. His lab is also focused on targeting persistently activated STAT5 in leukemia using novel calcium-modulating drugs delivered to the bone marrow via receptor-targeted nanoparticles. In addition, Dr. Bunting is studying the Grb2-associated binding (Gab) protein family and the role of these proteins in hematopoietic stem cell homeostasis and immune cell activation through compound mutant mice lacking Gab1, Gab2 and Gab3.
• Chimeric antigen receptor (CAR)-based cellular therapies: Sunil Raikar, MD, is working on developing novel CARs specifically for T-cell leukemia. Dr. Raikar is utilizing innovative CRISPR/Cas9 genome editing technology to knock down surface expression of target antigens on CAR-T cells, thus enabling its use in T-cell disease.

Innovative therapy in pediatric leukemia and lymphoma:

• Dr. Sabnis is leading a Phase 1 clinical trial using everolimus with chemotherapy to improve survival in patients with relapsed T-cell acute lymphoblastic leukemia or lymphoma (AflacLL1602/
• Melinda Pauly, MD, is the institutional principal investigator in the pediatric leukemia precision-based therapy (LEAP) consortium, which allows us to offer precision medicine approaches to children with leukemia.
She is also a principal investigator in the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium, which allows us to offer promising new therapies to children with relapsed and refractory leukemia.

National leadership in COG:

John Bergsagel, MD, is a leader on the COG Committee for Chronic Myelogenous Leukemia (CML), and William Woods, MD, is a leader on the Acute Myelogenous Leukemia (AML) Committee. Dr. Sharon Castellino and Frank Keller, MD, are leaders on the Hodgkin Lymphoma Committee, designing new trials for reducing the therapy burden. Drs. Pauly and Raikar are members of the Acute Lymphoblastic Leukemia (ALL) Committee. Drs. Graham, Tamara Miller and Sabnis are members of the AML Committee.

Sickle cell disease is an inherited blood disorder that causes red blood cells to change shape.

Our researchers are seeking ways to improve outcomes and quality of life for children with this disease through a blood and marrow transplant (BMT) and transfusion medicine (the transfer of blood and blood components).

Our clinical and translational researchers are seeking a cure and looking for ways to improve treatments and the quality of life for children with the disease. They’re studying:

• Health outcomes and new therapies, such as hydroxyurea (a medicine) and stem cell transplantation
• Prevention of sickle cell disease complications, such as kidney damage, pain and stroke
• Red blood cell alloimmunization, an undesired immune response that occurs after BMT
• Micronutrients (vitamins and minerals)

Our basic researchers are exploring:

• Whether angiogenic growth factors (which promote blood vessel formation) play a protective or destructive role in the structure of the lining of blood vessels in the lungs and in leg ulcers in sickle cell disease
• Antioxidant enzymes that protect the vessels in the lungs from oxidant-induced changes in the structural resistance of vessels in sickle cell disease pulmonary hypertension
• Cellular interactions in sickle cell disease to determine their relative contributions to blocked blood vessels, blood cell rupture or destruction and to the formation of reactive oxygen species (a natural byproduct of normal oxygen metabolism)
• The development of sickle cell disease in respect to the generation, prevention and treatment of organ dysfunction—specifically, the role of endothelial (inner lining of blood vessel) cells in the generation of kidney disease
• Genetic association studies to identify markers that influence the incidence of pulmonary hypertension and leg ulcers in sickle cell disease
• Nanotechnology—the study and creation of targeted, molecular-size nanoparticles to treat diseases—which has the potential to revolutionize the treatment and care of childhood conditions and could ultimately lead to cures

A solid tumor is an abnormal clump of cancer cells that do not contain any liquid or cysts. These can occur in the bones, tissues and organs.

Our researchers are looking for new ways to improve the health and quality of life for children with solid tumors by exploring:

• New medicines, including immunotherapies and targeted therapies, to treat a child’s cancer when it comes back or when it doesn’t respond to standard-of-care treatment
• New combinations of medicines
• Medicines that cause fewer side effects while allowing patients to maintain a good quality of life
• Mechanisms involved in chemoresistance, a trait found in some cancers that makes them less likely to respond to standard-of-care treatment
• High-risk neuroblastoma therapy and outcomes, including targeted radiotherapy MIBG

Our basic research focus includes:

• Improving the effectiveness of chemotherapy in patients with neuroblastoma or kidney cancers (e.g., Wilms tumor, rhabdoid tumor and renal medullary carcinoma)
• Developing and testing novel immunotherapies for neuroblastoma
• Validating new cancer agents for neuroblastoma, kidney cancers and other difficult-to-treat cancers
• Understanding the cellular signaling networks that cancers such as neuroblastoma and kidney cancers use to remain malignant cancers

Transfusion medicine involves transfusion of blood or blood components. It’s used to treat diseases such as bone cancer, leukemia, sickle cell disease and others.

Our clinical researchers are exploring ways to improve transfusion treatments and minimize potential complications by investigating:

• Transfusion-transmitted cytomegalovirus, a common virus that causes infection and can be dangerous for people with weakened immune systems
• Potential adverse effects of stored red blood cells
• Alloimmunization (an undesired immune response that can occur after transfusion) in sickle cell patients
• Development of a pediatric transfusion-medicine training curriculum
• Transfusion medicine and hemostasis (stopping bleeding or hemorrhage) network trials

Our basic research focus includes:

• Red blood cell alloimmunization
• BMT rejection primed by red blood cell or platelet transfusions
• Red blood cell autoimmunity (an immune response against an organism’s own cells and tissues)
• Red blood cell antigen loss