Research Summary 2009
Research Summary 2009
Leukemia
The majority of children who are diagnosed with acute lymphocytic leukemia (ALL) will be cured of their disease by receiving standard treatment. However, those whose cancer relapses or who are diagnosed with acute myelogenous leukemia (AML) have a significantly worse prognosis. At the Children’s Cancer Hospital at MD Anderson, leukemia researchers are focusing their labs on improving survival for these high-risk patients.
Drug Inhibits Leukemia Growth More Than 50 Percent
Presented at the American Society of Pediatric Hematology Oncology’s Annual Meeting
In April, Patrick Zweidler-McKay, M.D., Ph.D., from the Children’s Cancer Hospital and Mauricio Ghisoli, M.D., presented pre-clinical research on an anti-cancer agent, AZ23, which
caused a 50 percent reduction of AML cells in mice with no immune system and a 60 percent reduction in those with an immune system. AZ23 works by turning of a receptor that promotes the growth of leukemia cells.
Drug Combination Five Times More Powerful Against Leukemia
Published in BLOOD
Joya Chandra, Ph.D., from the Children’s Cancer Hospital, and graduate student Claudia Miller have found in pre-clinical tests that combining the novel proteasome inhibitor, NPI-0052, with the histone deacetylase (HDAC) inhibitor, vorinostat, is five times more effective against leukemia than either cancer agent alone. The two drugs share similar functions, which creates a synergistic effect against the leukemia cells.
Decreasing Cardiotoxicity of Common Leukemia Drugs
Presented at American Society of Hematology’s Annual Meeting
Anthracyclines are a group of chemotherapy agents that have been instrumental in improving childhood cancer survival rates over the past 40 years, but they also are highly toxic to a patient’s cardiovascular system. Chandra and Joy Fulbright, M.D., have discovered in their laboratory that a new anthracycline, amrubicin, causes less cardiotoxicity than other drugs in its class. They believe this discovery relates to oxidative stress, which is damaging to healthy cells, and that administering an antioxidant with the agent will further reduce cardiotoxicity.
Use Notch to Induce Leukemia Cell Death
Presented at American Society of Hematology’s Annual Meeting
Previous studies done at the Children’s Cancer Hospital have illustrated the importance that Notch signaling has on suppressing B-cell leukemia and AML. Notch is a receptor found on both normal and leukemia cells, and when turned on by a specific ligand, the receptor causes certain cancerous cells to die.
Most recently, Children’s Cancer Hospital researchers Zweidler-McKay and Sankaranarayanan Kannan, Ph.D., found a way to imitate the behaviors of Notch using a synthetic peptide developed in their laboratory. Future studies will test this novel peptide in mouse models to see if it will turn on the Notch signal in B-cell leukemia and AML and induce cell death.
Lymphocytes Help Predict a Patient’s Prognosis
Presented at American Society of Hematology’s Annual Meeting
Previously, Zweidler-McKay has shown the importance of the absolute lymphocyte count (ALC) in evaluating a patient’s prognosis. He has completed a nationwide retrospective analysis of pediatric patients studying ALC data along with another prognostic factor, minimal residual disease (MRD). Researchers were able to predict prognosis even more efficiently. Patients who tested negative for MRD and had a high ALC at diagnosis had a 99 percent 7-year survival rate while those who tested positive for MRD and had a low ALC had a 41 percent overall survival rate.
Zweidler-McKay will co-chair a Children’s Oncology Group study in 2010 to better determine which patients would benefit from more aggressive treatment at diagnosis.
Brain Tumors
New Protocol Improves Outcome for High-Grade Glioma Patients
Published in Cancer
Johannes Wolff, M.D., from the Children’s Cancer Hospital, is first author on a study that found a better way to treat pediatric patients with high-grade glioma. Using a new protocol, HIT-gBM-c, that consists of surgery (when possible), radiation and a chemotherapy regimen, researchers found that patients who had a complete surgical resection of their tumor achieved higher survival rates on the new protocol. Specifically, the 5-year overall survival rate for patients with complete resection on the protocol was more than 60 percent compared to less than 20 percent on the older protocol.
New Standard Treatment Established for Rare Brain Tumor
Presented at International Society of Pediatric Oncology’s Annual Meeting
Wolff also led a team of researchers in the largest-ever collaborative study addressing the treatment of a rare pediatric brain cancer called choroid plexus tumors. The findings suggest a new standard protocol could improve survival nearly two-fold for pediatric patients with the disease. The protocol, consisting of three chemotherapy agents and radiation, had projected overall survival rates of 93 percent at one year, 82 percent at five years, and 78 percent at eight years.
With the data they collected, the team can tell which patients are prone to do better and which ones have a poor prognosis. In addition, they have established a standard protocol for these patients.
HDAC Inhibitor Shows Potential Against Medulloblastoma
Published in the Journal of Neurooncology
Vidya Gopalakrishnan, Ph.D., dedicates her research to studying brain tumors at the Children’s Cancer Hosptial. This year, she uncovered a mechanism that assists medulloblastoma tumor cells in evading cell death.
Gopalakrishnan’s pre-clinical research showed that medulloblastoma cells have decreased expression of the death receptor, D4, compared to healthy tissue. She found that the expression could be increased with the HDAC inhibitor, MS-275, which resulted in increased cell death. Cell death was further magnified with the addition of TRAIL, a treatment that targets tumor cells and leaves normal cells largely unaffected. Gopalakrishnan hopes to minimize long-term side effects by finding less toxic ways, such as TRAIL, to target brain tumor cells.
Researchers Find Way to Cross Blood-Brain Tumor Barrier and Deliver Therapy
Published in Cancer Biology & Therapy
Most cancer agents fail to improve survival for patients with brain tumors because the agents fail to cross the blood-brain tumor barrier (BTB) at high enough doses. Recently, Tribhawan Vats, M.D., published a study that showed a potential way for physicians to overcome BTB.
Using a calcium-dependent potassium channel agonist, NS-1619, in the laboratory, the research team was able to deliver anti-cancer agents such as Temozolomide and Herceptin through the BTB at higher volumes to attack the tumor. The combination treatment of Temozolomide and Herceptin also showed improved anti-tumor effect compared to either drug alone.
Neuroblastoma
Novel Cancer Drug Reduces Neuroblastoma Growth by 75 Percent
Presented at the American Society of Pediatric Hematology Oncology’s Annual Meeting
Research conducted by Patrick Zweidler-McKay, M.D., Ph.D., and his team showed for the first time that the MD Anderson-developed drug, 3-BrOP, reduces neuroblastoma growth by more than 75 percent as a single agent. The study, conducted with human neuroblastoma cells transplanted into mice, showed how 3-BrOP, a glycolysis inhibitor, starved the cancer cells to death by shutting down their main energy source, glucose.
“As we explore alternative options to standard chemotherapy agents, we are finding drugs, like 3-BrOP, that have the potential to destroy cancer cells while leaving healthy cells unharmed,” said Zweidler-McKay. “These drugs can often enhance the efficacy of other treatments, potentially leading to more successful combinations and better outcomes for our young patients.”
New Drug Inhibits Neuroblastoma Blood Supply in Pre-Clinical Tests
Presented at the American Society of Pediatric Hematology Oncology’s Annual Meeting
Researchers Alejandro Levy, M.D., and Zweidler-McKay from the Children’s Cancer Hospital have found a way to prevent blood vessels from aiding the growth of neuroblastoma, using the drug AMD3100. In pre-clinical tests on mice, it has reduced human neuroblastoma tumor growth by more than 75 percent.
Zweidler-McKay, senior investigator on the study, reported that AMD3100 doesn’t kill neuroblastoma cells directly, but it prevents tumors from growing rapidly by disrupting their blood supply. There is also the possibility that this therapy could help prevent neuroblastoma metastasis to the bone marrow, but Zweidler-McKay says more studies are needed to investigate the theory.
First-Ever Trial Opened to Test Drug Combination in Children With Neuroblastoma
Presented at the American Society of Pediatric Hematology Oncology’s Annual Meeting
Peter Zage, M.D., Ph.D., has discovered a new drug combination that significantly hinders tumor growth in neuroblastoma. By combining a novel multi-kinase inhibitor, vandetanib, with 13-cis-retinoic acid (CRA), a drug often used for severe acne, researchers from the Children’s Cancer Hospital at MD Anderson found that the two therapies reduced neuroblastoma tumors by 86 percent in pre-clinical tests.
Zage, who specializes in neuroblastoma at the Children’s Cancer Hospital, received this year’s Young Investigator Award from ASPHO and was selected to present his research in a special platform session.
Currently, there is a Phase I clinical trial, a first in the world, open for children with multiple-relapsed neuroblastoma to further study the new therapy combination.
Bone Tumors and Other Solid Tumors
MEPACT Improves Osteosarcoma Survival, First Time in 20 Years
In early 2009, the European Commission approved a therapy for pediatric patients with non-metastatic, resectable osteosarcoma based on clinical studies led by researchers at the Children’s Cancer Hospital and the Children’s Oncology Group.
MEPACT (mifamurtide, L-MTP-PE) is an immune-based therapy, that when combined with chemotherapy, resulted in approximately a 30 percent decrease in the risk of death with 78 percent of patients surviving more than six years following treatment. This therapy is the first in more than 20 years to improve the long-term survival of osteosarcoma patients.
Eugenie Kleinerman, M.D., head of the Children's Cancer Hospital, was the first investigator to translate the drug from preclinical testing to a Phase I clinical trial in humans and also led the Phase II clinical trial. Kleinerman hopes by giving MEPACT to newly diagnosed patients, they will prevent relapse by taking care of any remaining tumor cells after chemotherapy.
Aerosol Chemotherapy Being Further Investigated to Target Lung Metastases
Published in the Journal of Aerosol Medicine and Pulmonary Drug Delivery
When osteosarcoma metastasizes to the lungs, a child’s chances of survival significantly decrease. Incorporating methods used in asthma treatment, investigators from the Children’s Cancer Hospital are combating pulmonary metastases by delivering chemotherapy directly to the lung and minimizing systemic toxicity. Patients are able to receive their therapy at home using this aerosol-based system.
Recently, Peter Anderson, M.D., Ph.D., from the Children’s Cancer Hospital, teamed up with a group of veterinarians to study aerosol gemcitabine in canines with osteosarcoma. The results showed the efficiency of aerosol gemcitabine against pulmonary metastases of osteosarcoma and supported further investigation of the drug in humans.
Clinicians Find Arsenal of Tools to Combat Cardiac Metastases in Sarcoma Patients
Presented at the American Society of Clinical Oncology’s Annual Meeting
Dennis Hughes, M.D., Ph.D., dedicates his research to fighting pediatric bone tumors. One focus of his research is investigating ways to attack cardiac metastases, which has earned him recognition at national oncology meetings. Using chemotherapy, radiotherapy, novel agents, cardiac tumor resection and neurosurgery, Hughes has illustrated how cardiac tumors are best managed. He is currently working with physicians at the Children’s Memorial Hermann Hospital to develop a multi-disciplinary pediatric cardiac tumor program for patients with malignant and benign cardiac tumors.
Novel Surgery Gives Patients Hope Against Rare Cancer
Desmoplastic small round cell tumor (DSRCT) is a soft tissue cancer primarily occurring in the abdominal area with a poor survival outcome for pediatric patients.
Wanting to improve outcomes for DSRCT patients, Hayes-Jordan translated an adult surgical procedure called continuous hyperthermic peritoneal perfusion (CHPP) so that it could be performed in children. She is the first and only surgeon performing this novel procedure on children in North America.
As part of the CHPP procedure, Hayes-Jordan surgically extracts as many tumors as possible before running heated chemotherapy agents through the abdominal area to kill remaining tumor cells. Hayes-Jordan reported that patients receiving this surgery have more than a 70 percent chance of surviving for three years or more compared to the 20 percent survival rate of those who don’t receive the procedure.
Retinoblastoma
Four Medical Institutions Collaborate to Form New Retinoblastoma Center
Doctors and researchers from the Children's Cancer Hospital at MD Anderson, Texas Children's Cancer Center, the Methodist Hospital and Baylor College of Medicine have joined together in the fight against retinoblastoma, a childhood cancer of the eye. The result of their collaboration is the Retinoblastoma Center of Houston.
Together these specialists are advancing retinoblastoma treatment through ground-breaking research and innovative therapies. The center is the first of its kind in the southwest region of the United States and is the only one in the nation using gene therapy in clinical trials for retinoblastoma. Patients also have access to genetic testing and a special form of radiation called proton therapy.
Cell Therapy
As pediatric oncologists and researchers are seeking less toxic, more efficient ways to fight cancer, they are turning to immunotherapy. The Children’s Cancer Hospital is part of the world’s largest cell therapy program and focuses its research on providing vital options to fight a variety of cancers.
Enhancing the Power of Natural Killer Cells to Fight Cancer
Presented at the American Society of Hematology’s Annual Meeting
Natural killer (NK) cells are white blood cells that now are being harnessed to help patients fight cancer. Dean Lee, M.D., Ph.D., from the Children’s Cancer Hospital focuses much of his research on finding ways to maximize the power of these immune cells. In the past year, Lee and his team have discovered ways to genetically modify NK cells in the laboratory so that they carry various antibodies that target specific cancers, such as leukemia and neuroblastoma.
In addition, his lab has developed a way to generate 100 times the amount of NK cells for transfusion, compared to the traditional apheresis method. They also discovered through their studies that a common leukemia drug, decitabine, can be highly toxic to NK cells at high doses. They are now further investigating the optimal dosage of decitabine that can be used to kill leukemia cells while minimizing damage to NK cells.
Modifying T Cells to Maximize Efficiency Against Cancer
Presented at the American Society of Hematology’s Annual Meeting and the BMT Tandem Meetings
Modifying T cells to target tumors is a promising approach for adoptive cell therapy, according to Laurence Cooper, M.D., Ph.D., at the Children’s Cancer Hospital. Similar to methods used with NK cells, Cooper and his team are genetically modifying T cells to carry antibodies that direct the T cells to specific cancer cells.
In addition, Cooper and a team of researchers are developing allogeneic, modified T cells for infusion after stem cell transplants to improve graft-versus-leukemia effect. Most recently, they have found a method to supercharge the T cells in the laboratory using Interleukin-7 (IL-7) prior to infusion in a patient. These boosted T cells will potentially grow faster and live longer, thus avoiding the need to directly infuse the patient with IL-7.
Improving Engraftment of Cord Blood Transplants
Presented at Annual BMT Tandem Meetings
Cord blood provides a readily available, ethnically diverse source of stem cells for transplantation. However, these stem cells are at risk of delayed engraftment and graft failure. Patrick Zweidler-McKay, M.D., Ph.D., found that cord blood cells have poorly fucosylated glycoproteins, which may lessen their ability to engraft compared to bone marrow and peripheral blood cells used in transplantation.
Zweidler-McKay found that using the drug, Engraftin, increased fucosylation of glycoproteins on cord blood cells and significantly improved the rate and magnitude of cord blood engraftment in mice. In the future, he plans to study this interaction in a clinical transplant setting.
Endocrine
The Children’s Cancer Hospital has one of the few pediatric endocrinology practices in the nation that specifically focuses on the diagnosis and treatment of children with endocrine tumors and disorders. Two full-time pediatric endocrinologists trained in both pediatric and adult endocrinology, as well as an experienced nurse practitioner, head up the multidisciplinary program and have dedicated research toward improving endocrine disorders in children.
Sorafenib Successful in Treating Pediatric Papillary Thyroid Cancer
Published in Thyroid
Pediatric papillary thyroid cancer (PTC) usually presents with more advanced disease in younger patients, yet prognosis is typically excellent. In most cases of metastasis, radioactive iodine is successful in systemically treating the disease. However, in a recent study where a teen with PTC had lung metastases that were non-responsive to radioactive iodine, Steven Waguespack, M.D., from the Children’s Cancer Hospital, showed the efficacy of sorafenib, a multi-kinase inhibitor, in treating and managing the patient’s disease.
Sunitinib Found Effective Against Advanced Von Hippel-Lindau Disease
Published in the Journal of Clinical Endocrinology Metabolism
Von Hippel-Lindau (VHL) disease is characterized by highly vascular tumors affecting multiple organs. Waguespack recently reported a case where a VHL pediatric patient presented with multiple renal and pancreatic tumors along with malignant pheochromocytoma (an adrenal tumor) and lymph node metastases. The patient had severe pain, weight loss and overall poor performance.
Once treated with the tyrosine kinase inhibitor, sunitinib, the patient’s symptoms began to dissipate and the tumors showed significant shrinkage. The study provided evidence that targeting tyrosine kinase receptors may have value in the treatment of VHL-related tumors.
The Year in Review
Overall, they year has brought many discoveries within the research laboratories of the Children’s Cancer Hospital. By investigating the biological and molecular fundamentals of difficult-to-treat cancers, researchers and clinicians have worked together to translate basic research into clinical therapies being used today. Capitalizing on the drugs and cell therapies being studied in adults at MD Anderson, pediatric patients continue to have first access to some of the most novel therapies coming down the pipeline.