By: Charles Moore
According to the Texas-based non-profit organization the Carson Leslie Foundation, each year around 16,000 children are diagnosed with cancer in the U.S., and one in every 285 Americans develops cancer before the age of twenty. The American Cancer Society’s (ACS) 2014 Facts & Figures Report estimates that 10,450 new cases and 1,350 cancer deaths are expected to occur among children (ages 0-14) in 2014, the corresponding figures among adolescents (ages 15-19) being 5,330 new cases and 610 cancer deaths.
Moreover, the ACS says childhood cancer occurs regularly and randomly, sparing no ethnic group, socioeconomic class, or geographic region, and in the United States, cancer incidence among adolescents and young adults is increasing at a greater rate than for any other age group, save in persons aged over 65 years, The ACS reports that cancer is the leading cause of death by disease in children under the age of 15 in the United States, and the second leading cause of death overall (following accidents) in children ages 5-14. Childhood cancers now affect more potential patient-years of life than any other cancers except breast and lung cancer, and they kill more children than AIDs, asthma, diabetes, cystic fibrosis and congenital anomalies combined.
Funding for a new Texas-based research project for treating pediatric cancers has been announced by the Cancer Prevention and Research Institute of Texas (CPRIT). This project and several other newly-funded projects for studying pediatric cancers in Texas are attributable to efforts of the Carson Leslie Foundation (CLF), which was founded by its Executive Director Annette Leslie in memoriam of her son, the late Carson Leslie, who tragically succumbed to pediatric cancer on January 12, 2010 after battling the disease for three and a half years. Carson’s dying wish was: “Momma, make sure they study those tumors in my brain, ’cause if those tumors can help some kid some day not die from cancer like I am, I’d like that, it’s hard to have cancer.”
During his illness, Carson Leslie wrote a book, “Carry Me,” of which he commented:
“I have written a book to give a voice to the teenagers and children who have cancer but are unable to express how such an illness affects their personal, social, physical and emotional life. I want others to understand how to be a better friend to someone he/she knows that has a life threatening disease. Even though every day of my life is a battle, I have learned that God is always there to lift me up, and I live each day as if it were the Day of Judgement.
“I believe my story will give readers a new perspective on the importance of how words and/or actions affect those around them. I wish to make a difference, and I know others my age want to do the same. Maybe after they read my book they will discover how to live the struggle…”
Earlier this year, Annette Leslie told BioNews Texas she is humbled to be part of CPRIT’s Advisory Council on Childhood Cancer and has learned so much by serving in that capacity the since Carson’s death. A result of a unique relationship between CLF and The Cancer Prevention and Research Institute of Texas (CPRIT) we’re pleased to fund over $3,200,000.00 in research for less toxic childhood brain cancer treatments.
These CPRIT awards will provide researchers with $500,000 in funding for a period of up to four years, and will be granted to Texas-based not-for-profit institutions or organizations that conduct laboratory, clinical, or population-based studies. CPRIT aims to “support applications for innovative research projects addressing questions that will advance knowledge of the causes, prevention, progression, detection, or treatment of cancer in children and adolescents,” according to a press release.
CPRIT-Funded Pediatric Cancer Research Begins To Stir
One CPRIT award recipient will conduct a study entitled, “Proton Beam Radiation Therapy vs. Conventional Beam RadiationTherapy: Toxicities During & After Craniospinal Radiation Therapy in Children” (Carson Leslie Award ID:RP130368). Principal Investigator M. Douglas Ris, Ph.D., head of the Section of Psychology and a Professor of Pediatrics at Baylor College of Medicine in Houston, also notes that the rate of survivors of pediatric brain tumors has greatly increased in the past two decades, which has made it more apparent that many whose cancer is nominally cured are left with life-long physical and neurodevelopmental impairments secondary to life-saving treatments (particularly radiotherapy) they’ve received for their disease.
Dr. Ris, whose research focus is on neuropsychological evaluations of children with a variety of conditions affecting the central nervous system, and particularly on neuropsychological sequelae of pediatric brain tumors, reports that an emerging radiotherapy technology using protons (Proton Beam Radiation Therapy or PBRT) rather than conventional photons or x-rays, promises to reduce the toxicity burden associated with radiotherapy, to improve both outcomes and quality of life in survivors. The report further notes that many herald the clinical potential of PBRT to minimize damage to healthy brain tissue and other organs of the body without sacrificing disease control.
Nevertheless, Dr. Ris notes there are no published reports to date of neurocognitive outcomes following PBRT for pediatric brain tumors. In this study, he and his team propose to evaluate the full range of side-effects (e.g. fatigue,nausea/vomiting, hearing loss, cognitive skills, behavioral and emotional adjustment) experienced by children undergoing PBRT in the first year after initiation of treatment,and comparing these to the side effects experienced by children receiving conventional radiation therapy (CRT). The researchers will also compare financial costs associated with the two types of radiotherapy, a line of research that they hope will guide clinicians on the range of outcomes that can be expected following PBRT, and also stands to influence clinical care in four contexts:1) decision making, 2) cost, 3) access, and 4) intervention.
Another CPRIT award recipient is the study “Proton Beam Radiation Therapy vs. Conventional Beam Radiation Therapy: Toxicities During & After Craniospinal Radiation Therapy in Children,” an ancillary study to “Proton Beam Radiation Therapy vs. Conventional Beam Radiation Therapy: Toxicities during & after Craniospinal Radiation Therapy in Children” (funded by Carson Leslie CPRIT Award #RP130368), is coauthored by Dr. Ris., Anita Mahajan, M.D., Fatih Okcu, M.D. The coauthors note that reducing neurocognitive effects of radiation therapy is a high priority, but an understanding of the biological mechanism of these effects is lacking. The researchers say animal studies suggest that inflammatory mechanisms in the brain may be important in understanding neurocognitive effects, and that by measuring brain cytokines and proteins in children undergoing radiation therapy, they can determine if there is any relationship between inflammatory processes and side-effects/toxicities being measured as part of the parent study funded by CPRIT.
They note that this additional funding by the Carson Leslie Foundation promises to increase their understanding of the biological basis of these debilitating neurocognitive effects in children leading to treatments that would preserve neurocognitive functioning.
The coauthors observe that while radiation plays an essential role in treating childhood brain tumors, with nearly 200,000 patients undergoing brain irradiation annually, for both patients and caregivers the most distressing adverse effect is impaired cognition. This effect is most problematic in survivors of childhood brain tumors, since contrast to adults, irradiation of a developing brain results in dramatic long-term consequences. For pediatric brain tumor patients, survival rates now approach 80% for many types, but survivors are faced with lifetimes of impairment characterized by diminished academic achievement, a narrower range of employment opportunities, inhibited social integration and ultimately poor quality of life.
The researchers’ specific aims are to a) characterize changes in neurotransmitter and cytokine levels following brain irradiation, hypothesizing that that radiation-induced alterations in cytokine levels will be seen post radiation in the absence of alterations in primary neurotransmitter levels and that such changes will correlate with cognitive function post-radiation therapy; b) To identify radiation induced alterations in CSF proteome profiles using mass spectrometry to test that discovery-based profiling of patient samples, both pre and post-cranial irradiation, will provide novel information in pathways that change due to radiation-induced damage; and c) To correlate changes in neurotransmitter, cytokine levels and proteome profiles with clinical parameters during radiation and short term cognitive impairment one year after radiation in children treated with craniospinal radiation. This is an exploratory aim to correlate the alterations in neurotransmitters, cytokines and proteomes with clinical symptoms and blood counts measured weekly during radiation and cognitive function evaluated one year after radiation therapy.
The researchers expect to identify multiple differences in the study biological indicators between pre- and post-RT samples using established statistical methods.
Genotype and Metabolic Phenotype in Pediatric Brain Cancer Research
Another project receiving Carson Leslie Award CPRIT funding (Award ID:RP130629) is “Genotype and Metabolic Phenotype in Pediatric Brain Cancer,” headed by principal Investigator Dr. Elizabeth A Maher M.D., PhD. , an associate professor and holder of the Theodore H. Strauss Professorship in Neuro-Oncology in the Department of Internal Medicine, Neurology & Neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas.
Dr. Maher notes that malignant brain tumors are the second most common cancer in children, and while there has been some improvement in overall survival rates for medulloblastoma over the past decade, it has come with significant long term toxicity. Despite the advances, for many patients with medulloblastoma and high grade glioma, there has been little change in outcome.
Large scale genetic analyses of pediatric brain cancer over the past several years has provided a major leap forward in terms of understanding what genes are abnormal in these diseases, but Dr. Maher says we’re still are a long way off from having new and improved therapies based on targeting a specific gene.
She proposes that a different approach to identifying possible ways of killing the cancer cell is by focusing on the “engine” of the cell, the metabolism that “fuels” ongoing cancer cell growth — the most direct way of doing this being administration of glucose manufactured from “heavy carbon” — a naturally occurring form of carbon in the environment that has the unique property of being able to be detected by MRI.
Dr. Maher’s team infuses the heavy carbon-labeled glucose in patients going to the operating room for removal of their brain tumors, to be taken up by the tumor cell. A small sample can be subsequently analyzed by MRI to identify all the breakdown products of glucose that got the label, which she says is a very easy but nevertheless highly sophisticated method of studying metabolism, that has been very informative for adult brain tumors.
Dr. Maher concludes that given the desperate need for identifying new targets in pediatric brain cancer, the current proposal is designed to get the metabolic information in medulloblastomas and gliomas directly using this technique, and that it is vitally important to capitalize on this unique methodology, to generate the primary data in pediatric patients, and to drive discovery rather than wait for targets to be developed in other cancers and apply them later. From this work she expects to be able to find new targets for treating these deadly brain tumors in children quickly.
Dr. Maher tells BioNews Texas part of the CPRIT award will fund a post-doctoral fellow or research scientist to focus exclusively on this project with a salary of $50,000. This person will work with the other members of the scientific team and would be expected to bring additional expertise and ideas to the project. There are only many experiments that can potentially be done once tumor tissue is acquired, but the limitation is personnel. Consequently, being able to hire another dedicated scientist will be of great added value to furtherance of the project.
Dr. Maher notes that the CPRIT award will also provide additional funds for the 13C-glucose. Any additional money would be added to the existing budget to pay for the 13C-glucose because this is a limiting point in terms of how many patients can be studied. Each infusion is ~$2500. The tumor samples obtained from each infusion are used for multiple analyses. So for each additional patient who can be given the 13C-glucose, significantly more tumor is available to analyze and increase the dataset.