Translating energy balance research from the bench to the clinic to the community: Parallel animal-human studies in cancer.

Advances in energy balance and cancer research to date have largely occurred in siloed work in rodents or patients. However, substantial benefit can be derived from parallel studies in which animal models inform the design of clinical and population studies or in which clinical observations become the basis for animal studies. The conference Translating Energy Balance from Bench to Communities: Application of Parallel Animal-Human Studies in Cancer, held in July 2021, convened investigators from basic, translational/clinical, and population science research to share knowledge, examples of successful parallel studies, and strong research to move the field of energy balance and cancer toward practice changes. This review summarizes key topics discussed to advance research on the role of energy balance, including physical activity, body composition, and dietary intake, on cancer development, cancer outcomes, and healthy survivorship.

Effects of a School-Based Gardening, Cooking, and Nutrition Cluster Randomized Controlled Trial on Unprocessed and Ultra-Processed Food Consumption.

BACKGROUND: School-based gardening and nutrition education interventions report improvements in dietary intake, notably through fruit and vegetables. However, gardening, cooking, and nutrition randomized controlled trials are limited in evaluating dietary quality, and none have examined processed food consumption to date. OBJECTIVES: The study examined the effects of Texas Sprouts (TX Sprouts), a gardening, cooking, and nutrition education intervention, compared with control on unprocessed and ultra-processed food (UPF) consumption in predominately low-income Hispanic children. METHODS: TX Sprouts was a school-based cluster randomized controlled trial that consisted of 16 elementary schools randomly assigned to either the TX Sprouts intervention (n = 8 schools) or control (delayed intervention; n = 8 schools) over 3 y (2016-2019). TX Sprouts schools received an outdoor teaching garden and 18 1-h lessons taught by trained educators throughout the school year. Dietary intake data via 2 24-h dietary recalls were collected on a random subsample (n = 468) at baseline and postintervention. All foods and beverages were categorized using the NOVA food classification system (e.g., unprocessed, processed, ultra-processed). Generalized linear mixed effects modeling tested changes in percent calories and grams of NOVA groups between the intervention and control estimates with schools as random clusters. RESULTS: Of the sample, 63% participated in the free and reduced-price lunch program, and 57% were Hispanic, followed by non-Hispanic White (21%) and non-Hispanic Black (12%). The intervention, compared to the control, resulted in an increase in consumption of unprocessed foods (2.3% compared with -1.8% g; P < 0.01) and a decrease in UPF (-2.4% compared with 1.4% g; P = 0.04). In addition, Hispanic children in the intervention group had an increase in unprocessed food consumption and a decrease in UPF consumption compared to non-Hispanic children (-3.4% compared with 1.5% g; P < 0.05). CONCLUSIONS: Study results suggest that school-based gardening, cooking, and nutrition education interventions can improve dietary intake, specifically increasing unprocessed food consumption and decreasing UPF consumption. This trial was registered at clinicaltrials.gov as NCT02668744.

Cooking After Cancer: the Structure and Implementation of a Community-Based Cooking Program for Cancer Survivors.

Cancer survivors are a growing population that may particularly benefit from nutrition and lifestyle interventions. Community-based programs teaching healthy cooking skills are increasingly popular and offer an opportunity to support survivors within communities. The objective of this study is to describe the curriculum and implementation of a cooking class program designed for cancer survivors, housed within an established community-based organization. First, we evaluated the class curriculum for specific constructs. An evidence-based measure of healthy cooking constructs, the Healthy Cooking Index (HCI), was used to analyze included recipes and revealed both summative cooking quality scores and individual constructs underlying the overall curriculum. Second, a self-report questionnaire based on the HCI was conducted during the first and last class of the 6-week series. This allowed for a comparison between baseline cooking practices of participants and class curricula, as well as changes in reported practices after class participation. Using the HCI items and coding system, we found the curriculum focused on seven recurring constructs (measuring fat and oil, using citrus, herbs and spices, low-fat cooking methods, olive oil, and adding fruit and vegetables). Baseline reports demonstrated that many participants already practiced the main constructs driving the curriculum. As a potential result of this overlap, no changes in practices were found between the first and last session among class participants. Cooking classes for cancer survivors should be structured to not only reinforce positive existing behaviors but also to promote other healthy cooking practices and reduce less healthy behaviors such as using red meat and animal fats. The HCI can be used to understand the underlying constructs of existing cooking class curricula and current practices of survivor populations, allowing for a more tailored approach to practical nutrition education in this high-risk group.

Unique Features of a Web-Based Nutrition Website for Childhood Cancer Populations: Descriptive Study.

BACKGROUND: Children with cancer experience a myriad of nutritional challenges that impact their nutrition status during treatment and into survivorship. Growing evidence suggests that weight at diagnosis impacts cancer outcomes, but provider guidance on nutrition and diet during treatment varies. Nutrition literacy and culinary resources may help mitigate some common nutritional problems; however, many patients may face barriers to accessing in-person classes. Along with dietitian-led clinical interventions, web-based resources such as the newly updated electronic cookbook (e-cookbook) created by The University of Texas MD Anderson Cancer Center, @TheTable, may facilitate access to nutrition and culinary education during treatment and into survivorship. OBJECTIVE: We sought to define and describe the features and content of the @TheTable e-cookbook and compare it with analogous resources for a lay audience of patients with childhood cancer and childhood cancer survivors as well as their families. METHODS: We evaluated freely available web-based resources via a popular online search engine (ie, Google). These searches yielded three web-based resources analogous to @TheTable: the American Institute for Cancer Research's Healthy Recipes, The Children's Hospital of San Antonio's Culinary Health Education for Families Recipe for Life, and Ann Ogden Gaffney and Fred Hutchinson Cancer Research Center's Cook for Your Life. These sites were analyzed for the following: number of recipes, search functionality, child or family focus, cancer focus, specific dietary guidance, videos or other media, and miscellaneous unique features. RESULTS: Cook for Your Life and Culinary Health Education for Families Recipe for Life were the most comparable to @TheTable with respect to cancer focus and family focus, respectively. Healthy Recipes is the least user-friendly, with few search options and no didactic videos. CONCLUSIONS: The @TheTable e-cookbook is unique in its offering of child- and family-focused content centered on the cancer and survivorship experience.

Pediatric high-grade glioma: aberrant epigenetics and kinase signaling define emerging therapeutic opportunities.

INTRODUCTION: Supratentorial pediatric high-grade gliomas (pHGGs) are aggressive malignancies that lack effective treatment options. Deep genomic sequencing by multiple groups has revealed that the primary alterations unique to pHGGs occur in epigenetic and kinase genes. These mutations, fusions, and deletions present a therapeutic opportunity by use of small molecules targeting epigenetic modifiers and kinases that contribute to pHGG growth. METHODS: Using a targeted search of the pre-clinical literature and clinicaltrials.gov for kinase and epigenetic pathways in pHGG, we collectively describe how these mechanisms are being targeted in pre-clinical animal models and in current clinical trials, as well as propose unexplored therapeutic possibilities for future investigations. RESULTS: Relevant pHGG kinases are targetable by several FDA-approved or clinical-stage kinase inhibitors, including altered BRAF/MET/NTRK/ALK and wild-type PI3K/EGFR/PDGFR/VEGF/AXL. Epigenetic proteins implicated in pHGG are also clinically targetable and include histone erasers, writers and readers such as HDACs, demethylases LSD1/JMJD3, methyltransferase EZH2, chromatin reader bromodomains, and chromatin remodeler subunit BMI-1. Crosstalk between these pathways can occur involving kinases such as EGFR and AMPK interacting with epigenetic modifiers such as HDACs or EZH2. Single agent trial results of kinase inhibitors or epigenetic targets alone are underwhelming and hampered by poor pharmacokinetics, adaptive resistance, and broad inclusion criteria. CONCLUSIONS: The genetic and phenotypic diversity of pHGGs is now well characterized after large-scale sequencing studies on patient tissue. However, clinical treatment paradigms have not yet shifted in response to this information. Combination therapies targeting multiple kinases or epigenetic targets may hold more promise, especially if attempted in selected patient populations with hemispheric pHGG tumors and relevant targeted therapeutic biomarkers.

Nutritional concerns of survivors of childhood cancer: A "First World" perspective.

Childhood cancer survivor (CCS) numbers are increasing as a result of advances in both treatment and supportive care. This positive outcome is tempered by the recognition of a high burden of chronic health conditions. Here, we review the nutritional concerns of CCS, including dietary habits after treatment and the factors during treatment that may contribute to chronic health conditions. Dietary interventions that have been conducted in CCS will be summarized along with focused goals of these interventions. We will also address the need to leverage these interventions to reduce the risk of chronic disease in CCS.

Meal planning values impacted by the cancer experience in families with school-aged survivors-a qualitative exploration and recommendations for intervention development.

PURPOSE: Increased cardiovascular disease and second cancer risks among childhood cancer survivors (CCS) makes them and their families important audiences for nutrition intervention. Family meals and home cooking practices have been associated with improved diet and health, but there is a gap in the literature on understanding these behaviors and their motivating values among CCS families. This study qualitatively explores family meal values and behaviors in a sample of CCS parent-child dyads. METHODS: This observational and qualitative study recruited a convenience sample of 11 parent-CCS dyads. Data collection included audio and video recording of food preparation events in participant homes, which were analyzed with an inductive coding technique to examine meal-related values in CCS families. RESULTS: Analyses revealed four major categories of meal values. Effort, including time and difficulty, as well as budget, healthfulness, and family preferences emerged as recurrent values impacting meal preparation. These values were impacted by the cancer experience upon diagnosis, during treatment, and into survivorship. CONCLUSIONS: A better understanding of CCS family meal planning values, the impact of the cancer experience on these values, and the inclusion of CCS in food preparation reveals potential intervention targets, facilitators, and barriers for future interventions to improve dietary behaviors among CCS.

Exploring food preparation practices in families with and without school-aged childhood cancer survivors.

OBJECTIVE: Survival rates for paediatric cancers have increased dramatically since the 1970s, but childhood cancer survivors (CCS) are at increased risk for several chronic diseases throughout life. Nutrition interventions promoting healthy family meals may support wellness for survivors, but little research has explored CCS family food preparation habits. The goal of the present study was to describe and compare food preparation practices of CCS and non-CCS families. DESIGN: Observational. SETTING: Typical evening meal preparation events were observed and recorded in participant homes. Recordings and notes were analysed using the Healthy Cooking Index (HCI), a measure of nutrition-optimizing food preparation practices relevant to survivor wellness. Demographics, BMI and nutrient composition of prepared meals were also collected. PARTICIPANTS: Forty parents with a CCS or non-CCS child aged 5-17 years were recruited. RESULTS: There were no major differences between the CCS and non-CCS families with regard to summative HCI score or specific food preparation behaviours. Meals prepared by CCS and non-CCS families had similar nutrient compositions. CONCLUSIONS: The study revealed areas for practical nutrition intervention in CCS and non-CCS families. Future studies should consider adopting and tailoring nutrition intervention methods that have been successful in non-CCS communities.

The ubiquitin-proteasome pathway in adult and pediatric brain tumors: biological insights and therapeutic opportunities.

Nearly 20 years ago, the concept of targeting the proteasome for cancer therapy began gaining momentum. This concept was driven by increased understanding of the biology/structure and function of the 26S proteasome, insight into the role of the proteasome in transformed cells, and the synthesis of pharmacological inhibitors with clinically favorable features. Subsequent in vitro, in vivo, and clinical testing culminated in the FDA approval of three proteasome inhibitors-bortezomib, carfilzomib, and ixazomib -for specific hematological malignancies. However, despite in vitro and in vivo studies pointing towards efficacy in solid tumors, clinical responses broadly have been evasive. For brain tumors, a malignancy in dire need of new approaches both in adult and pediatric patients, this has also been the case. Elucidation of proteasome-dependent processes in specific types of brain tumors, the evolution of newer proteasome targeting strategies, and the use of proteasome inhibitors in combination strategies will clarify how these agents can be leveraged more effectively to treat central nervous system malignancies. Since brain tumors represent a heterogeneous subset of solid tumors, and in particular, pediatric brain tumors possess distinct biology from adult brain tumors, tailoring of proteasome inhibitor-based strategies to specific subtypes of these tumors will be critical for advancing care for affected patients, and will be discussed in this review.

Diet and exercise interventions for pediatric cancer patients during therapy: tipping the scales for better outcomes.

Obesity at diagnosis is a negative prognostic indicator for several pediatric cancers including acute leukemia and bone tumors. Incidence of obesity in children has increased three-fold over the past 2 decades, and causes for this include poor diet, excessive caloric intake, and lack of physical activity, which are collectively referred to as energy balance-related behaviors. Few energy balance interventions have been implemented in pediatric cancer patients during treatment, and here we will probe the rationale for pursuing such studies. The need to modify composition of calories consumed and to identify specific beneficial exercise regimens will be discussed, relative to weight reduction or management.

Metachronous Medulloblastoma in a Child With Successfully Treated Neuroblastoma: Case Report and Novel Findings of DNA Sequencing.

Metachronous neoplasms have rarely been reported in patients with neuroblastoma. This report presents the clinical case of a 23-month-old child who was diagnosed with an anaplastic medulloblastoma 5 months after completing treatment for stage IV neuroblastoma. The patient was treated with complete surgical resection and adjuvant chemoradiation followed by maintenance chemotherapy at an outside institution and came to our institution for further management. A pathologic diagnosis and review of both the suprarenal and posterior fossa masses were performed, as well as a genetic analysis of both cerebellar tumor tissue and blood using next-generation gene sequencing. At our institution, the patient was submitted to induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation and remains free of disease 2 years after completion of treatment. Genetic analysis revealed multiple somatic copy number variations with most deleted genes located in 2q37, a region which harbors genes involved in epigenetic regulation and tumor suppression. A homozygous deletion was found in the TSC2 gene, which is a clinically actionable gene, and patients with activating deletions in TSC2 can potentially be eligible for basket clinical trials with mTOR inhibitors. Germline single nucleotide variants were also identified in multiple genes involved in cancer (ALK, FGFR3, FLT3/4, HNF1A, NCOR1, and NOTCH2/3), cancer predisposition (TP53, TSC1, and BRCA1/2), and genes involved in DNA repair (MSH6, PMS2, POLE, and ATM). Metachronous neoplasms are rare and challenging to treat, hence genetic analysis and referral are needed to exclude hereditary cause. DNA sequencing of the tumor and germline can help identify alterations that increase predisposition or can be used to guide treatment decisions on recurrence and when standard options fail.

Aerobic Exercise During Early Murine Doxorubicin Exposure Mitigates Cardiac Toxicity.

We report the cardioprotective effects of moderate aerobic exercise from parallel pediatric murine models of doxorubicin (Doxo) exposure in non-tumor-bearing immune competent (NTB-IC) mice and tumor-bearing nude mice (TB-NM). In both models, animals at 4 weeks of age underwent Doxo treatment with or without 2 weeks of simultaneous exercise. In sedentary NTB-IC or TB-NM mice, Doxo treatment resulted in a statistically significant decrease in ejection fraction and fractional shortening compared with control animals. Interestingly, moderate aerobic exercise during Doxo treatment significantly mitigated decreases in ejection fraction and fractional shortening. In contrast, these protective effects of exercise were not observed when exercise was started after completion of Doxo treatments. Moreover, in the TB-NM model, Doxo caused a decrease in heart mass: tibia length and in body weight that was prevented by exercise, whereas NTB-IC mice exhibited no change in these measurements. Doxo delivery to the hearts of TB-NM was decreased by consistent moderate aerobic exercise before Doxo injection. These findings demonstrate the important but subtle differences in cardiotoxicity observed in different mouse models. Collectively, these results also strongly suggest that aerobic exercise during early-life Doxo exposure mitigates cardiotoxicity, possibly through altered delivery of Doxo to myocardial tissue.

Development and Feasibility of a Community-Based, Culturally Flexible Colorectal Cancer Prevention Program.

Comprehensive cancer centers are an important community resource for cancer prevention education in their catchment areas. Colorectal cancer remains one of the most commonly diagnosed cancers in the United States, making prevention a priority. Colorectal cancer prevention targets include lifestyle modifications that are influenced by cultural norms, such as diet change, physical activity and screening behavior. Cancer centers must tailor prevention efforts to multiethnic catchment areas. This paper describes the development and feasibility of a comprehensive cancer center's approach to community-based colorectal cancer prevention in Houston, Texas, specifically targeting Hispanic and Asian populations. Sites were recruited through a city-wide network of partnerships between the community relations department in the hospital and community organizations. The program consisted of three workshop-style classes per community site. Each class had a similar overall structure, but cultural and site-specific adaptations were made for each group. A total of 33 classes were taught at nine distinct community sites to 1054 participants over 9 months. This program structure may be adapted for the future dissemination of other cancer prevention tools to communities in the area.

A randomized nutrition counseling intervention in pediatric leukemia patients receiving steroids results in reduced caloric intake.

BACKGROUND: Quality of life in survivors of pediatric acute lymphocytic leukemia (ALL) can be compromised by chronic diseases including increased risk of second cancers, cardiovascular disease, and diabetes. Overweight or obesity further increases these risks. Steroids are a component of chemotherapy for ALL, and weight gain is a common side effect. To impact behaviors associated with weight gain, we conducted a randomized nutrition counseling intervention in ALL patients on treatment. PROCEDURE: ALL patients on a steroid-based treatment regimen at the MD Anderson Children's Cancer Hospital were recruited and randomized into control or intervention groups. The control group received standard care and nutrition education materials. The intervention group received monthly one-on-one nutrition counseling sessions, consisting of a baseline and 12 follow-up visits. Anthropometrics, dietary intake (3-day 24-hr dietary recalls) and oxidative stress measures were collected at baseline, 6 months, and postintervention. Dietary recall data were analyzed using the Nutrition Data System for Research. RESULTS: Twenty-two patients (median age 11.5 years), all in the maintenance phase of treatment, were recruited. The intervention group (n = 12) reported significantly lower calorie intake from baseline to 12-month follow-up and significant changes in glutamic acid and selenium intake (P < 0.05). Waist circumference was significantly associated with calorie, vitamin E, glutamic acid, and selenium intake. CONCLUSIONS: A year-long dietary intervention was effective at reducing caloric intake in pediatric ALL patients receiving steroid-based chemotherapy, indicating that this is a modality that can be built upon for obesity prevention and management.

Healthy cooking classes at a children's cancer hospital and patient/survivor summer camps: initial reactions and feasibility.

OBJECTIVE: Childhood cancer survivors (CCS) have been shown to practise suboptimal dietary intake and may benefit from nutrition interventions during and after treatment. Cooking classes have become popular for encouraging healthy eating behaviours in community-based programming and academic research; however, literature on teaching cooking classes in CCS is limited. The purpose of the present study was to address the development and implementation of classes for CCS based on a recently developed framework of healthy cooking behaviour. DESIGN: A conceptual framework was developed from a systematic literature review and used to guide healthy cooking classes for CCS in different settings. SETTING: One paediatric cancer hospital inpatient unit, one paediatric cancer in-hospital camp programme and two off-site paediatric cancer summer camp programmes. SUBJECTS: One hundred and eighty-nine CCS of varying ages and thirteen parents of CCS. RESULTS: Seventeen classes were taught at camps and seven classes in the hospital inpatient unit. Healthy cooking classes based on the conceptual framework are feasible and were well received by CCS. CONCLUSIONS: Cooking classes for CCS, both at the hospital and at camp, reinforced the principles of the conceptual framework. Future trials should assess the dietary and anthropometric impact of evidence-based healthy cooking classes in CCS.

Parental involvement in exercise and diet interventions for childhood cancer survivors: a systematic review.

Childhood cancer survivors (CCS) are at risk of becoming overweight or obese due to treatment effects and/or post-treatment behaviors. Parents are key agents influencing child diet and physical activity (PA), which are modifiable risk factors for obesity. A systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was undertaken to evaluate current interventions that include diet and PA elements for CCS to determine if and to what extent parents were included, and whether parent involvement had a significant effect on behavioral outcomes or adiposity. A total of 2,386 potential articles were reviewed and 25 individual studies fulfilled inclusion criteria. Parental involvement was classified into three categories and varied across studies, although most had indirect or no parental involvement. The studies that included direct parental involvement showed positive outcomes on a variety of measures suggesting that increasing parental involvement in interventions for CCS may be one way to promote long-term lifestyle changes for pediatric cancer patients. However, additional research directly addressing parental involvement in obesity prevention and treatment among CCS is warranted.

Smooth muscle hyperplasia due to loss of smooth muscle α-actin is driven by activation of focal adhesion kinase, altered p53 localization and increased levels of platelet-derived growth factor receptor-ß.

Mutations in ACTA2, encoding the smooth muscle cell (SMC)-specific isoform of α-actin (α-SMA), cause thoracic aortic aneurysms and dissections and occlusive vascular diseases, including early onset coronary artery disease and stroke. We have shown that occlusive arterial lesions in patients with heterozygous ACTA2 missense mutations show increased numbers of medial or neointimal SMCs. The contribution of SMC hyperplasia to these vascular diseases and the pathways responsible for linking disruption of α-SMA filaments to hyperplasia are unknown. Here, we show that the loss of Acta2 in mice recapitulates the SMC hyperplasia observed in ACTA2 mutant SMCs and determine the cellular pathways responsible for SMC hyperplasia. Acta2(-/-) mice showed increased neointimal formation following vascular injury in vivo, and SMCs explanted from these mice demonstrated increased proliferation and migration. Loss of α-SMA induced hyperplasia through focal adhesion (FA) rearrangement, FA kinase activation, re-localization of p53 from the nucleus to the cytoplasm and increased expression and ligand-independent activation of platelet-derived growth factor receptor beta (Pdgfr-ß). Disruption of α-SMA in wild-type SMCs also induced similar cellular changes. Imatinib mesylate inhibited Pdgfr-ß activation and Acta2(-/-) SMC proliferation in vitro and neointimal formation with vascular injury in vivo. Loss of α-SMA leads to SMC hyperplasia in vivo and in vitro through a mechanism involving FAK, p53 and Pdgfr-ß, supporting the hypothesis that SMC hyperplasia contributes to occlusive lesions in patients with ACTA2 missense mutations.

Impact of electronic cigarettes on pediatric, adolescent and young adult leukemia patients.

Electronic cigarettes, which deliver an aerosolized, nicotine-containing product upon inhalation, are a public health issue that continue to gain popularity among adolescents and young adults in the United States. Use of electronic cigarettes is wide, and extends to pediatric patients with multiple comorbidities, including childhood cancer, leaving them vulnerable to further negative health outcomes. Acute leukemias are the most common type of cancer in pediatric populations, and treatment outcomes for these patients are improving; consequently, there is an increased emphasis on the effect of behavioral lifestyle factors on quality of life in survivorship. The rate of electronic cigarette use is higher among pediatric patients with a history of cancer than those without a history of cancer. Because electronic cigarettes are relatively new, much about their acute and long-term consequences remains unknown, as is their effect on therapy outcomes and long-term survivorship. This review article summarizes current knowledge about electronic cigarettes, including their composition and the trends in use among pediatric patients. Furthermore, this review provides a comprehensive description of the impact electronic cigarettes have on leukemia development, treatment and survivorship and highlights gaps in knowledge that will be necessary for developing recommendations, management strategies, and tailored treatments for pediatric leukemia patients and survivors who use these nicotine products.

Current and future therapeutic strategies for high-grade gliomas leveraging the interplay between epigenetic regulators and kinase signaling networks.

Targeted therapies, including small molecule inhibitors directed against aberrant kinase signaling and chromatin regulators, are emerging treatment options for high-grade gliomas (HGG). However, when translating these inhibitors into the clinic, their efficacy is generally limited to partial and transient responses. Recent studies in models of high-grade gliomas reveal a convergence of epigenetic regulators and kinase signaling networks that often cooperate to promote malignant properties and drug resistance. This review examines the interplay between five well-characterized groups of chromatin regulators, including the histone deacetylase (HDAC) family, bromodomain and extraterminal (BET)-containing proteins, protein arginine methyltransferase (PRMT) family, Enhancer of zeste homolog 2 (EZH2), and lysine-specific demethylase 1 (LSD1), and various signaling pathways essential for cancer cell growth and progression. These specific epigenetic regulators were chosen for review due to their targetability via pharmacological intervention and clinical relevance. Several studies have demonstrated improved efficacy from the dual inhibition of the epigenetic regulators and signaling kinases. Overall, the interactions between epigenetic regulators and kinase signaling pathways are likely influenced by several factors, including individual glioma subtypes, preexisting mutations, and overlapping/interdependent functions of the chromatin regulators. The insights gained by understanding how the genome and epigenome cooperate in high-grade gliomas will guide the design of future therapeutic strategies that utilize dual inhibition with improved efficacy and overall survival.

Targeting DNA Repair and Survival Signaling in Diffuse Intrinsic Pontine Gliomas to Prevent Tumor Recurrence.

Therapeutic resistance remains a major obstacle to successful clinical management of diffuse intrinsic pontine glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. On the basis of these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary studies demonstrated that micromolar levels of this inhibitor can be achieved in murine brain tissue and that MTX-241F exhibits promising single-agent efficacy and radiosensitizing activity in patient-derived DIPG neurospheres. Its physiochemical properties include high exposure in the brain, indicating excellent brain penetrance. Because radiotherapy results in double-strand breaks that are repaired by homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have tested the combination of MTX-241F with an inhibitor of Ataxia Telangiectasia Mutated to achieve blockade of HR and NHEJ, respectively, with or without radiotherapy. When HR blockers were combined with MTX-241F and radiotherapy, synthetic lethality was observed, providing impetus to explore this combination in clinically relevant models of DIPG. Our data provide proof-of-concept evidence to support advanced development of MTX-241F for the treatment of DIPG. Future studies will be designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease.