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

Therapeutic Strategies to Enhance the Anticancer Efficacy of Histone Deacetylase Inhibitors

Histone acetylation is a posttranslational modification that plays a role in regulating gene expression. More recently, other nonhistone proteins have been identified to be acetylated which can regulate their function, stability, localization, or interaction with other molecules. Modulating acetylation with histone deacetylase inhibitors (HDACi) has been validated to have anticancer effects in preclinical and clinical cancer models. This has led to development and approval of the first HDACi, vorinostat, for the treatment of cutaneous T cell lymphoma. However, to date, targeting acetylation with HDACi as a monotherapy has shown modest activity against other cancers. To improve their efficacy, HDACi have been paired with other antitumor agents. Here, we discuss several combination therapies, highlighting various epigenetic drugs, ROS-generating agents, proteasome inhibitors, and DNA-damaging compounds that together may provide a therapeutic advantage over single-agent strategies

Comparison of pharmacological inhibitors of lysine-specific demethylase 1 in glioblastoma stem cells reveals inhibitor-specific efficacy profiles

IntroductionImproved therapies for glioblastoma (GBM) are desperately needed and require preclinical evaluation in models that capture tumor heterogeneity and intrinsic resistance seen in patients. Epigenetic alterations have been well documented in GBM and lysine-specific demethylase 1 (LSD1/KDM1A) is amongst the chromatin modifiers implicated in stem cell maintenance, growth and differentiation. Pharmacological inhibition of LSD1 is clinically relevant, with numerous compounds in various phases of preclinical and clinical development, but an evaluation and comparison of LSD1 inhibitors in patient-derived GBM models is lacking.MethodsTo assess concordance between knockdown of LSD1 and inhibition of LSD1 using a prototype inhibitor in GBM, we performed RNA-seq to identify genes and biological processes associated with inhibition. Efficacy of various LSD1 inhibitors was assessed in nine patient-derived glioblastoma stem cell (GSC) lines and an orthotopic xenograft mouse model.ResultsLSD1 inhibitors had cytotoxic and selective effects regardless of GSC radiosensitivity or molecular subtype. In vivo, LSD1 inhibition via GSK-LSD1 led to a delayed reduction in tumor burden; however, tumor regrowth occurred. Comparison of GBM lines by RNA-seq was used to identify genes that may predict resistance to LSD1 inhibitors. We identified five genes that correlate with resistance to LSD1 inhibition in treatment resistant GSCs, in GSK-LSD1 treated mice, and in GBM patients with low LSD1 expression.ConclusionCollectively, the growth inhibitory effects of LSD1 inhibition across a panel of GSC models and identification of genes that may predict resistance has potential to guide future combination therapies

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 \u3c 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 \u3c 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

PCI-24781, a Novel Hydroxamic Acid HDAC Inhibitor, Exerts Cytotoxicity and Histone Alterations via Caspase-8 and FADD in Leukemia Cells

Histone deacetylase inhibitors (HDACi) have become a promising new avenue for cancer therapy, and many are currently in Phase I/II clinical trials for various tumor types. In the present study, we show that apoptosis induction and histone alterations by PCI-24781, a novel hydroxamic acid-based HDAC inhibitor, require caspase-8 and the adaptor molecule, Fas-associated death domain (FADD), in acute leukemia cells. PCI-24781 treatment also causes an increase in superoxide levels, which has been reported for other HDACi. However, an antioxidant does not reverse histone alterations caused by PCI-24781, indicating that ROS generation is likely downstream of the effects that PCI-24781 exerts on histone H3. Taken together, these results provide insight into the mechanism of apoptosis induction by PCI-24781 in leukemia by highlighting the roles of caspase-8, FADD and increased superoxide levels

School-Based Intervention Impacts Availability of Vegetables and Beverages in Participants’ Homes

As rates of metabolic syndrome rise, children consume too few vegetables and too much added sugar. Because children tend to eat what is available at home, the home environment plays a key role in shaping dietary habits. This secondary analysis evaluated the effects of a school-based gardening, cooking, and nutrition education intervention (TX Sprouts) compared to control on the availability of vegetables, fruit juice, and sugar-sweetened beverages (SSBs) at home. In the TX Sprouts cluster-randomized trial, 16 schools were randomized to TX Sprouts

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

Feasible Diet and Circadian Interventions Reduce In Vivo Progression of FLT3-ITD-Positive Acute Myeloid Leukemia

BACKGROUND: Acute myeloid leukemia (AML) with an internal tandem duplication in the fms-like tyrosine kinase receptor 3 gene (FLT3-ITD) is associated with poor survival, and few studies have examined the impact of modifiable behaviors, such as nutrient quality and timing, in this subset of acute leukemia. METHODS: The influence of diet composition (low-sucrose and/or low-fat diets) and timing of diet were tested in tandem with anthracycline treatment in orthotopic xenograft mouse models. A pilot clinical study to test receptivity of pediatric leukemia patients to macronutrient matched foods was conducted. A role for the circadian protein, BMAL1 (brain and muscle ARNT-like 1), in effects of diet timing was studied by overexpression in FLT3-ITD-bearing AML cells. RESULTS: Reduced tumor burden in FLT3-ITD AML-bearing mice was observed with interventions utilizing low-sucrose and/or low-fat diets, or time-restricted feeding (TRF) compared to mice fed normal chow ad libitum. In a tasting study, macronutrient matched low-sucrose and low-fat meals were offered to pediatric acute leukemia patients who largely reported liking the meals. Expression of the circadian protein, BMAL1, was heightened with TRF and the low-sucrose diet. BMAL1 overexpression and treatment with a pharmacological inducer of BMAL1 was cytotoxic to FLT3-ITD AML cells. CONCLUSIONS: Mouse models for FLT3-ITD AML show that diet composition and timing slows progression of FLT3-ITD AML growth in vivo, potentially mediated by BMAL1. These interventions to enhance therapy efficacy show preliminary feasibility, as pediatric leukemia patients responded favorable to preparation of macronutrient matched meals