Short-acting b2-adrenergic receptor agonists are commonly used bronchodilators for symptom relief in asthmatics. The aim of this study was to test whether genetic variants in PDE4D gene, a key ...regulator of b2-adrenoceptor-induced cAMP turnover in airway smooth muscle cells, affect the response to short-acting b2-agonists. Bronchodilator responsiveness was assessed in 133 asthmatic children by % change in baseline forced expiratory volume in one second (FEV1) after administration of albuterol. The analyses were performed in patients with airway obstruction (FEV1/FVC ratio below 90%, n=93). FEV1 % change adjusted for baseline FEV1 values was significantly different between genotypes of rs1544791 G/A polymorphism (P=0.006) and −1345 C/T (rs1504982) promoter variation (P=0.03). The association remained significant with inclusion of age, sex, atopy, and controller medication into multivariate model (P=0.004 and P=0.02, resp.). Our work identifies new genetic variants implicated in modulation of asthma treatment, one of them (rs1544791) previously associated with asthma phenotype.
Alterations of FLT3 are among the most common driver events in acute leukaemia with important clinical implications, since it allows patient classification into prognostic groups and the possibility ...of personalising therapy thanks to the availability of FLT3 inhibitors. Most of the knowledge on FLT3 implications comes from the study of acute myeloid leukaemia and so far, few studies have been performed in other leukaemias.
A comprehensive genomic (DNA-seq in 267 patients) and transcriptomic (RNA-seq in 160 patients) analysis of FLT3 in 342 childhood acute lymphoblastic leukaemia (ALL) patients was performed. Mutations were functionally characterised by in vitro experiments.
Point mutations (PM) and internal tandem duplications (ITD) were detected in 4.3% and 2.7% of the patients, respectively. A new activating mutation of the TKD, G846D, conferred oncogenic properties and sorafenib resistance. Moreover, a novel alteration involving the circularisation of read-through transcripts (rt-circRNAs) was observed in 10% of the cases. Patients presenting FLT3 alterations exhibited higher levels of the receptor. In addition, patients with ZNF384- and MLL/KMT2A-rearranged ALL, as well as hyperdiploid subtype, overexpressed FLT3.
Our results suggest that specific ALL subgroups may also benefit from a deeper understanding of the biology of FLT3 alterations and their clinical implications.
An increased risk of neurocognitive deficits, anxiety, and depression has been reported in childhood cancer survivors.
We analyzed associations of neurocognitive deficits, as well as anxiety and ...depression, with common and rare genetic variants derived from whole-exome sequencing data of acute lymphoblastic leukemia (ALL) survivors from the PETALE cohort. In addition, significant associations were assessed using stratified and multivariable analyses. Next, top-ranking common associations were analyzed in an independent SJLIFE replication cohort of ALL survivors.
Significant associations were identified in the entire discovery cohort (N = 229) between the AK8 gene and changes in neurocognitive function, whereas PTPRZ1, MUC16, TNRC6C-AS1 were associated with anxiety. Following stratification according to sex, the ZNF382 gene was linked to a neurocognitive deficit in males, whereas APOL2 and C6orf165 were associated with anxiety and EXO5 with depression. Following stratification according to prognostic risk groups, the modulatory effect of rare variants on depression was additionally found in the CYP2W1 and PCMTD1 genes. In the replication SJLIFE cohort (N = 688), the male-specific association in the ZNF382 gene was not significant; however, a P value<0.05 was observed when the entire SJLIFE cohort was analyzed. ZNF382 was significant in males in the combined cohorts as shown by meta-analyses as well as the depression-associated gene EXO5.
Further research is needed to confirm whether the current findings, along with other known risk factors, may be valuable in identifying patients at increased risk of these long-term complications.
Our results suggest that specific genes may be related to increased neuropsychological consequences.
PKMYT1 is a regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal ...relationship with CCNE1 amplification. To date, no selective inhibitors have been reported for this kinase that would allow for investigation of the pharmacological role of PKMYT1. To address this need compound 1 was identified as a weak PKMYT1 inhibitor. Introduction of a dimethylphenol increased potency on PKMYT1. These dimethylphenol analogs were found to exist as atropisomers that could be separated and profiled as single enantiomers. Structure-based drug design enabled optimization of cell-based potency. Parallel optimization of ADME properties led to the identification of potent and selective inhibitors of PKMYT1. RP-6306 inhibits CCNE1-amplified tumor cell growth in several preclinical xenograft models. The first-in-class clinical candidate RP-6306 is currently being evaluated in Phase 1 clinical trials for treatment of various solid tumors.
Determining the mechanism of action of bacterial growth inhibitors can be a formidable challenge in the progression of small molecules into antibacterial therapies. To help address this bottleneck, ...we have developed a robust transposon mutagenesis system using a suite of outward facing promoters in order to generate a comprehensive range of expression genotypes in Staphylococcus aureus from which to select defined compound-resistant transposon insertion mutants. Resistance stemming from either gene or operon over/under-expression, in addition to deletion, provides insight into multiple factors that contribute to a compound's observed activity, including means of cell envelope penetration and susceptibility to efflux. By profiling the entire resistome, the suitability of an antibacterial target itself is also evaluated, sometimes with unanticipated results. We herein show that for the staphylococcal signal peptidase (SpsB) inhibitors, modulating expression of lipoteichoic acid synthase (LtaS) confers up to a 100-fold increase in the minimal inhibitory concentration. As similarly efficient transposition systems are or will become established in other bacteria and cell types, we discuss the utility, limitations and future promise of Tnp mutagenesis for determining both a compound's mechanism of action and in the evaluation of novel targets.
ATR is a key kinase in the DNA-damage response (DDR) that is synthetic lethal with several other DDR proteins, making it an attractive target for the treatment of genetically selected solid tumors. ...Herein we describe the discovery of a novel ATR inhibitor guided by a pharmacophore model to position a key hydrogen bond. Optimization was driven by potency and selectivity over the related kinase mTOR, resulting in the identification of camonsertib (RP-3500) with high potency and excellent ADME properties. Preclinical evaluation focused on the impact of camonsertib on myelosuppression, and an exploration of intermittent dosing schedules to allow recovery of the erythroid compartment and mitigate anemia. Camonsertib is currently undergoing clinical evaluation both as a single agent and in combination with talazoparib, olaparib, niraparib, lunresertib, or gemcitabine (NCT04497116, NCT04972110, NCT04855656). A preliminary recommended phase 2 dose for monotherapy was identified as 160 mg QD given 3 days/week.
Abstract
Purpose: Cancer survivors’ exposure to chemotherapeutic agents leads to multiple long-term side effects with a decrease in their cardiorespiratory fitness. The first aim was to determine ...whether cardiorespiratory fitness and physical activity levels were lower among survivors than healthy Canadians, while the second aim was to report associations between genetic variants and cardiorespiratory fitness in survivors.
Methods: Cardiorespiratory fitness (VO2peak) and moderate to vigorous physical activity (MVPA) were compared between childhood ALL survivors (N=221) and healthy Canadians (N=825). We performed whole-exome sequencing in survivors. Germline variants (both common and rare) in a selected set of trainability genes were analyzed for an association with cardiorespiratory fitness.
Results: Survivors’ VO2 peak was found to be 22% lower than healthy Canadians. The cardiorespiratory fitness level was different between survivors and healthy Canadians despite a clinically equivalent level of MVPA. Positive associations between the cardiorespiratory fitness level and trainability genes (TTN, LEPR, IGFBPI, and ENO3 genes) were reported, especially in female survivors with a low cardiorespiratory fitness level.
Conclusion: The cardiorespiratory fitness was significantly lower in survivors, which can be associated with variants in genes related to subjects’ trainability. At this time, it appears that more physical activity would be beneficial to survivors to achieve the same benefits as the healthy population. However, the optimal amount of physical activity needed to reach these benefits is not yet clear. The survivors’ responder or nonresponder status several years after the end of the treatments is unknown. This study has important implications for the field of exercise in oncology.
Citation Format: Maxime Caru, Kateryna Petrykey, Mariia Samoilenko, Simon Drouin, Valérie Lemay, Laurence Kern, Lucia Romo, Patrick Beaulieu, Pascal St-Onge, Laurence Bertout, Geneviéve Lefebvre, Gregor Andelfinger, Maja Krajinovic, Caroline Laverdière, Daniel Sinnett, Daniel Curnier. The need to improve exercise prescriptions to support care in pediatric oncology abstract. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B62.
To evaluate the association between human leukocyte antigen (HLA) alleles and native
asparaginase hypersensitivity (AH) in children with acute lymphoblastic leukemia (ALL) who received Dana-Farber ...Cancer Institute treatment protocols.
,
and
alleles were retrieved from available whole exome sequencing data of a subset of childhood ALL patients from Quebec ALL cohort and analyzed for an association with AH. PCR assay was developed to analyze associated alleles in the entire discovery and replication cohorts.
Two alleles in linkage disequilibrium (
and
) were associated with AH. Additional analyses, performed to distinguish between
haplotypes with and without
allele, showed that the association was dependent on the presence of
.
This study confirms the implication of
,
and
alleles in developing AH in childhood ALL.
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