Abiraterone acetate plus prednisone for the Management of Metastatic Castration-Resistant Prostate Cancer (mCRPC) without prior use of chemotherapy: report from a large, international, real-world retrospective cohort study.

BACKGROUND: With the recent introduction of novel treatment options, real-world data from patients with metastatic castration-resistant prostate cancer (mCRPC) are required to better understand the impact on routine clinical practice. This study primarily aimed to describe the time to treatment failure (TTF) of mCRPC patients treated with abiraterone acetate plus prednisone or the corticosteroid of choice (AAP) in the pre-chemotherapy setting. Other relevant outcomes, clinical and treatment characteristics of these patients were also evaluated. METHODS: This retrospective, observational study collected data from chemotherapy-naïve mCRPC patients treated with AAP from four European countries. Kaplan-Meier curves were used to estimate TTF, progression-free survival (PFS), and time to first skeletal-related event. The impact of baseline characteristics on TTF and PFS was explored using univariate and multivariate Cox proportional hazard models. Log-rank test was used to assess the potential role of duration of response to ADT in predicting response to AAP treatment. RESULTS: Data from 481 eligible patients (Belgium: 68; France: 61; Germany: 150; UK: 202) were analysed. At AAP initiation, the median age of patients was 75.0 years (interquartile range [IQR]: 69.0-81.0), and the median PSA was 56.2 ng/mL (IQR: 22.2-133.1), with over 50% of patients presenting an ECOG score of 0 or 1. Visceral metastases were present in 7.5% of patients; an exclusion criterion in the COU-AA-302 clinical trial. The median TTF with AAP was 10.0 months (95%CI: 9.2-11.1) and the median PFS was 10.8 months (95%CI: 9.6-11.8). Shorter TTF was significantly associated with higher ALP (> 119 units/L), higher PSA (> 56.2 ng/mL), or poorer ECOG PS scores at AAP initiation (p < 0.05). Patients with longer duration of response to ADT (≥12 months) presented longer TTF and longer time to progression (p < 0.0001). CONCLUSIONS: This European real-world study provides valuable insights into the characteristics, treatment, and outcomes of chemotherapy-naïve patients with mCRPC who received AAP in routine clinical practice. Treatment effectiveness of AAP in the real-world is maintained despite patients having poorer clinical features at initiation than those observed in the COU-AA-302 trial population.

Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2.

5-(Hetero)aryl-3-(4-carboxamidophenyl)-2-aminopyridine inhibitors of CHK2 were identified from high throughput screening of a kinase-focussed compound library. Rapid exploration of the hits through straightforward chemistry established structure-activity relationships and a proposed ATP-competitive binding mode which was verified by X-ray crystallography of several analogues bound to CHK2. Variation of the 5-(hetero)aryl substituent identified bicyclic dioxolane and dioxane groups which improved the affinity and the selectivity of the compounds for CHK2 versus CHK1. The 3-(4-carboxamidophenyl) substituent could be successfully replaced by acyclic omega-aminoalkylamides, which made additional polar interactions within the binding site and led to more potent inhibitors of CHK2. Compounds from this series showed activity in cell-based mechanistic assays for inhibition of CHK2.

Impact of abiraterone acetate plus prednisone or enzalutamide on fatigue and cognition in patients with metastatic castration-resistant prostate cancer: initial results from the observational AQUARiUS study.

Introduction: Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are commonly prescribed for metastatic castration-resistant prostate cancer (mCRPC). Data comparing their effects on patient-reported outcomes (PROs) from routine clinical practice are limited. Methods: AQUARiUS (NCT02813408) is an ongoing, two-cohort, prospective, observational, non-randomised, multicentre, phase IV European study assessing the effects of AAP and ENZ on PROs in 211 patients with mCRPC over 12 months. Patients receive AAP or ENZ per routine clinical practice. Data on cognition, fatigue, pain and health-related quality of life are measured using the Functional Assessment of Cancer Therapy-Cognitive Function, Brief Fatigue Inventory-Short Form, Brief Pain Inventory-Short Form and European Organization for Research and Treatment of Cancer Quality of Life-C30 questionnaires, respectively. Results: This 3-month analysis was conducted in 105 patients; 46 received AAP and 59 received ENZ. There were statistically significant differences in mean change from baseline favouring AAP over ENZ at months 1, 2 and 3 for perceived cognitive impairments and cognitive functioning. At each time-point, ENZ-treated patients had a significantly higher risk of experiencing clinically meaningful worsening in perceived cognitive impairments versus those receiving AAP.Statistically significant differences in mean change from baseline favouring AAP over ENZ were seen for usual level of fatigue and fatigue interference at months 2 and 3 and for current fatigue and worse level of fatigue at month 3. Differences favouring AAP versus ENZ were seen for the fatigue scale of the QLQ-C30 questionnaire (months 1 and 3). There was a significantly higher risk of clinically meaningful worsening in usual level of fatigue with ENZ versus AAP at month 3.No significant differences between cohorts were observed for pain (BPI-SF) at any time-point. Conclusion: This analysis suggests more favourable outcomes with AAP versus ENZ for cognition and fatigue in the first 3 months of treatment initiation for mCRPC. These findings require confirmation from future analyses of data from AQUARiUS from a larger number of patients with a longer follow-up period.

Identification of known and novel genes whose expression is regulated by endogenous retinoic acid during early embryonic development of the mouse.

Retinoic acid (RA) derived from vitamin A is necessary for, among other things, mammalian embryonic development. Although the impact of RA-dependent gene-regulation on embryonic development has been examined through genetic disruption of the retinoid receptors, the understanding of the underlying molecular mechanism remain unclear, in part, due to the difficulty in identifying RA-regulated genes in an intact embryo. We report here that RA-regulated genes can be identified from total RA-deficient embryos created by retinol-binding protein antisense (RBP-AS) oligodeoxynucleotide treatment in conjunction with differential display. Of the 28 genes isolated, 15 genes matched known genes in the GenBank database and the others either represented EST sequences or encoded novel genes. Semi-quantitative reverse transcriptase-polymerase chain reaction verified that the mRNA levels of mouse DN 38, COL VI 3 alpha, cul-1, alpha-tropomyosin, and PP2A-C alpha were substantially increased, whereas mouse Msh 2, Ndufa2, Ribosomal protein S19, sFRP-1, GDAP-10 and mSmcD were significantly decreased in vitamin A deficient (VAD) embryos compared to the control embryos. The utility of the method is exemplified by our finding that several genes in the Wnt signaling pathway are vitamin A regulated in day 9.0 post coitum (p.c.) embryos.

CCT241533 is a potent and selective inhibitor of CHK2 that potentiates the cytotoxicity of PARP inhibitors.

CHK2 is a checkpoint kinase involved in the ATM-mediated response to double-strand DNA breaks. Its potential as a drug target is still unclear, but inhibitors of CHK2 may increase the efficacy of genotoxic cancer therapies in a p53 mutant background by eliminating one of the checkpoints or DNA repair pathways contributing to cellular resistance. We report here the identification and characterization of a novel CHK2 kinase inhibitor, CCT241533. X-ray crystallography confirmed that CCT241533 bound to CHK2 in the ATP pocket. This compound inhibits CHK2 with an IC(50) of 3 nmol/L and shows minimal cross-reactivity against a panel of kinases at 1 µmol/L. CCT241533 blocked CHK2 activity in human tumor cell lines in response to DNA damage, as shown by inhibition of CHK2 autophosphorylation at S516, band shift mobility changes, and HDMX degradation. CCT241533 did not potentiate the cytotoxicity of a selection of genotoxic agents in several cell lines. However, this compound significantly potentiates the cytotoxicity of two structurally distinct PARP inhibitors. Clear induction of the pS516 CHK2 signal was seen with a PARP inhibitor alone, and this activation was abolished by CCT241533, implying that the potentiation of PARP inhibitor cell killing by CCT241533 was due to inhibition of CHK2. Consequently, our findings imply that CHK2 inhibitors may exert therapeutic activity in combination with PARP inhibitors.

Structure-based design of potent and selective 2-(quinazolin-2-yl)phenol inhibitors of checkpoint kinase 2.

Structure-based design was applied to the optimization of a series of 2-(quinazolin-2-yl)phenols to generate potent and selective ATP-competitive inhibitors of the DNA damage response signaling enzyme checkpoint kinase 2 (CHK2). Structure-activity relationships for multiple substituent positions were optimized separately and in combination leading to the 2-(quinazolin-2-yl)phenol 46 (IC(50) 3 nM) with good selectivity for CHK2 against CHK1 and a wider panel of kinases and with promising in vitro ADMET properties. Off-target activity at hERG ion channels shown by the core scaffold was successfully reduced by the addition of peripheral polar substitution. In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533).

Expression of WNT signalling pathway genes during chicken craniofacial development.

A comprehensive expression analysis of WNT signalling pathway genes during several stages of chicken facial development was performed. Thirty genes were surveyed including: WNT1, 2B, 3A, 4, 5A, 5B, 6, 7A, 7B, 8B, 8C, 9A, 9B, 11, 11B, 16, CTNNB1, LEF1, FRZB1, DKK1, DKK2, FZD1-8, FZD10. The strictly canonical WNTs (2B, 7A, 9B, and 16) in addition to WNT4 WNT6 (both canonical and non-canonical) are epithelially expressed, whereas WNT5A, 5B, 11 are limited to the mesenchyme. WNT16 is limited to the invaginating nasal pit, respiratory epithelium, and lip fusion zone. Antagonists DKK1 and FRZB1 are expressed in the fusing primary palate but then are decreased at stage 28 when fusion is beginning. This suggests that canonical WNT signalling may be active during lip fusion. Mediators of canonical signalling, CTNNB1, LEF1, and the majority of the FZD genes are expressed ubiquitously. These data show that activation of the canonical WNT pathway is feasible in all regions of the face; however, the localization of ligands and antagonists confers specificity.

CHK2 kinase: cancer susceptibility and cancer therapy - two sides of the same coin?

In the past decade, CHK2 has emerged as an important multifunctional player in the DNA-damage response signalling pathway. Parallel studies of the human CHEK2 gene have also highlighted its role as a candidate multiorgan tumour susceptibility gene rather than a highly penetrant predisposition gene for Li-Fraumeni syndrome. As discussed here, our current understanding of CHK2 function in tumour cells, in both a biological and genetic context, suggests that targeted modulation of the active kinase or exploitation of its loss in tumours could prove to be effective anti-cancer strategies.

Pitx2 promotes development of splanchnic mesoderm-derived branchiomeric muscle.

Recent experiments, showing that both cranial paraxial and splanchnic mesoderm contribute to branchiomeric muscle and cardiac outflow tract (OFT) myocardium, revealed unexpected complexity in development of these muscle groups. The Pitx2 homeobox gene functions in both cranial paraxial mesoderm, to regulate eye muscle, and in splanchnic mesoderm to regulate OFT development. Here, we investigated Pitx2 in branchiomeric muscle. Pitx2 was expressed in branchial arch core mesoderm and both Pitx2 null and Pitx2 hypomorphic embryos had defective branchiomeric muscle. Lineage tracing with a Pitx2cre allele indicated that Pitx2 mutant descendents moved into the first branchial arch. However, markers of both undifferentiated core mesoderm and specified branchiomeric muscle were absent. Moreover, lineage tracing with a Myf5cre allele indicated that branchiomeric muscle specification and differentiation were defective in Pitx2 mutants. Conditional inactivation in mice and manipulation of Pitx2 expression in chick mandible cultures revealed an autonomous function in expansion and survival of branchial arch mesoderm.

Regulation of myogenic differentiation in the developing limb bud.

The limb myogenic precursors arise by delamination from the lateral dermomyotome in response to signals from the lateral plate mesoderm. They subsequently migrate into the developing limb bud where they switch on the expression of the myogenic regulatory factors, MyoD and Myf5, and coalese to form the dorsal and ventral muscle masses. The myogenic cells subsequently undergo terminal differentiation into slow or fast fibres which have distinct contractile properties determining how a muscle will function. In general, fast fibres contract rapidly with high force and are characterized by the expression of fast myosin heavy chains (MyHC). These fibres are needed for movement. In contrast, slow fibres express slow MyHC, contract slowly and are required for maintenance of posture. This review focuses on the molecular signals that control limb myogenic development from the initial delamination and migration of the premyogenic cells to the ultimate formation of the complex muscle pattern and differentiation of slow and fast fibres.