Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient-derived osteosarcoma cells and synergizes with cisplatin and talazoparib

Progress in the systemic control of osteosarcoma has been limited over the past decades thus indicating the urgent clinical need for the development of novel treatment strategies. Therefore, we have recently developed new preclinical models to study promising novel agents for the treatment of pediatric osteosarcoma. The checkpoint kinase (chk) inhibitor prexasertib (LY2606368) and its salt form (LSN2940930) have recently been shown to be active in adult and pediatric malignancies, including sarcoma. We have now tested the potency of prexasertib in clonogenic survival assays in two new lines of primary patient-derived osteosarcoma cells and in two established osteosarcoma cell lines as a single agent and in combination with cisplatin and the poly ADP-ribose polymerase (PARP) inhibitor talazoparib. Prexasertib alone results in strongly reduced clonogenic survival at low nanomolar concentrations and acts by affecting cell cycle progression, induction of apoptosis and induction of double-stranded DNA breakage at concentrations that are well below clinically tolerable and safe plasma concentrations. In combination with cisplatin and talazoparib, prexasertib acts in a synergistic fashion. Chk1 inhibition by prexasertib and its combination with the DNA damaging agent cisplatin and the PARP-inhibitor talazoparib thus emerges as a potential new treatment option for pediatric osteosarcoma which will now have to be tested in preclinical primary patient derived in vivo models and clinical studies.     

PELP1 signaling contributes to medulloblastoma progression by regulating the NF-κB pathway

Medulloblastoma (MB) is the most common and deadliest brain tumor in children. Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is a scaffolding protein and its oncogenic signaling is implicated in the progression of several cancers. However, the role of PELP1 in the progression of MB remains unknown. The objective of this study is to examine the role of PELP1 in the progression of MB. Immunohistochemical analysis of MB tissue microarrays revealed that PELP1 is overexpressed in the MB specimens compared to normal brain. Knockdown of PELP1 reduced cell proliferation, cell survival, and cell invasion of MB cell lines. The RNA-sequencing analysis revealed that PELP1 knockdown significantly downregulated the pathways related to inflammation and extracellular matrix. Gene set enrichment analysis confirmed that the PELP1-regulated genes were negatively correlated with nuclear factor-κB (NF-κB), extracellular matrix, and angiogenesis gene sets. Interestingly, PELP1 knockdown reduced the expression of NF-κB target genes, NF-κB reporter activity, and inhibited the nuclear translocation of p65. Importantly, the knockdown of PELP1 significantly reduced in vivo MB progression in orthotopic models and improved the overall mice survival. Collectively, these results suggest that PELP1 could be a novel target for therapeutic intervention in MB.     

Prevalence and correlates of everyday discrimination among black Caribbeans in the United States: the impact of nativity and country of origin

Objectives: Black Caribbeans in the United States have been the victims of major discrimination (e.g. unfairly fired, denied a promotion, denied housing). What is not known is the degree to which they also experience more routine forms of everyday discrimination such as receiving poor restaurant service, being perceived as dishonest, and being followed in stores. This paper investigates the distribution and correlates of everyday discrimination among a national sample of black Caribbeans in the U.S.

Design: This analysis used the black Caribbean sub-sample (n?=?1,621) of the National Survey of American Life. Demographic and immigration status correlates of ten items from the Everyday Discrimination Scale were investigated: being treated with less courtesy, treated with less respect, receiving poor restaurant service, being perceived as not smart, being perceived as dishonest, being perceived as not as good as others, and being feared, insulted, harassed, or followed in stores.

Results: Roughly one out of ten black Caribbeans reported that, on a weekly basis, they were treated with less courtesy and other people acted as if they were better than them, were afraid of them, and as if they were not as smart. Everyday discrimination was more frequent for black Caribbeans who were male, never married, divorced/separated, earned higher incomes, and who were second or third generation immigrants. Black Caribbeans attributed the majority of the discrimination they experienced to their race.

Conclusion: To our knowledge, this is the first study to provide an in-depth investigation of everyday discrimination among the black Caribbean population. It provides the frequency, types and correlates of everyday discrimination reported by black Caribbeans in the United States. Understanding the frequency and types of discrimination is important because of the documented negative impacts of everyday discrimination on physical and mental health.     

Integration of Genomic and Transcriptional Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases

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Anthropometric and reproductive factors and risk of esophageal and gastric cancer by subtype and subsite: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Obesity has been associated with upper gastrointestinal cancers; however, there are limited prospective data on associations by subtype/subsite. Obesity can impact hormonal factors, which have been hypothesized to play a role in these cancers. We investigated anthropometric and reproductive factors in relation to esophageal and gastric cancer by subtype and subsite for 476,160 participants from the European Prospective Investigation into Cancer and Nutrition cohort. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox models. During a mean follow-up of 14 years, 220 esophageal adenocarcinomas (EA), 195 esophageal squamous cell carcinomas, 243 gastric cardia (GC) and 373 gastric noncardia (GNC) cancers were diagnosed. Body mass index (BMI) was associated with EA in men (BMI ≥30 vs. 18.5–25 kg/m²: HR = 1.94, 95% CI: 1.25–3.03) and women (HR = 2.66, 95% CI: 1.15–6.19); however, adjustment for waist-to-hip ratio (WHR) attenuated these associations. After mutual adjustment for BMI and HC, respectively, WHR and waist circumference (WC) were associated with EA in men (HR = 3.47, 95% CI: 1.99–6.06 for WHR >0.96 vs. <0.91; HR = 2.67, 95% CI: 1.52–4.72 for WC >98 vs. <90 cm) and women (HR = 4.40, 95% CI: 1.35–14.33 for WHR >0.82 vs. <0.76; HR = 5.67, 95% CI: 1.76–18.26 for WC >84 vs. <74 cm). WHR was also positively associated with GC in women, and WC was positively associated with GC in men. Inverse associations were observed between parity and EA (HR = 0.38, 95% CI: 0.14–0.99; >2 vs. 0) and age at first pregnancy and GNC (HR = 0.54, 95% CI: 0.32–0.91; >26 vs. <22 years); whereas bilateral ovariectomy was positively associated with GNC (HR = 1.87, 95% CI: 1.04–3.36). These findings support a role for hormonal pathways in upper gastrointestinal cancers.     

Impact of postoperative radiotherapy on survival and loco-regional control in node-negative oral cavity tumours classified as T3 using the AJCC Cancer Staging Manual eighth edition

According to the eighth edition of the AJCC Cancer Staging Manual (AJCC8), a depth of invasion (DOI) >10 mm is classified as pT3, representing a locally advanced tumour requiring postoperative radiotherapy (PORT). When node-negative, however, evidence regarding whether PORT improves loco-regional control or survival is unclear. To clarify this, two cohorts of patients were studied: (1) patients classified as pT3N0 by the seventh edition of the AJCC manual (AJCC7), with DOI >10 mm and a tumour diameter >4 cm (17 patients who received PORT), and (2) patients classified as pT1N0 and pT2N0 by AJCC7, with DOI >10 mm and a tumour diameter <4 cm (55 patients who did not receive PORT). Loco-regional control and survival were analysed. PORT was found not to impact overall survival or disease-free survival. It was also found not to impact local, regional, or distant recurrence. Although the two subsets of patients considered here (DOI >10 mm with tumour diameter below or above 4 cm) were previously distinct, they are both considered pT3 in AJCC8. Data from this study indicate that the routine administration of PORT to patients with a DOI >10 mm may not be warranted in the absence of other risk features such as nodal disease or close margins.