Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Πέμπτη 18 Μαΐου 2017
Scarlet Fever
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
Panobinostat Enhances Growth Suppressive Effects of Progestin on Endometrial Carcinoma by Increasing Progesterone Receptor and Mitogen-Inducible Gene-6
Abstract
Although progestin has been used to treat endometrial hyperplasia and endometrial carcinoma (EC), its therapeutic efficacy is limited. In order to improve this, the underlining mechanisms of the effects of progestin need to be elucidated in more detail. In the present study, we examined the involvement of mitogen-inducible gene-6 (MIG6), a negative regulator of the EGF receptor, in the progestin-mediated growth suppression of endometrial epithelia. The immunohistochemical expression of MIG6 was elevated in the early to mid-secretory phases of normal endometrium and also with endometrial hyperplasia after medroxyprogesterone acetate (MPA) therapy. The addition of progesterone (P4) to progesterone receptor (PR)-positive EC cells reduced the viability and induced MIG6 messenger RNA (mRNA) and protein expression. The silencing of MIG6 using siRNA eliminated the P4-mediated reduction of EC cell viability, indicating that MIG6 is an essential downstream component of PR-mediated growth suppression. In order to enhance PR-driven signals, we examined the effects of histone deacetylase (HDAC) inhibitors because histone acetylation has been shown to increase the expression of PR. The addition of three HDAC inhibitors (panobinostat, LBH589; trichostatin A, TSA; suberoylanilide hydroxamic acid, SAHA) decreased the viability of EC cells and up-regulated the expression of PR and MIG6, and these effects were the strongest with LBH589. The addition of LBH589 and MPA synergistically decreased the viability and increased apoptosis in EC cells. These results indicate that LBH589 has potential as an enhancer of progestin therapy via the up-regulation of PR and MIG6.
http://ift.tt/2rxyhtk
Clinical experience of stereotactic radiosurgery at a linear accelerator for intraocular melanoma.
Long-term results with linear accelerator LINAC-based stereotactic radiosurgery for intraocular uveal malignant melanoma were assessed. A retrospective study was carried out of patients with uveal melanoma after a 1-day session stereotactic radiosurgery at LINAC in Slovakia. In the period 2001-2015, a group of 150 patients with uveal melanoma (139 choroidal melanoma, 11 ciliary body melanoma) was treated. The median tumor volume at baseline was 0.5 cm3 (with range from 0.2 to 1.6 cm3). Tumors ranged in size from 2.4 to 20.8 mm in basal diameter and from 2.0 to 18.3 mm in thickness. The therapeutic dose was 35.0 Gy by 99% of dose volume histogram. Older age at treatment was correlated with the largest basal tumor diameter, tumor thickness, and TNM stage. The survival after stereotactic irradiation was 96% in 1 year, 93% in 2 years, 84% in 5 years, 80% in 7 years, and 53% in 11 years. In 20 (13.3%) patients, secondary enucleation was necessary because of complications (secondary glaucoma). Enucleation-free interval ranged from 1 to 6 years. The median age at death was lower (65.7 years) for patients who died from metastatic disease than for those who died from any other cause (75.0 years). Survival rates at 5-year intervals and the need for secondary enucleation because of complications after linear accelerator irradiation are comparable to other techniques. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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Cancer incidence in the Western Australian mining industry (1996–2013)
Source:Cancer Epidemiology, Volume 49
Author(s): Nita Sodhi-Berry, Alison Reid, Lin Fritschi, AW (Bill) Musk, Roel Vermeulen, Nicholas de Klerk, Susan Peters
BackgroundMiners are frequently exposed to established and potential carcinogens. We aimed to assess cancer incidence in miners relative to the general population and identify high-risk subgroups.MethodsIncident cancers in Western Australian miners (n=153,922; 86% male) during 1996–2013 were identified. Indirectly standardised incidence ratios (SIRs) were calculated and mixed-effects Poisson models were used to calculate Incidence Rate Ratios (IRRs) to identify high-risk within-cohort subgroups.ResultsCompared with the general population, the overall cancer incidence in miners (n=4194 cases) was lower for both females (SIR:0.83, 95%CI:0.74–0.92) and males (SIR:0.96, 95%CI:0.93–0.99). Overall, cancer incidence did not differ by employment duration or employment commencement time. Ever-underground work was associated with lung cancer (IRR:1.81, 95%CI:1.11–2.93). Relative to multi-ore miners, IRRs for specific cancers were significantly different when exclusively mining: iron (prostate:0.73, 95%CI:0.56–0.94); gold (lung:1.77, 95%CI:1.04–3.01 and colorectum:1.70, 95%CI:1.16–2.51); and other metals (urinary tract:1.85, 95%CI:1.03–3.31 and leukaemia:0.36, 95%CI:0.14–0.96).ConclusionWorking underground emerged as a significant determinant of lung cancer risk in our contemporary mining cohort. Increased risks of lung, prostate, colorectal and urinary tract cancers and leukaemia were identified in miners of specific ores. These findings underline the importance of continued surveillance of the health and exposures of this relatively young cohort of miners.
http://ift.tt/2pZagKS
Modelling lung cancer mortality rates from smoking prevalence: Fill in the gap
Source:Cancer Epidemiology, Volume 49
Author(s): Juan Carlos Martín-Sánchez, Usama Bilal, Ramon Clèries, Cristina Lidón-Moyano, Marcela Fu, Luís González-de Paz, Manuel Franco, Esteve Fernandez, Jose M. Martínez-Sánchez
BackgroundThe objective of this study is to estimate the gap between smoking prevalence and lung cancer mortality and provide predictions of lung cancer mortality based on previous smoking prevalence.Materials and methodsWe used data from the Spanish National Health Surveys (2003, 2006 and 2011) to obtain information about tobacco use and data from the Spanish National Statistics Institute to obtain cancer mortality rates from 1980 to 2013. We calculated the cross-correlation among the historical series of smoking prevalence and lung cancer mortality rate (LCMR) to estimate the most likely time gap between both series. We also predicted the magnitude and timing of the LCMR peak.ResultsAll cross-correlations were statistically significant and positive (all above 0.8). For men, the most likely gap ranges from 20 to 34 years. The age-adjusted LCMR increased by 3.2 deaths per 100,000 people for every 1 unit increase in the smoking prevalence 29 years earlier. The highest rate for men was observed in 1995 (55.6 deaths). For women, the most likely gap ranges from 10 to 37 years. The age-adjusted LCMR increased by 0.28 deaths per 100,000 people for every 1 unit increase in the smoking prevalence 32 years earlier. The maximum rate is expected to occur in 2026 (10.3 deaths).ConclusionThe time series of prevalence of tobacco smoking explains the mortality from lung cancer with a distance (or gap) of around 30 years. According to the lagged smoking prevalence, the lung cancer mortality among men is declining while in women continues to rise (maximum expected in 2026).
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The association of lifetime physical inactivity with bladder and renal cancer risk: A hospital-based case-control analysis
Source:Cancer Epidemiology, Volume 49
Author(s): Rikki Cannioto, John Lewis Etter, Lauren Beryl Guterman, Janine M. Joseph, Nicholas R. Gulati, Kristina L. Schmitt, Michael J. LaMonte, Ryan Nagy, Albina Minlikeeva, James Brian Szender, Kirsten B. Moysich
ObjectivesRecreational physical inactivity has been gaining recognition as an independent epidemiological exposure of interest in relation to cancer endpoints due to evidence suggesting that it may associate with cancer independent of obesity. In the current analyses, we examined the associations of lifetime recreational physical inactivity with renal and bladder cancer risk.MethodsIn this hospital-based case-control study, we identified N=160 renal cancer patients, N=208 bladder cancer patients, and N=766 age frequency-matched controls without cancer. Participants self-reporting never participating in any regular/weekly recreational physical activity throughout their lifetime were classified as physically inactive. Utilizing unconditional multivariable logistic regression analyses, we estimated odds ratios and 95% confidence intervals to represent the associations between lifetime physical inactivity and renal and bladder cancer risk.ResultsIn multivariable logistic regression models, we observed significant positive associations between lifetime recreational physical inactivity and renal cancer and bladder cancer risk: odds ratio=1.77 (95% CI: 1.10–2.85) and odds ratio=1.73 (95% CI: 1.13–2.63), respectively. Similar associations also persisted among individuals who were not obese for both renal and bladder cancer: odds ratio=1.75 (95% CI: 1.03–2.98) and odds ratio=1.70 (95% CI: 1.08–2.69), respectively.ConclusionsIn this case-control study, we observed evidence of a positive association between renal and bladder cancer with lifetime recreational physical inactivity. These data add to the growing body of evidence suggesting that physical inactivity may be an important independent risk factor for cancer. However, additional studies using a larger sample and prospectively collected data are needed to substantiate the current findings.
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Changes in clinical laboratory parameters and pharmacodynamic markers in response to blinatumomab treatment of patients with relapsed/refractory ALL
Abstract
Background
Blinatumomab has shown a remission rate of 69% in an exploratory single-arm, phase II dose-escalation study in adult patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We evaluated changes in laboratory parameters and immunopharmacodynamic markers in patients who received blinatumomab in the exploratory phase II study.
Methods
Data from 36 adults with relapsed/refractory ALL receiving blinatumomab as 4-week continuous IV infusions in various dose cohorts were analyzed for changes in liver enzymes, first-dose parameters, peripheral blood cell subpopulations, and cytokine/granzyme B release. Associations with clinical response were evaluated.
Results
Liver enzymes and inflammatory parameters transiently increased primarily during the first treatment week without clinical symptoms and reversed to baseline levels thereafter. B and T cells showed expected depletion and redistribution kinetics, respectively. Similarly, thrombocytes and T cells displayed an initial decline in cell counts, whereas neutrophils peaked during the first days after infusion start. T-cell redistribution coincided with upregulation of LFA-1 and CD69. Patients who responded to blinatumomab had more pronounced T-cell expansion, which was associated with proliferation of CD4+ and CD8+ T cells and memory subsets. Release of cytokines and granzyme B primarily occurred during the first week of cycle 1, except for IL-10, which was released in subsequent cycles. Blinatumomab step-dosing was associated with lower cytokine release and lower body temperature.
Conclusions
In this study of relapsed/refractory ALL, blinatumomab-induced changes in laboratory parameters were transient and reversible. The evaluated PD markers demonstrated blinatumomab activity, and the analysis of cytokines supported the rationale for stepwise dosing.
(ClinicalTrials.gov Identifier NCT01209286.)
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Prognostic factors of adenoid cystic carcinoma of the head and neck in carbon-ion radiotherapy: The impact of histological subtypes
The aim of this study was to evaluate the effect of histological subtypes of head and neck adenoid cystic carcinoma (ACC) on the results of carbon-ion radiotherapy (CIRT).
http://ift.tt/2qzoPYm
Clinical and prognostic significance of HIF-1α overexpression in oral squamous cell carcinoma: a meta-analysis
Abstract
Background
Recent studies have indicated an association between hypoxia inducible factor-1 alpha (HIF-1α) expression and poor prognosis in patients with oral squamous cell carcinoma (OSCC); however, definitive evidence of this association is yet to be obtained. We performed a meta-analysis to evaluate the association of HIF-1α expression with clinicopathological characteristics and overall survival (OS) of patients with OSCC.
Methods
A literature search for relevant studies published in English language as of February 05, 2016, was performed on PubMed, Web of Science, and EMBASE databases. Eighteen studies with a combined study population of 1474 patients with OSCC are included in the meta-analysis. Odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) was calculated using random-effects model or fixed-effects model.
Results
HIF-1α overexpression was significantly associated with larger tumor size (OR = 2.28, 95% CI = 1.49–3.50, P = 0.017), advanced TNM stage (OR = 2.29, 95% CI = 1.50–3.49, P = 0.158), and lymph node metastasis (OR = 2.05, 95% CI = 1.19–3.53, P < 0.001), but not with poor differentiation (OR = 1.21, 95% CI = 0.55–2.64, P = 0.024). These results demonstrated an association between HIF-1α expression and biological behavior of OSCC. On pooled analyses, high expression of HIF-1α was associated with worse OS (HR = 1.70, 95% CI = 1.10–2.61, P < 0.001). On subgroup analyses, overexpression of HIF-1α was significantly associated with poor prognosis in Asian population (HR = 2.33, 95% CI = 1.72–3.15, P = 0.862).
Conclusions
Our findings demonstrate an association of HIF-1α overexpression with tumor size, tumor stage, lymph node metastasis, and overall survival. HIF-1α could be an independent prognostic marker in patients with OSCC.
http://ift.tt/2rxrPTi
Clinical and prognostic significance of HIF-1α overexpression in oral squamous cell carcinoma: a meta-analysis
Abstract
Background
Recent studies have indicated an association between hypoxia inducible factor-1 alpha (HIF-1α) expression and poor prognosis in patients with oral squamous cell carcinoma (OSCC); however, definitive evidence of this association is yet to be obtained. We performed a meta-analysis to evaluate the association of HIF-1α expression with clinicopathological characteristics and overall survival (OS) of patients with OSCC.
Methods
A literature search for relevant studies published in English language as of February 05, 2016, was performed on PubMed, Web of Science, and EMBASE databases. Eighteen studies with a combined study population of 1474 patients with OSCC are included in the meta-analysis. Odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) was calculated using random-effects model or fixed-effects model.
Results
HIF-1α overexpression was significantly associated with larger tumor size (OR = 2.28, 95% CI = 1.49–3.50, P = 0.017), advanced TNM stage (OR = 2.29, 95% CI = 1.50–3.49, P = 0.158), and lymph node metastasis (OR = 2.05, 95% CI = 1.19–3.53, P < 0.001), but not with poor differentiation (OR = 1.21, 95% CI = 0.55–2.64, P = 0.024). These results demonstrated an association between HIF-1α expression and biological behavior of OSCC. On pooled analyses, high expression of HIF-1α was associated with worse OS (HR = 1.70, 95% CI = 1.10–2.61, P < 0.001). On subgroup analyses, overexpression of HIF-1α was significantly associated with poor prognosis in Asian population (HR = 2.33, 95% CI = 1.72–3.15, P = 0.862).
Conclusions
Our findings demonstrate an association of HIF-1α overexpression with tumor size, tumor stage, lymph node metastasis, and overall survival. HIF-1α could be an independent prognostic marker in patients with OSCC.
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Differential effects of early-life nutrient restriction in long-lived GHR-KO and normal mice
Abstract
There is increasing evidence that growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling (collectively referred to as somatotropic signaling) during development has a profound influence on aging and longevity. Moreover, the absence of GH action was shown to modify responses of adult mice to calorie restriction (CR) and other antiaging interventions. It was therefore of interest to determine whether GH resistance in GH receptor knockout (GHR-KO) mice would modify the effects of mild pre-weaning CR imposed by increasing the number of pups in a litter (the so-called litter crowding). In addition to the expected impact on body weight, litter crowding affected glucose homeostasis, hepatic expression of IGF-1 and genes related to lipid metabolism, and expression of inflammatory markers in white adipose tissue, with some of these effects persisting until the age of 2 years. Litter crowding failed to further extend the remarkable longevity of GHR-KO mice and, instead, reduced late life survival of GHR-KO females, an effect opposite to the changes detected in normal animals. We conclude that the absence of GH actions alters the responses to pre-weaning CR and prevents this intervention from extending longevity.
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Breast cancer and exposure to tobacco smoke during potential windows of susceptibility
Abstract
Purpose
An association between smoking and breast cancer is unresolved, although a higher risk from exposure during windows of susceptibility has been proposed. The objective of this prospective study was to evaluate the association between tobacco smoke and breast cancer with a focus on timing of exposure, especially during early life.
Methods
Sister study participants (n = 50,884) aged 35–74 were enrolled from 2003 to 2009. Women in the United States and Puerto Rico were eligible if they were breast cancer-free but had a sister with breast cancer. Participants completed questionnaires on smoking and environmental tobacco smoke (ETS) exposure. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for breast cancer risk.
Results
During follow-up (mean = 6.4 years), 1,843 invasive breast cancers were diagnosed. Neither active smoking nor adult ETS was associated with breast cancer risk. However, never smoking women exposed to ETS throughout their childhood had a 17% higher risk of breast cancer (95% CI 1.00–1.36) relative to those with no exposure. In utero ETS exposure was also associated with breast cancer (HR = 1.16, 95% CI 1.01–1.32) and the HR was most elevated for women born in earlier birth cohorts (<1940, HR = 1.44, 95% CI 1.02–2.02; 1940–1949, HR = 1.28, 95% CI 1.01–1.62).
Conclusion
In utero ETS and ETS exposure during childhood and adolescence were associated with increased risk of breast cancer and associations varied by birth cohort.
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Breast cancer and exposure to tobacco smoke during potential windows of susceptibility
Abstract
Purpose
An association between smoking and breast cancer is unresolved, although a higher risk from exposure during windows of susceptibility has been proposed. The objective of this prospective study was to evaluate the association between tobacco smoke and breast cancer with a focus on timing of exposure, especially during early life.
Methods
Sister study participants (n = 50,884) aged 35–74 were enrolled from 2003 to 2009. Women in the United States and Puerto Rico were eligible if they were breast cancer-free but had a sister with breast cancer. Participants completed questionnaires on smoking and environmental tobacco smoke (ETS) exposure. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for breast cancer risk.
Results
During follow-up (mean = 6.4 years), 1,843 invasive breast cancers were diagnosed. Neither active smoking nor adult ETS was associated with breast cancer risk. However, never smoking women exposed to ETS throughout their childhood had a 17% higher risk of breast cancer (95% CI 1.00–1.36) relative to those with no exposure. In utero ETS exposure was also associated with breast cancer (HR = 1.16, 95% CI 1.01–1.32) and the HR was most elevated for women born in earlier birth cohorts (<1940, HR = 1.44, 95% CI 1.02–2.02; 1940–1949, HR = 1.28, 95% CI 1.01–1.62).
Conclusion
In utero ETS and ETS exposure during childhood and adolescence were associated with increased risk of breast cancer and associations varied by birth cohort.
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SMAD4 loss is associated with cetuximab resistance and induction of MAPK/JNK activation in head and neck cancer cells
Purpose: We previously demonstrated an association between decreased SMAD4 expression and cetuximab resistance in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to further elucidate the clinical relevance of SMAD4 loss in HNSCC. Experimental Design: SMAD4 expression was assessed by immunohistochemistry in 130 newly diagnosed and 43 recurrent HNSCC patients. Correlative statistical analysis with clinicopathological data was also performed. OncoFinder, a bioinformatics tool, was used to analyze molecular signaling in TCGA tumors with low or high SMAD4 mRNA levels. The role of SMAD4 was investigated by shRNA knockdown and gene reconstitution of HPV-negative HNSCC cell lines in vitro and in vivo. Results: Our analysis revealed that SMAD4 loss was associated with an aggressive, HPV-negative, cetuximab-resistant phenotype. We found a signature of pro-survival and anti-apoptotic pathways that were commonly dysregulated in SMAD4-low cases derived from TCGA-HNSCC dataset and an independent oral cavity squamous cell carcinoma (OSCC) cohort obtained from GEO. We show that SMAD4 depletion in a HNSCC cell line induces cetuximab resistance and results in worse survival in an orthotopic mouse model in vivo. We implicate JNK and MAPK activation as mediators of cetuximab resistance and provide the foundation for the concomitant EGFR and JNK/MAPK inhibition as a potential strategy for overcoming cetuximab resistance in HNSCCs with SMAD4 loss. Conclusions: Our study demonstrates that loss of SMAD4 expression is a signature characterizing the cetuximab-resistant phenotype and suggests that SMAD4 expression may be a determinant of sensitivity/resistance to EGFR/MAPK or EGFR/JNK inhibition in HPV-negative HNSCC tumors.
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Can Microsatellite Status of Colorectal Cancer be Reliably Assessed after Neoadjuvant Therapy?
Purpose: Determination of microsatellite instability (MSI) by PCR is the gold standard; however, immunohistochemistry (IHC) of mismatch repair (MMR) proteins is frequently performed instead. The reliability of these methods on post-neoadjuvant-therapy specimens is unknown. We examined the effect of neoadjuvant therapy on MSI results by PCR and IHC. Experimental design: A total of 239 colorectal cancers resected after neoadjuvant therapy were assessed for MSI with PCR and IHC. PCR and IHC results for matched paired pre- and post-treatment specimens were compared. In parallel, two isogenic cell lines conditioned for MMR functioning and two different patient-derived xenografts (PDX) were exposed to chemotherapy, radiation or both. We also examined whether establishment of PDXs induced MSI changes in five tumors. IHC and MSI were tested after treatment to assess for changes. Results: We identified paired pre- and post-treatment specimens for 37 patients: 2 with PCR only, 34 with IHC only, and 1 with both. All three patients with PCR had microsatellite stable pre- and post-treatment specimens. Of the 35 patients with IHC, 30 had intact MMR proteins in pre- and post-treatment specimens, 1 had equivocal MLH1 staining in the pre-treatment and loss in the post-treatment specimen, and 4 had intact pre-treatment MSH6 but variable post-treatment staining. In the experimental setting, no changes in MSI status were detected after treatment or tumor implantation in animals. Conclusions: Our findings show that expression of MMR proteins, commonly MSH6, can change after neoadjuvant therapy and confirm PCR as the gold-standard test for MSI after neoadjuvant therapy.
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Cyclin D1 restrains oncogene-induced autophagy by regulating the AMPK-LKB1 signaling axis
Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclinD1-deficient model, we observed a cyclin D1-mediated reduction in AMPK activation. Mechanistic investigations showed that Cyclin D1 inhibited mitochondrial function, promoted glycolysis and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1. Our findings suggest how AMPK activation by cyclin D1 may couple cell proliferation to energy homeostasis.
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MET exon 14 mutation encodes an actionable therapeutic target in lung adenocarcinoma
Targeting somatically activated oncogenes has revolutionized the treatment of non-small cell lung cancer (NSCLC). Mutations in the gene mesenchymal-epithelial transition (MET) near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (METΔ14). Here we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. METΔ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a Hepatocyte growth factor (HGF)-dependent manner. Additionally, overexpression of the orthologous mouse allele induced lung adenocarcinoma in a novel, immunocompetent mouse model. Met inhibition showed clinical benefit in this model. Additionally, we observed a clinical response to crizotinib in a patient with METΔ14-driven NSCLC, only to observe new missense mutations in the MET activation loop, critical for binding to crizotinib, upon clinical progression. These findings support genomically selected clinical trials directed towards METΔ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an in vivo system for the study of METΔ14 in an immunocompetent host.
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Mismatch Repair Proteins Initiate Epigenetic Alterations During Inflammation-Driven Tumorigenesis
Aberrant silencing of genes by DNA methylation contributes to cancer, yet how this process is initiated remains unclear. Using a murine model of inflammation-induced tumorigenesis, we tested the hypothesis that inflammation promotes recruitment of epigenetic proteins to chromatin, initiating methylation and gene silencing in tumors. Compared to normal epithelium and non-inflammation-induced tumors, inflammation-induced tumors gained DNA methylation at CpG islands, some of which are associated with putative tumor suppressor genes. Hypermethylated genes exhibited enrichment of repressive chromatin marks and reduced expression prior to tumorigenesis, at a time point coinciding with peak levels of inflammation-associated DNA damage. Loss of MutS homolog 2 (MSH2), a mismatch repair (MMR) protein, abrogated early inflammation-induced epigenetic alterations and DNA hypermethylation alterations observed in inflammation-induced tumors. These results indicate that early epigenetic alterations initiated by inflammation and MMR proteins lead to gene silencing during tumorigenesis, revealing a novel mechanism of epigenetic alterations in inflammation-driven cancer. Understanding such mechanisms will inform development of pharmacotherapies to reduce carcinogenesis.
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Targeting FBW7 as a strategy to overcome resistance to targeted therapy in non-small cell lung cancer
Inhibition of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) signaling is highly effective in a subgroup of non-small cell lung cancer (NSCLC) patients with distinct clinicopathological features. However, resistance to EGFR and ALK inhibitors inevitably occurs, and the molecular mechanism underlying resistance is not fully understood. In this study, we report a PI3K/Akt- and MEK/Erk-independent resistance mechanism by which loss of the E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBW7α) leads to targeted therapy resistance via stabilization of anti-apoptotic protein MCL-1. Using a panel of in vitro and in vivo studies, we showed that the regulatory machinery responsible for MCL-1 protein degradation was a step-wise event involving phosphorylation and nucleus translocation. Erk cooperated with GSKβ to phosphorylate MCL-1 Ser159 residue, which enabled MCL-1 to translocate into the nucleus and bind FBW7. Defects in this sequence impaired MCL-1 degradation and cell apoptosis, recapitulating phenotypes observed in FBW7 deficiency. Downregulation of FBW7 was found in EGFR inhibitor-resistant human NSCLC specimens and correlated with increased MCL-1 protein expression. Reactivation of FBW7 sensitized resistant cells to targeted therapy and facilitated MCL-1 degradation. Overall, our study provides proof-of-principle insight into a PI3K/Akt- and MEK/Erk-independent resistant model and suggests that targeting FBW7 can overcome resistance to targeted therapy.
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Inhibition of mitochondrial matrix chaperones and anti-apoptotic Bcl-2 family proteins empower antitumor therapeutic responses
Rational therapeutic approaches based on synthetic lethality may improve cancer management. Based on a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and Obatoclax) or selective (ABT199, WEHI-539 and A1210477), along with the established mitochondrial matrix chaperone inhibitor Gamitrinib-TPP. Drug combinations were tested in various therapy-resistant tumors in vitro and in vivo in murine model systems of melanoma, triple-negative breast cancer and patient-derived orthotopic xenografts of human glioblastoma (PDX). We found that combining BH3-mimetics and Gamitrinib-TPP blunted cellular proliferation in a synergistic manner by massive activation of intrinsic apoptosis. In like manner, suppressing either Bcl-2, Bcl-xL or Mcl-1 recapitulated the effects of BH3-mimetics and enhanced the effects of Gamitrinib-TPP. Mechanistic investigations revealed that Gamitrinib-TPP activated a PERK-dependent integrated stress response which activated the pro-apoptotic BH3 protein Noxa and its downstream targets Usp9X and Mcl-1. Notably, in the PDX glioblastoma and BRAFi-resistant melanoma models, this drug combination safely and significantly extended host survival. Our results show how combining mitochondrial chaperone and Bcl-2 family inhibitors can synergize to safely degrade the growth of tumors recalcitrant to other treatments.
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Expansion of tumor-infiltrating CD8+ T cells expressing PD-1 improves the efficacy of adoptive T cell therapy
Recent studies have found that tumor-infiltrating lymphocytes (TIL) expressing PD-1 can recognize autologous tumor cells, suggesting that cells derived from PD-1+ TIL can be used in adoptive T cell therapy (ACT). However, no study thus far has evaluated the antitumor activity of PD-1-selected TIL in vivo. In two mouse models of solid tumors, we show that PD-1 allows identification and isolation of tumor-specific TIL without previous knowledge of their antigen specificities. Importantly, despite the high proportion of tumor-reactive T cells present in bulk CD8 TIL before expansion, only T cell products derived from sorted PD-1+, but not from PD-1- or bulk CD8 TIL, specifically recognized tumor cells. The fold-expansion of PD-1+ CD8 TIL was 10 times lower than that of PD-1- cells, suggesting that outgrowth of PD-1- cells was the limiting factor in the tumor specificity of cells derived from bulk CD8 TIL. The highly differentiated state of PD-1+ cells was likely the main cause hampering ex vivo expansion of this subset. Moreover, PD-1 precisely identified marrow-infiltrating, myeloma-specific T cells in a mouse model of multiple myeloma. In vivo, only cells expanded from PD-1+ CD8 TIL contained tumor progression, and their efficacy was enhanced by PDL-1 blockade. Overall, our data provide a rationale for the use of PD-1-selected TIL in ACT.
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SMAD4 loss is associated with cetuximab resistance and induction of MAPK/JNK activation in head and neck cancer cells
Purpose: We previously demonstrated an association between decreased SMAD4 expression and cetuximab resistance in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to further elucidate the clinical relevance of SMAD4 loss in HNSCC. Experimental Design: SMAD4 expression was assessed by immunohistochemistry in 130 newly diagnosed and 43 recurrent HNSCC patients. Correlative statistical analysis with clinicopathological data was also performed. OncoFinder, a bioinformatics tool, was used to analyze molecular signaling in TCGA tumors with low or high SMAD4 mRNA levels. The role of SMAD4 was investigated by shRNA knockdown and gene reconstitution of HPV-negative HNSCC cell lines in vitro and in vivo. Results: Our analysis revealed that SMAD4 loss was associated with an aggressive, HPV-negative, cetuximab-resistant phenotype. We found a signature of pro-survival and anti-apoptotic pathways that were commonly dysregulated in SMAD4-low cases derived from TCGA-HNSCC dataset and an independent oral cavity squamous cell carcinoma (OSCC) cohort obtained from GEO. We show that SMAD4 depletion in a HNSCC cell line induces cetuximab resistance and results in worse survival in an orthotopic mouse model in vivo. We implicate JNK and MAPK activation as mediators of cetuximab resistance and provide the foundation for the concomitant EGFR and JNK/MAPK inhibition as a potential strategy for overcoming cetuximab resistance in HNSCCs with SMAD4 loss. Conclusions: Our study demonstrates that loss of SMAD4 expression is a signature characterizing the cetuximab-resistant phenotype and suggests that SMAD4 expression may be a determinant of sensitivity/resistance to EGFR/MAPK or EGFR/JNK inhibition in HPV-negative HNSCC tumors.
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Can Microsatellite Status of Colorectal Cancer be Reliably Assessed after Neoadjuvant Therapy?
Purpose: Determination of microsatellite instability (MSI) by PCR is the gold standard; however, immunohistochemistry (IHC) of mismatch repair (MMR) proteins is frequently performed instead. The reliability of these methods on post-neoadjuvant-therapy specimens is unknown. We examined the effect of neoadjuvant therapy on MSI results by PCR and IHC. Experimental design: A total of 239 colorectal cancers resected after neoadjuvant therapy were assessed for MSI with PCR and IHC. PCR and IHC results for matched paired pre- and post-treatment specimens were compared. In parallel, two isogenic cell lines conditioned for MMR functioning and two different patient-derived xenografts (PDX) were exposed to chemotherapy, radiation or both. We also examined whether establishment of PDXs induced MSI changes in five tumors. IHC and MSI were tested after treatment to assess for changes. Results: We identified paired pre- and post-treatment specimens for 37 patients: 2 with PCR only, 34 with IHC only, and 1 with both. All three patients with PCR had microsatellite stable pre- and post-treatment specimens. Of the 35 patients with IHC, 30 had intact MMR proteins in pre- and post-treatment specimens, 1 had equivocal MLH1 staining in the pre-treatment and loss in the post-treatment specimen, and 4 had intact pre-treatment MSH6 but variable post-treatment staining. In the experimental setting, no changes in MSI status were detected after treatment or tumor implantation in animals. Conclusions: Our findings show that expression of MMR proteins, commonly MSH6, can change after neoadjuvant therapy and confirm PCR as the gold-standard test for MSI after neoadjuvant therapy.
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Cyclin D1 restrains oncogene-induced autophagy by regulating the AMPK-LKB1 signaling axis
Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclinD1-deficient model, we observed a cyclin D1-mediated reduction in AMPK activation. Mechanistic investigations showed that Cyclin D1 inhibited mitochondrial function, promoted glycolysis and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1. Our findings suggest how AMPK activation by cyclin D1 may couple cell proliferation to energy homeostasis.
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MET exon 14 mutation encodes an actionable therapeutic target in lung adenocarcinoma
Targeting somatically activated oncogenes has revolutionized the treatment of non-small cell lung cancer (NSCLC). Mutations in the gene mesenchymal-epithelial transition (MET) near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (METΔ14). Here we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. METΔ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a Hepatocyte growth factor (HGF)-dependent manner. Additionally, overexpression of the orthologous mouse allele induced lung adenocarcinoma in a novel, immunocompetent mouse model. Met inhibition showed clinical benefit in this model. Additionally, we observed a clinical response to crizotinib in a patient with METΔ14-driven NSCLC, only to observe new missense mutations in the MET activation loop, critical for binding to crizotinib, upon clinical progression. These findings support genomically selected clinical trials directed towards METΔ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an in vivo system for the study of METΔ14 in an immunocompetent host.
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Mismatch Repair Proteins Initiate Epigenetic Alterations During Inflammation-Driven Tumorigenesis
Aberrant silencing of genes by DNA methylation contributes to cancer, yet how this process is initiated remains unclear. Using a murine model of inflammation-induced tumorigenesis, we tested the hypothesis that inflammation promotes recruitment of epigenetic proteins to chromatin, initiating methylation and gene silencing in tumors. Compared to normal epithelium and non-inflammation-induced tumors, inflammation-induced tumors gained DNA methylation at CpG islands, some of which are associated with putative tumor suppressor genes. Hypermethylated genes exhibited enrichment of repressive chromatin marks and reduced expression prior to tumorigenesis, at a time point coinciding with peak levels of inflammation-associated DNA damage. Loss of MutS homolog 2 (MSH2), a mismatch repair (MMR) protein, abrogated early inflammation-induced epigenetic alterations and DNA hypermethylation alterations observed in inflammation-induced tumors. These results indicate that early epigenetic alterations initiated by inflammation and MMR proteins lead to gene silencing during tumorigenesis, revealing a novel mechanism of epigenetic alterations in inflammation-driven cancer. Understanding such mechanisms will inform development of pharmacotherapies to reduce carcinogenesis.
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Targeting FBW7 as a strategy to overcome resistance to targeted therapy in non-small cell lung cancer
Inhibition of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) signaling is highly effective in a subgroup of non-small cell lung cancer (NSCLC) patients with distinct clinicopathological features. However, resistance to EGFR and ALK inhibitors inevitably occurs, and the molecular mechanism underlying resistance is not fully understood. In this study, we report a PI3K/Akt- and MEK/Erk-independent resistance mechanism by which loss of the E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBW7α) leads to targeted therapy resistance via stabilization of anti-apoptotic protein MCL-1. Using a panel of in vitro and in vivo studies, we showed that the regulatory machinery responsible for MCL-1 protein degradation was a step-wise event involving phosphorylation and nucleus translocation. Erk cooperated with GSKβ to phosphorylate MCL-1 Ser159 residue, which enabled MCL-1 to translocate into the nucleus and bind FBW7. Defects in this sequence impaired MCL-1 degradation and cell apoptosis, recapitulating phenotypes observed in FBW7 deficiency. Downregulation of FBW7 was found in EGFR inhibitor-resistant human NSCLC specimens and correlated with increased MCL-1 protein expression. Reactivation of FBW7 sensitized resistant cells to targeted therapy and facilitated MCL-1 degradation. Overall, our study provides proof-of-principle insight into a PI3K/Akt- and MEK/Erk-independent resistant model and suggests that targeting FBW7 can overcome resistance to targeted therapy.
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Inhibition of mitochondrial matrix chaperones and anti-apoptotic Bcl-2 family proteins empower antitumor therapeutic responses
Rational therapeutic approaches based on synthetic lethality may improve cancer management. Based on a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and Obatoclax) or selective (ABT199, WEHI-539 and A1210477), along with the established mitochondrial matrix chaperone inhibitor Gamitrinib-TPP. Drug combinations were tested in various therapy-resistant tumors in vitro and in vivo in murine model systems of melanoma, triple-negative breast cancer and patient-derived orthotopic xenografts of human glioblastoma (PDX). We found that combining BH3-mimetics and Gamitrinib-TPP blunted cellular proliferation in a synergistic manner by massive activation of intrinsic apoptosis. In like manner, suppressing either Bcl-2, Bcl-xL or Mcl-1 recapitulated the effects of BH3-mimetics and enhanced the effects of Gamitrinib-TPP. Mechanistic investigations revealed that Gamitrinib-TPP activated a PERK-dependent integrated stress response which activated the pro-apoptotic BH3 protein Noxa and its downstream targets Usp9X and Mcl-1. Notably, in the PDX glioblastoma and BRAFi-resistant melanoma models, this drug combination safely and significantly extended host survival. Our results show how combining mitochondrial chaperone and Bcl-2 family inhibitors can synergize to safely degrade the growth of tumors recalcitrant to other treatments.
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Expansion of tumor-infiltrating CD8+ T cells expressing PD-1 improves the efficacy of adoptive T cell therapy
Recent studies have found that tumor-infiltrating lymphocytes (TIL) expressing PD-1 can recognize autologous tumor cells, suggesting that cells derived from PD-1+ TIL can be used in adoptive T cell therapy (ACT). However, no study thus far has evaluated the antitumor activity of PD-1-selected TIL in vivo. In two mouse models of solid tumors, we show that PD-1 allows identification and isolation of tumor-specific TIL without previous knowledge of their antigen specificities. Importantly, despite the high proportion of tumor-reactive T cells present in bulk CD8 TIL before expansion, only T cell products derived from sorted PD-1+, but not from PD-1- or bulk CD8 TIL, specifically recognized tumor cells. The fold-expansion of PD-1+ CD8 TIL was 10 times lower than that of PD-1- cells, suggesting that outgrowth of PD-1- cells was the limiting factor in the tumor specificity of cells derived from bulk CD8 TIL. The highly differentiated state of PD-1+ cells was likely the main cause hampering ex vivo expansion of this subset. Moreover, PD-1 precisely identified marrow-infiltrating, myeloma-specific T cells in a mouse model of multiple myeloma. In vivo, only cells expanded from PD-1+ CD8 TIL contained tumor progression, and their efficacy was enhanced by PDL-1 blockade. Overall, our data provide a rationale for the use of PD-1-selected TIL in ACT.
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The potential role of infectious agents and pelvic inflammatory disease in ovarian carcinogenesis
Abstract
Background
The etiological cause of ovarian cancer is poorly understood. It has been theorized that bacterial or viral infection as well as pelvic inflammatory disease could play a role in ovarian carcinogenesis.
Aim
To review the literature on studies examining the association between ovarian cancer and bacterial or viral infection or pelvic inflammatory disease.
Methods
Database search through MEDLINE, applying the medical subject headings: "Ovarian neoplasms", AND "Chlamydia infections", "Neisseria gonorrhoeae", "Mycoplasma genitalium", "Papillomaviridae", or "pelvic inflammatory disease". Corresponding searches were performed in EMBASE, and Web of Science. The literature search identified 935 articles of which 40 were eligible for inclusion in this review.
Results
Seven studies examined the association between bacterial infection and ovarian cancer. A single study found a significant association between chlamydial infection and ovarian cancer, while another study identified Mycoplasma genitalium in a large proportion of ovarian cancer cases. The remaining studies found no association. Human papillomavirus detection rates varied from 0 to 67% and were generally higher in the Asian studies than in studies from Western countries. Cytomegalovirus was the only other virus to be detected and was found in 50% of cases in a case-control study. The association between ovarian cancer and pelvic inflammatory disease was examined in seven epidemiological studies, two of which, reported a statistically significant association.
Conclusions
Data indicate a potential association between pelvic inflammatory disease and ovarian cancer. An association between ovarian cancer and high-risk human papillomavirus genotypes may exist in Asia, whereas an association in Western countries seems unlikely due to the low reported prevalence. Potential carcinogenic bacteria were found, but results were inconsistent, and further research is warranted.
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Differences in age-specific HPV prevalence between self-collected and health personnel collected specimen in a cross-sectional study in Ghana
Abstract
Background
HPV infections are ubiquitous and particularly common among sexually active young women. However, there are regional and national variations in age-specific HPV prevalence, which have implications for cervical cancer control. Data on age-specific HPV prevalences for Ghana and most sub-Saharan countries are scanty. Therefore, this study primarily sought to determine the age-specific HPV prevalence among women in a Ghanaian community and to determine whether these prevalences determined with health-personnel and self-collected specimens were comparable.
Methods
In this cross-sectional study, conducted between March 2012 and March 2013, cervical specimens were collected by self- and health-personnel collection from 251 women who were between the ages of 15 and 65 years. HPV present in these specimens were genotyped by a nested-multiplex PCR and Luminex fluoro-microspheres based method. Information on the demographic, sexual and reproductive characteristics of the women were also obtained. A Chi-square test of association was employed to determine the association of the distribution of age groups with each categorised sexual and reproductive characteristic and HPV risk type's status.
Results
The age group distribution of the participants was significantly associated with overall (χ 2 = 36.1; p = 0.001), high risk (χ 2 = 26.09; p = 0.002) and low risk (χ 2 = 21.49; p = 0.011) HPV prevalences. The age-specific HPV prevalence pattern for each of the HPV risk types, determined with self-collected specimen, showed three peaks (at 20–24 years; 40–44 years and ≥ 55 years), while those determined with health-personnel collected specimen, showed two peaks (at 20–24 years and ≥ 55 years) for each HPV risk type's prevalence pattern. The high risk HPV prevalences determined with self-collected specimen were often higher than those determined with health-personnel specimen for the age groups between 25 and 45 years, who are mostly targeted for screening by HPV testing. Additionally, there were interesting variations in patterns of age-specific HPV genotype-specific prevalence between the two specimen collection methods.
Conclusions
The usefulness of self-collected specimen for high risk HPV burden determination and the existence of a two peaked and three peaked age-specific HPV prevalences in Ghana have been clearly indicated.
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The potential role of infectious agents and pelvic inflammatory disease in ovarian carcinogenesis
Abstract
Background
The etiological cause of ovarian cancer is poorly understood. It has been theorized that bacterial or viral infection as well as pelvic inflammatory disease could play a role in ovarian carcinogenesis.
Aim
To review the literature on studies examining the association between ovarian cancer and bacterial or viral infection or pelvic inflammatory disease.
Methods
Database search through MEDLINE, applying the medical subject headings: "Ovarian neoplasms", AND "Chlamydia infections", "Neisseria gonorrhoeae", "Mycoplasma genitalium", "Papillomaviridae", or "pelvic inflammatory disease". Corresponding searches were performed in EMBASE, and Web of Science. The literature search identified 935 articles of which 40 were eligible for inclusion in this review.
Results
Seven studies examined the association between bacterial infection and ovarian cancer. A single study found a significant association between chlamydial infection and ovarian cancer, while another study identified Mycoplasma genitalium in a large proportion of ovarian cancer cases. The remaining studies found no association. Human papillomavirus detection rates varied from 0 to 67% and were generally higher in the Asian studies than in studies from Western countries. Cytomegalovirus was the only other virus to be detected and was found in 50% of cases in a case-control study. The association between ovarian cancer and pelvic inflammatory disease was examined in seven epidemiological studies, two of which, reported a statistically significant association.
Conclusions
Data indicate a potential association between pelvic inflammatory disease and ovarian cancer. An association between ovarian cancer and high-risk human papillomavirus genotypes may exist in Asia, whereas an association in Western countries seems unlikely due to the low reported prevalence. Potential carcinogenic bacteria were found, but results were inconsistent, and further research is warranted.
http://ift.tt/2rxvYFU
Differences in age-specific HPV prevalence between self-collected and health personnel collected specimen in a cross-sectional study in Ghana
Abstract
Background
HPV infections are ubiquitous and particularly common among sexually active young women. However, there are regional and national variations in age-specific HPV prevalence, which have implications for cervical cancer control. Data on age-specific HPV prevalences for Ghana and most sub-Saharan countries are scanty. Therefore, this study primarily sought to determine the age-specific HPV prevalence among women in a Ghanaian community and to determine whether these prevalences determined with health-personnel and self-collected specimens were comparable.
Methods
In this cross-sectional study, conducted between March 2012 and March 2013, cervical specimens were collected by self- and health-personnel collection from 251 women who were between the ages of 15 and 65 years. HPV present in these specimens were genotyped by a nested-multiplex PCR and Luminex fluoro-microspheres based method. Information on the demographic, sexual and reproductive characteristics of the women were also obtained. A Chi-square test of association was employed to determine the association of the distribution of age groups with each categorised sexual and reproductive characteristic and HPV risk type's status.
Results
The age group distribution of the participants was significantly associated with overall (χ 2 = 36.1; p = 0.001), high risk (χ 2 = 26.09; p = 0.002) and low risk (χ 2 = 21.49; p = 0.011) HPV prevalences. The age-specific HPV prevalence pattern for each of the HPV risk types, determined with self-collected specimen, showed three peaks (at 20–24 years; 40–44 years and ≥ 55 years), while those determined with health-personnel collected specimen, showed two peaks (at 20–24 years and ≥ 55 years) for each HPV risk type's prevalence pattern. The high risk HPV prevalences determined with self-collected specimen were often higher than those determined with health-personnel specimen for the age groups between 25 and 45 years, who are mostly targeted for screening by HPV testing. Additionally, there were interesting variations in patterns of age-specific HPV genotype-specific prevalence between the two specimen collection methods.
Conclusions
The usefulness of self-collected specimen for high risk HPV burden determination and the existence of a two peaked and three peaked age-specific HPV prevalences in Ghana have been clearly indicated.
http://ift.tt/2qzcaoz
Association of post-treatment hypoalbuminemia and survival in Chinese patients with metastatic renal cell carcinoma
Hypoalbuminemia adversely affects the clinical outcomes of various cancers. The purpose of this study was to estimate the prognostic value of hypoalbuminemia 3–5 weeks after treatment in patients with metastat...
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Sensitization of EGFR wild-type non-small cell lung cancer cells to EGFR-tyrosine kinase inhibitor erlotinib.
The benefit of EGFR-TKI in non-small cell lung cancer has been demonstrated in mutant EGFR tumors as first-line treatment but the benefit in wild-type EGFR tumors is marginal as well as restricted to maintenance therapy in pretreated patients. This work aimed at questioning the effects of cisplatin initial treatment on the EGFR pathway in non-small cell lung cancer and the functional consequences in vitro and in in vivo animal models of Patient-Derived Xenografts (PDX). We establish here that cisplatin pretreatment specifically sensitizes wild-type EGFR expressing cells to erlotinib, contrary to what happens in mutant-EGFR cells and with a blocking EGFR antibody, both in vitro and in vivo. The sensitization entails the activation of the kinase Src upstream of EGFR, thereafter transactivating EGFR through a ligand-independent activation. We propose a combination of markers which enable to discriminate between the tumors sensitized to erlotinib or not in PDX models, that should be worth testing in patients. These markers might be useful for the selection of patients who would benefit from erlotinib as a maintenance therapy.
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Inhibition of Aurora A and Aurora B is required for the sensitivity of HPV-driven cervical cancers to Aurora kinase inhibitors
The activity and efficacy of Aurora inhibitors have been reported in a wide range of cancer types. The most prominent Aurora inhibitor is Alisertib, an investigational Aurora inhibitor that has been the subject of more than 30 clinical trials. Alisertib has inhibitory activity against both Aurora A and B, although it is considered to be primarily an Aurora A inhibitor in vivo. Here we show that Alisertib inhibits both Aurora A and B in vivo in preclinical models of HPV-driven cervical cancer, and that it is the inhibition of Aurora A and B that provide the selectivity and efficacy of this drug in vivo in this disease setting. We also present formal evidence that Alisertib requires progression through mitosis for its efficacy, and that it is unlikely to combine with drugs that promote a G2 DNA damage checkpoint response. This work demonstrates that inhibition of Aurora A and B are required for effective control of HPV-driven cancers by Aurora kinase inhibitors.
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Notch inhibitor PF-03084014 inhibits hepatocellular carcinoma growth and metastasis via suppression of cancer stemness due to reduced activation of Notch1-Stat3
Aberrant activation of the Notch signaling pathway is implicated in many solid tumors, including hepatocellular carcinoma (HCC), indicating a potential use of Notch inhibitors for treatment. In this study, we investigated the antitumor and antimetastasis efficacy of the novel Notch inhibitor (-secretase inhibitor) PF-03084014 in HCC. HCC spherical cells (stem-like cancer cells), a sphere-derived orthotopic tumor model and one patient-derived xenograft (PDX) model were used in our experiment. We demonstrated that PF-03084014 inhibited the self-renewal and proliferation of cancer stem cells. PF-03084014 reduced the HCC sphere-derived orthotopic tumor and blocked the HCC tumor liver to lung metastasis. We further tested the PF-03084014 in PDX models and confirmed the inhibition tumor growth effect. In addition, a low dose of PF-03084014 induced HCC sphere differentiation, resulting in chemosensitization. Antitumor activity was associated with PF-03084014-induced suppression of Notch1 activity, decreased Stat3 activation and phosphorylation of the Akt signaling pathway, and reduced epithelial-mesenchymal transition. These are the key contributors to the maintenance of cancer stemness and the promotion of cancer metastasis. Moreover, the Notch-Stat3 association was implicated in the clinical HCC prognosis. Collectively, PF-03084014 revealed antitumor and antimetastatic effects in hepatocellular carcinoma, providing evidence for the potential use of GSIs as a therapeutic option for the treatment of HCC.
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A Potential Mechanism for ADC-Induced Neutropenia: Role of Neutrophils in Their Own Demise
Neutropenia is a common adverse event in cancer patients treated with antibody-drug conjugates (ADCs) and we aimed to elucidate the potential mechanism of this toxicity. To investigate if ADCs affect neutrophil production from bone marrow, an in vitro assay was developed in which hematopoietic stem cells (HSCs) were differentiated to neutrophils. Several antibodies against targets absent in HSCs and neutrophils were conjugated to MMAE via a cleavable valine-citrulline linker (vcMMAE-ADCs) or MMAF via a non-cleavable maleimidocaproyl linker (mcMMAF-ADCs), and their cytotoxicity was tested in the neutrophil differentiation assay. Results showed that HSCs had similar sensitivity to vcMMAE-ADCs and mcMMAF-ADCs; however, vcMMAE-ADCs were more cytotoxic to differentiating neutrophils than the same antibody conjugated to mcMMAF. This inhibitory effect was not mediated by internalization of ADC either by macropinocytosis or FcRs. Our results suggested that extracellular proteolysis of the cleavable valine-citrulline linker is responsible for the cytotoxicity to differentiating neutrophils. Mass spectrometry analyses indicated that free MMAE was released from vcMMAE-ADCs in the extracellular compartment when they were incubated with differentiating neutrophils or neutrophil conditioned medium, but not with HSC conditioned medium. Using different protease inhibitors, our data suggested that serine, but not cysteine proteases, were responsible for the cleavage. In vitro experiments demonstrated that the purified serine protease, elastase, was capable of releasing free MMAE from a vcMMAE-ADC. Here we propose that ADCs containing protease cleavable linkers can contribute to neutropenia via extracellular cleavage mediated by serine proteases secreted by differentiating neutrophils in bone marrow.
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Herpes simplex virus glycoprotein D targets a specific dendritic cell subset and improves the performance of vaccines to human papillomavirus-associated tumors
Cervical cancer is a major public health problem and one of the leading causes of cancer deaths in women. Virtually all cases of cervical cancer, as well as a growing share of anal and head/neck tumors, are associated with human papillomavirus (HPV) infection. Despite the effectiveness, the available prophylactic vaccines do not benefit women with cervical lesions or cancer. Therefore, the search of new immunotherapeutic approaches to treat HPV-induced tumors is still a priority. The present study characterizes a therapeutic antitumor vaccine based on the genetic fusion of the Herpes simplex virus-1 (HSV-1) glycoprotein D (gD) with the E7 oncoprotein from HPV-16 (gDE7). Two subcutaneous doses of gDE7, admixed with poly (I:C), conferred complete and long lasting therapeutic antitumor protection to mice previously challenged with tumor cells expressing the HPV-16 oncoproteins. The vaccine induced multifunctional E7-specific CD8+ T cells with cytotoxic activity and effector memory phenotype (CD44+ CD62Llow). Additionally, gDE7 admixed with poly (I:C) vaccination controlled the expansion of tumor-induced regulatory T cells and myeloid-derived suppressor cells (MDSCs). More importantly, gDE7 activated mouse CD11c+ CD8α+ and human BDCA3+ dendritic cells (DCs), specialized in antigen cross-presentation to CD8+ T cells, under in vitro conditions. These results indicated that the activation of a specific DC population, mediated by gD, improved the antigen-specific immune responses and the therapeutic performance induced by antitumor vaccines. These results open perspectives for the clinical testing of gDE7-based vaccines under the concept of active immunization as a tool for the therapeutic control of cancer.
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Identification of Cancer-Targeted Tropomyosin Inhibitors and Their Synergy With Microtubule Drugs
Actin filaments, with their associated tropomyosin polymers, and microtubules are dynamic cytoskeletal systems regulating numerous cell functions. While anti-microtubule drugs are well-established, anti-actin drugs have been more elusive. We previously targeted actin in cancer cells by inhibiting the function of a tropomyosin isoform enriched in cancer cells, Tpm3.1, using a first-in-class compound, TR100. Here, we screened over 200 other anti-tropomyosin analogues for anti-cancer and on-target activity using a series of in vitro cell-based and biochemical assays. ATM-3507 was selected as the new lead based on its ability to disable Tpm3.1 containing filaments, its cytotoxicity potency and more favorable drug-like characteristics. We tested ATM-3507 and TR100 alone and in combination with anti-microtubule agents against neuroblastoma models in vitro and in vivo. Both ATM-3507 and TR100 showed a high degree of synergy in vitro with vinca alkaloid and taxane anti-microtubule agents. In vivo, combination treated animals bearing human neuroblastoma xenografts treated with etiher anti-tropomyosin combined with vincristine showed minimal weight loss, a significant and profound regression of tumor growth and improved survival compared to control and either drug alone. Anti-tropomyosin combined with vincristine resulted in G2/M phase arrest, disruption of mitotic spindle formation and cellular apoptosis. Our data suggest that small molecules targeting the actin cytoskeleton via tropomyosin sensitize cancer cells to anti-microtubule agents and are tolerated together in vivo. This combination warrants further study.
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Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation
Cancer treatments often require combinations of molecularly targeted agents to be effective. mTORi (rapamycin) and HDACi (MS-275/entinostat) inhibitors have been shown to be effective in limiting tumor growth, and here we define part of the cooperative action of this drug combination. More than 60 human cancer cell lines responded synergistically (CI<1) when treated with this drug combination compared to single agents. In addition, a breast cancer patient-derived xenograft, and a BCL-XL plasmacytoma mouse model both showed enhanced responses to the combination compared to single agents. Mice, bearing plasma cell tumors lived an average of 70 days longer on combination treatment compared to single agents. A set of 37 genes cooperatively affected (34 down-regulated; 3 up-regulated) by the combination responded pharmacodynamically in human myeloma cell lines, xenografts, and a P493 model, and were both enriched in tumors, and correlated with prognostic markers in myeloma patient datasets. Genes down-regulated by the combination were overexpressed in several untreated cancers (breast, lung, colon, sarcoma, head and neck, myeloma) compared to normal tissues. The MYC/E2F axis, identified by upstream regulator analyses and validated by immunoblots, was significantly inhibited by the drug combination in several myeloma cell lines. Furthermore, 88% of the 34 genes downregulated have MYC binding sites in their promoters, and the drug combination cooperatively reduced MYC half-life by 55% and increased degradation. Cells with MYC mutations were refractory to the combination. Thus, integrative approaches to understand drug synergy identified a clinically actionable strategy to inhibit MYC/E2F activity and tumor cell growth in vivo.
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Preclinical evaluation of MEDI0641, a pyrrolobenzodiazepine-conjugated antibody-drug conjugate targeting 5T4
Antibody-drug conjugates (ADCs) are used to selectively deliver cytotoxic agents to tumors and have the potential for increased clinical benefit to cancer patients. 5T4 is an oncofetal antigen overexpressed on the cell surface in many carcinomas on both bulk tumor cells as well as cancer stem cells (CSCs), has very limited normal tissue expression, and can internalize when bound by an antibody. An anti-5T4 antibody was identified and optimized for efficient binding and internalization in a target-specific manner, and engineered cysteines were incorporated into the molecule for site-specific conjugation. ADCs targeting 5T4 were constructed by site-specifically conjugating the antibody with payloads that possess different mechanisms of action, either a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer or a microtubule-destabilizing tubulysin, so that each ADC had a drug:antibody ratio of 2. The resulting ADCs demonstrated significant target-dependent activity in vitro and in vivo, however the ADC conjugated with a PBD payload (5T4-PBD) elicited more durable anti-tumor responses in vivo than the tubulysin conjugate in xenograft models. Likewise, the 5T4-PBD more potently inhibited the growth of 5T4-positive CSCs in vivo, which likely contributed to its superior anti-tumor activity. Given that the 5T4-PBD possessed both potent anti-tumor activity as well as anti-CSC activity, and thus could potentially target bulk tumor cells and CSCs in target-positive indications, it was further evaluated in non-GLP rat toxicology studies that demonstrated excellent in vivo stability with an acceptable safety profile. Taken together, these preclinical data support further development of 5T4-PBD, also known as MEDI0641, against 5T4+ cancer indications.
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Antitumor Synergism and Enhanced Survival with a Tumor Vasculature-Targeted Enzyme Prodrug System, Rapamycin, and Cyclophosphamide
Mutant cystathionine gamma-lyase was targeted to phosphatidylserine exposed on tumor vasculature through fusion with annexin A1 or annexin A5. Cystathionine gamma-lyase E58N, R118L, and E338N mutations impart non-native methionine gamma-lyase activity, resulting in tumor-localized generation of highly toxic methylselenol upon systemic administration of non-toxic selenomethionine. The described therapeutic system circumvents systemic toxicity issues using a novel drug delivery/generation approach and avoids the administration of non-native proteins and/or DNA required with other enzyme prodrug systems. The enzyme fusion exhibits strong and stable in vitro binding with dissociation constants in the nanomolar range for both human and mouse breast cancer cells and in a cell model of tumor vascular endothelium. Daily administration of the therapy suppressed growth of highly aggressive triple negative murine 4T1 mammary tumors in immune competent BALB/cJ mice and MDA-MB-231 tumors in SCID mice. Treatment did not result in occurrence of negative side effects or the elicitation of neutralizing antibodies. Based on the vasculature-targeted nature of the therapy, combinations with rapamycin and cyclophosphamide were evaluated. Rapamycin, an MTOR inhibitor, reduces the pro-survival signaling of cells in a hypoxic environment potentially exacerbated by a vasculature-targeted therapy. Immunohistochemistry revealed, unsurprisingly, a significant hypoxic response (increase in hypoxia inducible factor 1 alpha subunit, HIF1A) in the enzyme prodrug treated tumors and a dramatic reduction of HIF1A upon rapamycin treatment. Cyclophosphamide, an immunomodulator at low doses, was combined with the enzyme prodrug therapy and rapamycin; this combination synergistically reduced tumor volumes, inhibited metastatic progression, and enhanced survival. <br />
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Association of post-treatment hypoalbuminemia and survival in Chinese patients with metastatic renal cell carcinoma
Hypoalbuminemia adversely affects the clinical outcomes of various cancers. The purpose of this study was to estimate the prognostic value of hypoalbuminemia 3–5 weeks after treatment in patients with metastat...
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Sensitization of EGFR wild-type non-small cell lung cancer cells to EGFR-tyrosine kinase inhibitor erlotinib.
The benefit of EGFR-TKI in non-small cell lung cancer has been demonstrated in mutant EGFR tumors as first-line treatment but the benefit in wild-type EGFR tumors is marginal as well as restricted to maintenance therapy in pretreated patients. This work aimed at questioning the effects of cisplatin initial treatment on the EGFR pathway in non-small cell lung cancer and the functional consequences in vitro and in in vivo animal models of Patient-Derived Xenografts (PDX). We establish here that cisplatin pretreatment specifically sensitizes wild-type EGFR expressing cells to erlotinib, contrary to what happens in mutant-EGFR cells and with a blocking EGFR antibody, both in vitro and in vivo. The sensitization entails the activation of the kinase Src upstream of EGFR, thereafter transactivating EGFR through a ligand-independent activation. We propose a combination of markers which enable to discriminate between the tumors sensitized to erlotinib or not in PDX models, that should be worth testing in patients. These markers might be useful for the selection of patients who would benefit from erlotinib as a maintenance therapy.
http://ift.tt/2rktJcC
Inhibition of Aurora A and Aurora B is required for the sensitivity of HPV-driven cervical cancers to Aurora kinase inhibitors
The activity and efficacy of Aurora inhibitors have been reported in a wide range of cancer types. The most prominent Aurora inhibitor is Alisertib, an investigational Aurora inhibitor that has been the subject of more than 30 clinical trials. Alisertib has inhibitory activity against both Aurora A and B, although it is considered to be primarily an Aurora A inhibitor in vivo. Here we show that Alisertib inhibits both Aurora A and B in vivo in preclinical models of HPV-driven cervical cancer, and that it is the inhibition of Aurora A and B that provide the selectivity and efficacy of this drug in vivo in this disease setting. We also present formal evidence that Alisertib requires progression through mitosis for its efficacy, and that it is unlikely to combine with drugs that promote a G2 DNA damage checkpoint response. This work demonstrates that inhibition of Aurora A and B are required for effective control of HPV-driven cancers by Aurora kinase inhibitors.
http://ift.tt/2pZ7DII
Notch inhibitor PF-03084014 inhibits hepatocellular carcinoma growth and metastasis via suppression of cancer stemness due to reduced activation of Notch1-Stat3
Aberrant activation of the Notch signaling pathway is implicated in many solid tumors, including hepatocellular carcinoma (HCC), indicating a potential use of Notch inhibitors for treatment. In this study, we investigated the antitumor and antimetastasis efficacy of the novel Notch inhibitor (-secretase inhibitor) PF-03084014 in HCC. HCC spherical cells (stem-like cancer cells), a sphere-derived orthotopic tumor model and one patient-derived xenograft (PDX) model were used in our experiment. We demonstrated that PF-03084014 inhibited the self-renewal and proliferation of cancer stem cells. PF-03084014 reduced the HCC sphere-derived orthotopic tumor and blocked the HCC tumor liver to lung metastasis. We further tested the PF-03084014 in PDX models and confirmed the inhibition tumor growth effect. In addition, a low dose of PF-03084014 induced HCC sphere differentiation, resulting in chemosensitization. Antitumor activity was associated with PF-03084014-induced suppression of Notch1 activity, decreased Stat3 activation and phosphorylation of the Akt signaling pathway, and reduced epithelial-mesenchymal transition. These are the key contributors to the maintenance of cancer stemness and the promotion of cancer metastasis. Moreover, the Notch-Stat3 association was implicated in the clinical HCC prognosis. Collectively, PF-03084014 revealed antitumor and antimetastatic effects in hepatocellular carcinoma, providing evidence for the potential use of GSIs as a therapeutic option for the treatment of HCC.
http://ift.tt/2rjMYDm
A Potential Mechanism for ADC-Induced Neutropenia: Role of Neutrophils in Their Own Demise
Neutropenia is a common adverse event in cancer patients treated with antibody-drug conjugates (ADCs) and we aimed to elucidate the potential mechanism of this toxicity. To investigate if ADCs affect neutrophil production from bone marrow, an in vitro assay was developed in which hematopoietic stem cells (HSCs) were differentiated to neutrophils. Several antibodies against targets absent in HSCs and neutrophils were conjugated to MMAE via a cleavable valine-citrulline linker (vcMMAE-ADCs) or MMAF via a non-cleavable maleimidocaproyl linker (mcMMAF-ADCs), and their cytotoxicity was tested in the neutrophil differentiation assay. Results showed that HSCs had similar sensitivity to vcMMAE-ADCs and mcMMAF-ADCs; however, vcMMAE-ADCs were more cytotoxic to differentiating neutrophils than the same antibody conjugated to mcMMAF. This inhibitory effect was not mediated by internalization of ADC either by macropinocytosis or FcRs. Our results suggested that extracellular proteolysis of the cleavable valine-citrulline linker is responsible for the cytotoxicity to differentiating neutrophils. Mass spectrometry analyses indicated that free MMAE was released from vcMMAE-ADCs in the extracellular compartment when they were incubated with differentiating neutrophils or neutrophil conditioned medium, but not with HSC conditioned medium. Using different protease inhibitors, our data suggested that serine, but not cysteine proteases, were responsible for the cleavage. In vitro experiments demonstrated that the purified serine protease, elastase, was capable of releasing free MMAE from a vcMMAE-ADC. Here we propose that ADCs containing protease cleavable linkers can contribute to neutropenia via extracellular cleavage mediated by serine proteases secreted by differentiating neutrophils in bone marrow.
http://ift.tt/2pZ31T5
Herpes simplex virus glycoprotein D targets a specific dendritic cell subset and improves the performance of vaccines to human papillomavirus-associated tumors
Cervical cancer is a major public health problem and one of the leading causes of cancer deaths in women. Virtually all cases of cervical cancer, as well as a growing share of anal and head/neck tumors, are associated with human papillomavirus (HPV) infection. Despite the effectiveness, the available prophylactic vaccines do not benefit women with cervical lesions or cancer. Therefore, the search of new immunotherapeutic approaches to treat HPV-induced tumors is still a priority. The present study characterizes a therapeutic antitumor vaccine based on the genetic fusion of the Herpes simplex virus-1 (HSV-1) glycoprotein D (gD) with the E7 oncoprotein from HPV-16 (gDE7). Two subcutaneous doses of gDE7, admixed with poly (I:C), conferred complete and long lasting therapeutic antitumor protection to mice previously challenged with tumor cells expressing the HPV-16 oncoproteins. The vaccine induced multifunctional E7-specific CD8+ T cells with cytotoxic activity and effector memory phenotype (CD44+ CD62Llow). Additionally, gDE7 admixed with poly (I:C) vaccination controlled the expansion of tumor-induced regulatory T cells and myeloid-derived suppressor cells (MDSCs). More importantly, gDE7 activated mouse CD11c+ CD8α+ and human BDCA3+ dendritic cells (DCs), specialized in antigen cross-presentation to CD8+ T cells, under in vitro conditions. These results indicated that the activation of a specific DC population, mediated by gD, improved the antigen-specific immune responses and the therapeutic performance induced by antitumor vaccines. These results open perspectives for the clinical testing of gDE7-based vaccines under the concept of active immunization as a tool for the therapeutic control of cancer.
http://ift.tt/2rk4MhF
Identification of Cancer-Targeted Tropomyosin Inhibitors and Their Synergy With Microtubule Drugs
Actin filaments, with their associated tropomyosin polymers, and microtubules are dynamic cytoskeletal systems regulating numerous cell functions. While anti-microtubule drugs are well-established, anti-actin drugs have been more elusive. We previously targeted actin in cancer cells by inhibiting the function of a tropomyosin isoform enriched in cancer cells, Tpm3.1, using a first-in-class compound, TR100. Here, we screened over 200 other anti-tropomyosin analogues for anti-cancer and on-target activity using a series of in vitro cell-based and biochemical assays. ATM-3507 was selected as the new lead based on its ability to disable Tpm3.1 containing filaments, its cytotoxicity potency and more favorable drug-like characteristics. We tested ATM-3507 and TR100 alone and in combination with anti-microtubule agents against neuroblastoma models in vitro and in vivo. Both ATM-3507 and TR100 showed a high degree of synergy in vitro with vinca alkaloid and taxane anti-microtubule agents. In vivo, combination treated animals bearing human neuroblastoma xenografts treated with etiher anti-tropomyosin combined with vincristine showed minimal weight loss, a significant and profound regression of tumor growth and improved survival compared to control and either drug alone. Anti-tropomyosin combined with vincristine resulted in G2/M phase arrest, disruption of mitotic spindle formation and cellular apoptosis. Our data suggest that small molecules targeting the actin cytoskeleton via tropomyosin sensitize cancer cells to anti-microtubule agents and are tolerated together in vivo. This combination warrants further study.
http://ift.tt/2pZdeia
Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation
Cancer treatments often require combinations of molecularly targeted agents to be effective. mTORi (rapamycin) and HDACi (MS-275/entinostat) inhibitors have been shown to be effective in limiting tumor growth, and here we define part of the cooperative action of this drug combination. More than 60 human cancer cell lines responded synergistically (CI<1) when treated with this drug combination compared to single agents. In addition, a breast cancer patient-derived xenograft, and a BCL-XL plasmacytoma mouse model both showed enhanced responses to the combination compared to single agents. Mice, bearing plasma cell tumors lived an average of 70 days longer on combination treatment compared to single agents. A set of 37 genes cooperatively affected (34 down-regulated; 3 up-regulated) by the combination responded pharmacodynamically in human myeloma cell lines, xenografts, and a P493 model, and were both enriched in tumors, and correlated with prognostic markers in myeloma patient datasets. Genes down-regulated by the combination were overexpressed in several untreated cancers (breast, lung, colon, sarcoma, head and neck, myeloma) compared to normal tissues. The MYC/E2F axis, identified by upstream regulator analyses and validated by immunoblots, was significantly inhibited by the drug combination in several myeloma cell lines. Furthermore, 88% of the 34 genes downregulated have MYC binding sites in their promoters, and the drug combination cooperatively reduced MYC half-life by 55% and increased degradation. Cells with MYC mutations were refractory to the combination. Thus, integrative approaches to understand drug synergy identified a clinically actionable strategy to inhibit MYC/E2F activity and tumor cell growth in vivo.
http://ift.tt/2rkgfxD
Preclinical evaluation of MEDI0641, a pyrrolobenzodiazepine-conjugated antibody-drug conjugate targeting 5T4
Antibody-drug conjugates (ADCs) are used to selectively deliver cytotoxic agents to tumors and have the potential for increased clinical benefit to cancer patients. 5T4 is an oncofetal antigen overexpressed on the cell surface in many carcinomas on both bulk tumor cells as well as cancer stem cells (CSCs), has very limited normal tissue expression, and can internalize when bound by an antibody. An anti-5T4 antibody was identified and optimized for efficient binding and internalization in a target-specific manner, and engineered cysteines were incorporated into the molecule for site-specific conjugation. ADCs targeting 5T4 were constructed by site-specifically conjugating the antibody with payloads that possess different mechanisms of action, either a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer or a microtubule-destabilizing tubulysin, so that each ADC had a drug:antibody ratio of 2. The resulting ADCs demonstrated significant target-dependent activity in vitro and in vivo, however the ADC conjugated with a PBD payload (5T4-PBD) elicited more durable anti-tumor responses in vivo than the tubulysin conjugate in xenograft models. Likewise, the 5T4-PBD more potently inhibited the growth of 5T4-positive CSCs in vivo, which likely contributed to its superior anti-tumor activity. Given that the 5T4-PBD possessed both potent anti-tumor activity as well as anti-CSC activity, and thus could potentially target bulk tumor cells and CSCs in target-positive indications, it was further evaluated in non-GLP rat toxicology studies that demonstrated excellent in vivo stability with an acceptable safety profile. Taken together, these preclinical data support further development of 5T4-PBD, also known as MEDI0641, against 5T4+ cancer indications.
http://ift.tt/2pZ0JTV
Antitumor Synergism and Enhanced Survival with a Tumor Vasculature-Targeted Enzyme Prodrug System, Rapamycin, and Cyclophosphamide
Mutant cystathionine gamma-lyase was targeted to phosphatidylserine exposed on tumor vasculature through fusion with annexin A1 or annexin A5. Cystathionine gamma-lyase E58N, R118L, and E338N mutations impart non-native methionine gamma-lyase activity, resulting in tumor-localized generation of highly toxic methylselenol upon systemic administration of non-toxic selenomethionine. The described therapeutic system circumvents systemic toxicity issues using a novel drug delivery/generation approach and avoids the administration of non-native proteins and/or DNA required with other enzyme prodrug systems. The enzyme fusion exhibits strong and stable in vitro binding with dissociation constants in the nanomolar range for both human and mouse breast cancer cells and in a cell model of tumor vascular endothelium. Daily administration of the therapy suppressed growth of highly aggressive triple negative murine 4T1 mammary tumors in immune competent BALB/cJ mice and MDA-MB-231 tumors in SCID mice. Treatment did not result in occurrence of negative side effects or the elicitation of neutralizing antibodies. Based on the vasculature-targeted nature of the therapy, combinations with rapamycin and cyclophosphamide were evaluated. Rapamycin, an MTOR inhibitor, reduces the pro-survival signaling of cells in a hypoxic environment potentially exacerbated by a vasculature-targeted therapy. Immunohistochemistry revealed, unsurprisingly, a significant hypoxic response (increase in hypoxia inducible factor 1 alpha subunit, HIF1A) in the enzyme prodrug treated tumors and a dramatic reduction of HIF1A upon rapamycin treatment. Cyclophosphamide, an immunomodulator at low doses, was combined with the enzyme prodrug therapy and rapamycin; this combination synergistically reduced tumor volumes, inhibited metastatic progression, and enhanced survival. <br />
http://ift.tt/2rk4vel
Increasing utilization of intensity modulated radiation therapy in vulvar cancer: National Practice Patterns 2004–2012
Abstract
Objective
The aim of this study is to evaluate utilization of intensity modulated radiation therapy (IMRT) for vulvar cancer between 2004 and 2012, and determine the survival impact of IMRT and 2D/3D radiation therapy (RT) for women treated with postoperative, preoperative, or primary radiation.
Methods
Women with vulvar carcinoma who received IMRT or 2D/3D RT were identified in the National Cancer Data Base (NCDB) between 2004 and 2012. Patient characteristics were compared between those that received IMRT and 2D/3D RT using chi-square, Fisher's exact, and Mann-Whitney tests. Women were stratified by treatment approach, and overall survival (OS) was estimated via the Kaplan-Meier method and compared using the log-rank test. Factors associated with OS were determined using univariate and multivariate Cox proportional hazards regression models.
Results
A total of 6027 women were included (median age 67 years). Women received either 2D/3D RT (n = 4723) or IMRT (n = 1304). A total of 3.3% of women received IMRT in 2004, compared to 19.3% in 2008 and 43.0% in 2012. More women in the IMRT cohort received radiation doses >55 Gy compared to the 2D/3D RT cohort (47.5 vs. 40.3%, p < 0.001). Women received postoperative radiation (n = 3395), preoperative radiation (n = 478), or primary radiation (n = 1852). On multivariate analyses, the effect of radiation technique (IMRT vs. 2D/3D RT) on OS among women receiving post-operative, pre-operative, or primary radiation was not significant (p > 0.05).
Conclusions
IMRT utilization for vulvar cancer increased between the years 2004 and 2012. Survival was not significantly compromised with the use of IMRT compared to conventional 2D/3D RT techniques and may have allowed for dose escalation in some situations.
http://ift.tt/2rwJM4z
Increasing utilization of intensity modulated radiation therapy in vulvar cancer: National Practice Patterns 2004–2012
Abstract
Objective
The aim of this study is to evaluate utilization of intensity modulated radiation therapy (IMRT) for vulvar cancer between 2004 and 2012, and determine the survival impact of IMRT and 2D/3D radiation therapy (RT) for women treated with postoperative, preoperative, or primary radiation.
Methods
Women with vulvar carcinoma who received IMRT or 2D/3D RT were identified in the National Cancer Data Base (NCDB) between 2004 and 2012. Patient characteristics were compared between those that received IMRT and 2D/3D RT using chi-square, Fisher's exact, and Mann-Whitney tests. Women were stratified by treatment approach, and overall survival (OS) was estimated via the Kaplan-Meier method and compared using the log-rank test. Factors associated with OS were determined using univariate and multivariate Cox proportional hazards regression models.
Results
A total of 6027 women were included (median age 67 years). Women received either 2D/3D RT (n = 4723) or IMRT (n = 1304). A total of 3.3% of women received IMRT in 2004, compared to 19.3% in 2008 and 43.0% in 2012. More women in the IMRT cohort received radiation doses >55 Gy compared to the 2D/3D RT cohort (47.5 vs. 40.3%, p < 0.001). Women received postoperative radiation (n = 3395), preoperative radiation (n = 478), or primary radiation (n = 1852). On multivariate analyses, the effect of radiation technique (IMRT vs. 2D/3D RT) on OS among women receiving post-operative, pre-operative, or primary radiation was not significant (p > 0.05).
Conclusions
IMRT utilization for vulvar cancer increased between the years 2004 and 2012. Survival was not significantly compromised with the use of IMRT compared to conventional 2D/3D RT techniques and may have allowed for dose escalation in some situations.
from Cancer via ola Kala on Inoreader http://ift.tt/2rwJM4z
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Immunohistochemical evaluation of two antibodies against PD-L1 and prognostic significance of PD-L1 expression in epithelioid peritoneal malignant mesothelioma: a RENAPE study
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Séverine Valmary-Degano, Prudence Colpart, Laurent Villeneuve, Franck Monnien, Loubna M'Hamdi, Gerlinde Lang-Averous, Mathieu Capovilla, Frederic Bibeau, Marie-Hélène Laverriere, Véronique Verriele-Beurrier, Houda Ben Rejeb, Peggy Dartigues, Juliette Hommell-Fontaine, François-Noël Gilly, Sylvie Isaac, Eliane Mery
BackgroundEpithelioid peritoneal malignant mesothelioma (EPMM) is the most common subtype of this aggressive tumor. We compared two antibodies against PD-L1, a recent theranostic biomarker, and evaluated the prognostic value of PD-L1 expression by mesothelial and immune cells in EPMM.MethodsImmunohistochemistry was performed on 45 EPMM. Clinical and pathological data were extracted from the RENAPE database. Using E1L3N and SP142 clones, inter-observer agreement, PD-L1 expression by mesothelial and immune cells and inter-antibody agreement were evaluated. The prognostic relevance of PD-L1 expression was evaluated in 39 EPMM by univariate and multivariate analysis of overall survival (OS) and progression-free survival (PFS).ResultsInter-observer agreement on E1L3N immunostaining was moderate for mesothelial and immune cells, and fair for mesothelial and poor for immune cells using SP142. Using E1L3N, 31.1% of mesothelial and 15.6% of immune cells expressed PD-L1, and 22.2% of mesothelial and 26.7% of immune cells using SP142. Inter-antibody agreement was moderate. In most positive cases, 1 to 5% of tumor cells were positive. Using E1L3N, PD-L1 expression by lymphocytes was associated with better OS and PFS by both univariate and multivariate analysis. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy predicted better prognosis than other treatments. Solid subtype was an independent prognostic factor for worse OS.ConclusionE1L3N appeared easier to use than SP142 to evaluate PD-L1 expression. A minority of EPMM expressed PD-L1, and only a few cells were positive. PD-L1 expression by immune cells evaluated with E1L3N was an independent prognostic factor in EPMM.
http://ift.tt/2qXKOcu
Hepatotoxicity following systemic therapy for colorectal liver metastases and the impact of chemotherapy-associated liver injury on outcomes after curative liver resection
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Gregor Duwe, Sebastian Knitter, Sina Pesthy, Anika S. Beierle, Marcus Bahra, Moritz Schmelzle, Rosa B. Schmuck, Philipp Lohneis, Nathanael Raschzok, Robert Öllinger, Marianne Sinn, Benjamin Struecker, Igor M. Sauer, Johann Pratschke, Andreas Andreou
Patients with colorectal liver metastases (CLM) have remarkably benefited from the advances in medical multimodal treatment and surgical techniques over the last two decades leading to significant improvements in long-term survival. More patients are currently undergoing liver resection following neoadjuvant chemotherapy, which has been increasingly established within the framework of curative-indented treatment strategies. However, the use of several cytotoxic agents has been linked to specific liver injuries that not only impair the ability of liver tissue to regenerate but also decrease long-term survival. One of the most common agents included in modern chemotherapy regimens is oxaliplatin, which is considered to induce a parenchymal damage of the liver primarily involving the sinusoids defined as sinusoidal obstruction syndrome (SOS). Administration of bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF), has been reported to improve response of CLM to chemotherapy in clinical studies, concomitantly protecting the liver from the development of SOS. In this review, we aim to summarize current data on multimodal treatment concepts for CLM, give an in-depth overview of liver damage caused by cytostatic agents focusing on oxaliplatin-induced SOS, and evaluate the role of bevacizumab to improve clinical outcomes of patients with CLM and to protect the liver from the development of SOS.
http://ift.tt/2rx0DEj
Evolution of the Histologic Classification of Thyroid Neoplasms and its Impact on Clinical Management
Publication date: Available online 18 May 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Bin Xu, Ronald Ghossein
The vast majority of low grade follicular cell derived thyroid carcinomas follows an indolent clinical course and is associated with very low mortality. Risk stratification using multiple clinical and pathologic characteristics has become the standard of care to guide appropriate management and avoid overtreatment. Over the past few decades, the field of thyroid pathology has witnessed several major changes that significantly impacted upon patients' care. These are:1) The reclassification of non-invasive encapsulated follicular variant of papillary thyroid carcinoma as noninvasive follicular thyroid neoplasm with papillary-like nuclear features; 2) the diagnosis of Hurthle cell carcinoma based on the presence of capsular and vascular invasion; 3) a detailed definition of poorly differentiated thyroid carcinoma, taking into consideration mitosis and necrosis; and 4) the emphasis on a detailed pathologic analysis such as the extent of vascular invasion and extrathyroidal extension. This review describes these histological concepts and details the history, rationale, and clinical impacts of such changes. These shifts in the classification and characterization of thyroid carcinoma provided a platform supporting therapy de-escalation. In addition several lessons were learned from these changes especially from the misclassification of the non-invasive encapsulated follicular variant of papillary thyroid carcinoma. We hope that the lessons learned will help better classify tumors in the future whether arising in the thyroid or other organs.
http://ift.tt/2qXG7zr
Predictors of overall and recurrence-free survival after neoadjuvant chemotherapy for gastroesophageal adenocarcinoma: pooled analysis of individual patient data (IPD) from randomized controlled trials (RCTs)
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Ulrich Ronellenfitsch, Matthias Schwarzbach, Ralf Hofheinz, Peter Kienle, Kai Nowak, Meinhard Kieser, Tracy E. Slanger, Bryan Burmeister, David Kelsen, Donna Niedzwiecki, Christoph Schuhmacher, Susan Urba, Cornelis van de Velde, Thomas N. Walsh, Marc Ychou, Katrin Jensen
BackgroundNeoadjuvant chemotherapy improves prognosis of patients with locally advanced gastroesophageal adenocarcinoma. The aim of this study was to identify predictors for postoperative survival following neoadjuvant therapy. These could be useful in deciding about postoperative continuation of chemotherapy.MethodsThis meta-analysis used IPD from RCTs comparing neoadjuvant chemotherapy with surgery alone for gastroesophageal adenocarcinoma. Trials providing IPD on age, sex, performance status, pT/N stage, resection status, overall and recurrence-free survival were included. Survival was calculated in the entire study population and subgroups stratified by supposed predictors and compared using the log-rank test. Multivariable Cox models were used to identify independent survival predictors.ResultsFour RCTs providing IPD from 553 patients fulfilled the inclusion criteria. (y)pT and (y)pN stage and resection status strongly predicted postoperative survival both after neoadjuvant therapy and surgery alone. Patients with R1 resection after neoadjuvant therapy survived longer than those with R1 resection after surgery alone. Patients with stage pN0 after surgery alone had better prognosis than those with ypN0 after neoadjuvant therapy. Patients with stage ypT3/4 after neoadjuvant therapy survived longer than those with stage pT3/4 after surgery alone. Multivariable regression identified resection status and (y)pN stage as predictors of survival in both groups. (y)pT stage predicted survival only after surgery alone.ConclusionAfter neoadjuvant therapy for gastroesophageal adenocarcinoma, survival is determined by the same factors as after surgery alone. However, ypT stage is not an independent predictor. These results can facilitate the decision about postoperative continuation of chemotherapy in pretreated patients.
http://ift.tt/2rwQXcO
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