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The state of lung cancer research: a global analysis.

Lung cancer is the leading cause of cancer years of life lost and is associated with the highest economic burden relative to other tumour types. Research remains at the cornerstone of achieving improved outcomes from lung cancer. We present the results of a comprehensive analysis of global lung cancer research between 2004 and 2013 (10 years) METHODS: The study used bibliometrics to undertake a quantitative analysis of research outputs in the 24 leading cancer research countries internationally, based on articles and reviews in the Web of Science (WoS) database.
A total of 32,161 lung cancer research papers from 2,085 different journals were analysed. Lung cancer research represented only 5.6% of overall cancer research in 2013, a 1.2% increase since 2004. The commitment to lung cancer research has fallen in most countries, apart from China, and shows no correlation with lung cancer burden. A review of key research types demonstrated that diagnostics, screening and quality of life research represent 4.3%, 1.8% and 0.3% of total lung cancer research respectively. The leading research types were genetics (20%), systemic therapies (17%) and prognostic biomarkers (16%). Research outputs are increasingly basic science with a fall in clinical translational research output over this time period.
Our findings have established that relative to the huge health, social and economic burden associated with lung cancer, the level of world research output lags significantly behind that of other malignancies. Commitment to diagnostics, screening and quality of life research is much lower compared to basic science and medicines research. The study findings are expected to provide the requisite intelligence to guide future cancer research programs in lung cancer.
Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

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mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer.

The mechanistic target of rapamycin (mTOR) is a major regulator of cell growth and is frequently dysregulated in cancer. While mTOR complex-1 (mTORC1) is a validated cancer target, the role of mTOR complex-2 (mTORC2) remains less defined. Here, we reveal mTORC2 as a critical regulator of breast cancer metabolism. We showed that hyperphosphorylation in ATP citrate lyase (ACL) occurs frequently in human breast tumors and correlates well with HER2+ and/or PIK3CA-mutant (HER2+/PIK3CAmut) status in breast tumor cell lines. In HER2+/PIK3CAmut cells, mTORC2 controls Ser-455 phosphorylation of ACL thereby promoting acetyl-CoA production, de novo lipogenesis and mitochondrial physiology, all of which were inhibited by an mTORC1/mTORC2 kinase inhibitor (mTOR-KI) or cellular depletion of mTORC2 or ACL. mTOR-KI but not rapamycin blocked the IGF-1-induced ACL phosphorylation and glucose to lipid conversion. Depletion of mTORC2 but not mTORC1 specifically inhibited the ACL-dependent acetyl-CoA production. In the HER2+/PIK3CAmut MDA361, MDA453, BT-474 and T47D cells, depletion of mTORC2 or ACL led to growth inhibition and mitochondrial hyperpolarization, which were partially rescued by an alternate source of acetyl-CoA. These same changes were not apparent in mTORC2- or ACL-depleted HER2-/PIK3CAwt MDA231 and HCC1806 cells, highlighting a differential dependence of mTORC2-ACL for survival in these two cell types. Moreover, ACL Ser-455 mutants S455E (phosphomimetic) and S455A (non-phosphorylatable) each increased or decreased, respectively, the acetyl-CoA production, mitochondrial homeostasis and survival in ACL-depleted MDA453 cells. These studies define a new and rapamycin-resistant mechanism of mTORC2-ACL in lipogenesis and acetyl-CoA biology and provide a rationale for targeting of mTORC1 and mTORC2 in HER2+/PIK3CAmut breast cancer.

Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control.

DNA replication stress is a source of genomic instability. Here we identify changed mutation rate 1 (Cmr1) as a factor involved in the response to DNA replication stress in Saccharomyces cerevisiae and show that Cmr1–together with Mrc1/Claspin, Pph3, the chaperonin containing TCP1 (CCT) and 25 other proteins–define a novel intranuclear quality control compartment (INQ) that sequesters misfolded, ubiquitylated and sumoylated proteins in response to genotoxic stress. The diversity of proteins that localize to INQ indicates that other biological processes such as cell cycle progression, chromatin and mitotic spindle organization may also be regulated through INQ. Similar to Cmr1, its human orthologue WDR76 responds to proteasome inhibition and DNA damage by relocalizing to nuclear foci and physically associating with CCT, suggesting an evolutionarily conserved biological function. We propose that Cmr1/WDR76 plays a role in the recovery from genotoxic stress through regulation of the turnover of sumoylated and phosphorylated proteins.

PET Imaging of Tissue Factor in Pancreatic Cancer Using 64Cu-labeled Active Site Inhibited Factor VII.

Tissue factor (TF) is the main initiator of the extrinsic coagulation cascade. However, TF also plays an important role in cancer. TF expression has been reported in 53-89% of all pancreatic adenocarcinomas and the expression level of TF has in clinical studies correlated with advanced stage, increased micro vessel density, metastasis and poor overall survival. Imaging of TF expression is of clinical relevance as a prognostic biomarker, and as a companion diagnostics for TF directed therapies currently under clinical development. Factor VII (FVII) is the natural ligand to TF. The purpose of this study was to investigate the possibility of using active site inhibited FVII (FVIIai) labeled with(64)Cu for PET imaging of TF expression.
FVIIai was conjugated to 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) and labeled with(64)Cu ((64)Cu-NOTA-FVIIai). Longitudinal in vivo PET imaging was performed at 1, 4, 15 and 36 hours after injection of(64)Cu-NOTA-FVIIai in mice with pancreatic adenocarcinomas (BxPC-3). The specificity of TF imaging with(64)Cu-NOTA-FVIIai was investigated in subcutaneous pancreatic tumor models with different levels of TF expression and in a competition experiment. In addition, imaging of orthotopic pancreas tumors was performed using(64)Cu-NOTA-FVIIai and PET/MR imaging.In vivoimaging data were supported byex vivobiodistribution, flow cytometry and immunohistochemistry.
Longitudinal PET imaging with(64)Cu-NOTA-FVIIai showed a tumor uptake of 2.3 ± 0.2, 3.7 ± 0.3, 3.4 ± 0.3 and 2.4 ± 0.3 % injected dose per gram at 1, 4, 15 and 36 hours after injection, respectively. An increase in tumor to normal tissue contrast was observed over the imaging time-course. Competition with unlabeled FVIIai significantly (P&lt; 0.001) reduced the tumor uptake. The tumor uptake observed in models with different TF expression levels was significantly different from each other (P&lt; 0.001), and was in agreement with the TF level evaluated by TF immunohistochemistry staining. Orthotopic tumors were clearly visible on the PET/MR images and the uptake of(64)Cu-NOTA-FVIIai was co-localized with viable tumor tissue.
(64)Cu-NOTA-FVIIai is well suited for PET imaging of tumor TF expression, and imaging is capable of distinguishing the TF expression level of various pancreatic tumor models.
Copyright © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Transcription Blockage Leads to New Beginnings.

Environmental agents are constantly challenging cells by damaging DNA, leading to the blockage of transcription elongation. How do cells deal with transcription-blockage and how is transcription restarted after the blocking lesions are removed? Here we review the processes responsible for the removal of transcription-blocking lesions, as well as mechanisms of transcription restart. We also discuss recent data suggesting that blocked RNA polymerases may not resume transcription from the site of the lesion following its removal but, rather, are forced to start over from the beginning of genes.