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https://www.readbyqxmd.com/read/28534531/unravelling-the-biology-of-sclc-implications-for-therapy
#1
REVIEW
Joshua K Sabari, Benjamin H Lok, James H Laird, John T Poirier, Charles M Rudin
Small-cell lung cancer (SCLC) is an aggressive malignancy associated with a poor prognosis. First-line treatment has remained unchanged for decades, and a paucity of effective treatment options exists for recurrent disease. Nonetheless, advances in our understanding of SCLC biology have led to the development of novel experimental therapies. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models, and are under clinical investigation in combination with cytotoxic therapies and inhibitors of cell-cycle checkpoints...
May 23, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28520516/mesenchymal-stem-cell-migration-and-proliferation-are-mediated-by-hypoxia-inducible-factor-1%C3%AE-upstream-of-notch-and-sumo-pathways
#2
María Ciria, Nahuel A García, Imelda Ontoria-Oviedo, Hernán González-King, Rubén Carrero, José Luis De La Pompa, José Anastasio Montero, Pilar Sepúlveda
Mesenchymal stem cells (MSCs) are effective in treating several pathologies. We and others have demonstrated that hypoxia or hypoxia-inducible factor 1 alpha (HIF-1α) stabilization improves several MSC functions, including cell adhesion, migration, and proliferation, thereby increasing their therapeutic potential. To further explore the mechanisms induced by HIF-1α in MSCs, we studied its relationship with Notch signaling and observed that overexpression of HIF-1α in MSCs increased protein levels of the Notch ligands Jagged 1-2 and Delta-like (Dll)1, Dll3, and Dll4 and potentiated Notch signaling only when this pathway was activated...
May 18, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/28487384/non-invasive-interrogation-of-dll3-expression-in-metastatic-small-cell-lung-cancer
#3
Sai Kiran Sharma, Jacob Pourat, Dalya Abdel-Atti, Sean D Carlin, Alessandra Piersigilli, Alexander J Bankovich, Eric E Gardner, Omar Hamdy, Kumiko Isse, Sheila Bheddah, Joseph Sandoval, Kristen M Cunanan, Eric B Johansen, Viola Allaj, Vikram Sisodiya, David Liu, Brian M Zeglis, Charles M Rudin, Scott J Dylla, J T Poirier, Jason S Lewis
The Notch ligand DLL3 has emerged as a novel therapeutic target expressed in small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas. Rovalpituzumab teserine (Rova-T™; SC16LD6.5) is a first-in-class DLL3-targeted antibody-drug conjugate with encouraging initial safety and efficacy profiles in SCLC in the clinic. Here we demonstrate that tumor expression of DLL3, though orders of magnitude lower in surface protein expression than typical oncology targets of immunoPET, can serve as an imaging biomarker for SCLC...
May 9, 2017: Cancer Research
https://www.readbyqxmd.com/read/28482837/selective-gene-expression-analysis-of-the-neuroepithelial-body-microenvironment-in-postnatal-lungs-with-special-interest-for-potential-stem-cell-characteristics
#4
Line Verckist, Robrecht Lembrechts, Sofie Thys, Isabel Pintelon, Jean-Pierre Timmermans, Inge Brouns, Dirk Adriaensen
BACKGROUND: The pulmonary neuroepithelial body (NEB) microenvironment (ME) consists of innervated cell clusters that occur sparsely distributed in the airway epithelium, an organization that has so far hampered reliable selective gene expression analysis. Although the NEB ME has been suggested to be important for airway epithelial repair after ablation, little is known about their potential stem cell characteristics in healthy postnatal lungs. Here we report on a large-scale selective gene expression analysis of the NEB ME...
May 8, 2017: Respiratory Research
https://www.readbyqxmd.com/read/28366784/enhanced-osteogenic-differentiation-of-rat-bone-marrow-mesenchymal-stem-cells-on-titanium-substrates-by-inhibiting-notch3
#5
Huiming Wang, Zhiwei Jiang, Jing Zhang, Zhijian Xie, Ying Wang, Guoli Yang
OBJECTIVE: The role of the Notch pathway has already been identified as a crucial regulator of bone development. However, the Notch signaling pathway has gone largely unexplored during osseointegration. This study aims to investigate the role of Notch signaling on osteogenic differentiation of rat derived bone marrow mesenchymal stem cells (BMSCs) on sandblasted, large-grit, acid-etched (SLA) treated Ti disks. METHODS: The involved target genes in Notch pathways were identified by in vitro microarray and bioinformatics analyses with or without osteogenic induction...
March 19, 2017: Archives of Oral Biology
https://www.readbyqxmd.com/read/28258914/gene-expression-profiling-of-circulating-cd133-cells-of-hepatocellular-carcinoma-patients-associated-with-hcv-infection
#6
Abdel-Rahman N Zekri, Enas R El-Sisi, Zeinab F Abdallah, Alaa Ismail, Ahmed Barakat Barakat
AIM: Identifying the genetic expression profile of CD133(+) cells from HCC patients compared to CD133(+) cells from healthy volunteers that may contribute in hepatocarcinogenesis process. METHOD: Circulating CD133(+) cells were sorted from the peripheral blood of HCC patients as well as from healthy volunteers using magnetic activated cell sorting. The differential expression profile of stem cell related genes was performed using the Stem Cell PCR profiling assay...
March 2017: Journal of the Egyptian National Cancer Institute
https://www.readbyqxmd.com/read/28158294/deep-proteome-mapping-of-wm-266-4-human-metastatic-melanoma-cells-from-oncogenic-addiction-to-druggable-targets
#7
Eumorphia G Konstantakou, Athanassios D Velentzas, Athanasios K Anagnostopoulos, Zoi I Litou, Ourania A Konstandi, Aikaterini F Giannopoulou, Ema Anastasiadou, Gerassimos E Voutsinas, George Th Tsangaris, Dimitrios J Stravopodis
Cutaneous melanoma is a malignant tumor of skin melanocytes that are pigment-producing cells located in the basal layer (stratum basale) of epidermis. Accumulation of genetic mutations within their oncogenes or tumor-suppressor genes compels melanocytes to aberrant proliferation and spread to distant organs of the body, thereby resulting in severe and/or lethal malignancy. Metastatic melanoma's heavy mutational load, molecular heterogeneity and resistance to therapy necessitate the development of novel biomarkers and drug-based protocols that target key proteins involved in perpetuation of the disease...
2017: PloS One
https://www.readbyqxmd.com/read/28007595/the-notch-ligand-delta-like-3-promotes-tumor-growth-and-inhibits-notch-signaling-in-lung-cancer-cells-in-mice
#8
San-Ming Deng, Xian-Chun Yan, Liang Liang, Li Wang, Yuan Liu, Juan-Li Duan, Zi-Yan Yang, Tian-Fang Chang, Bai Ruan, Qi-Jun Zheng, Hua Han
Although it has been suggested that Dll3, one of the Notch ligands, promotes the proliferation and inhibits the apoptosis of cancer cells, the role of Dll3 in cancers remains unclear. In this study, we found that in the murine Lewis lung carcinoma (LLC) cells, the level of Dll3 mRNA changed upon tumor microenvironment (TME) stimulation, namely, decreased under hypoxia or stimulated with tumor necrosis factor (TNF)-α. Dll3 was also expressed at higher level in human lung carcinoma tissues than in the para-carcinoma tissues...
January 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27986711/rovalpituzumab-tesirine-is-active-in-patients-with-dll3-positive-tumors
#9
(no author information available yet)
Rovalpituzumab tesirine is well tolerated and has single-agent antitumor activity.
December 16, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27969444/oral02-01-safety-and-efficacy-of-single-agent-rovalpituzumab-tesirine-a-dll3-targeted-adc-in-recurrent-or%C3%A2-refractory-sclc-topic-medical-oncology
#10
Todd M Bauer, David Spigel, Neal Ready, Daniel Morgensztern, Bonnie S Glisson, Lauren A Byers, Howard Burris, Francisco Robert, Donald K Strickland, Maria C Pietanza, Ramaswamy Govindan, Scott J Dylla, Stanford Peng, Charles Rudin
No abstract text is available yet for this article.
November 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27932068/rovalpituzumab-tesirine-a-dll3-targeted-antibody-drug-conjugate-in-recurrent-small-cell-lung-cancer-a-first-in-human-first-in-class-open-label-phase-1-study
#11
Charles M Rudin, M Catherine Pietanza, Todd M Bauer, Neal Ready, Daniel Morgensztern, Bonnie S Glisson, Lauren A Byers, Melissa L Johnson, Howard A Burris, Francisco Robert, Tae H Han, Sheila Bheddah, Noah Theiss, Sky Watson, Deepan Mathur, Bharathi Vennapusa, Hany Zayed, Satwant Lally, Donald K Strickland, Ramaswamy Govindan, Scott J Dylla, Stanford L Peng, David R Spigel
BACKGROUND: Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identified in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen. METHODS: We conducted a phase 1 open-label study at ten cancer centres in the USA...
January 2017: Lancet Oncology
https://www.readbyqxmd.com/read/27932065/rovalpituzumab-tesirine-and-dll3-a-new-challenge-for-small-cell-lung-cancer
#12
Antonio Rossi
No abstract text is available yet for this article.
January 2017: Lancet Oncology
https://www.readbyqxmd.com/read/27929540/inflammation-and-notch-signaling-a-crosstalk-with-opposite-effects-on-tumorigenesis
#13
REVIEW
Chiara Fazio, Luigi Ricciardiello
The Notch cascade is a fundamental and highly conserved pathway able to control cell-fate. The Notch pathway arises from the interaction of one of the Notch receptors (Notch1-4) with different types of ligands; in particular, the Notch pathway can be activated canonically (through the ligands Jagged1, Jagged2, DLL1, DLL3 or DLL4) or non-canonically (through various molecules shared by other pathways). In the context of tumor biology, the deregulation of Notch signaling is found to be crucial, but it is still not clear if the activation of this pathway exerts a tumor-promoting or a tumor suppressing function in different cancer settings...
December 8, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27922280/ganetespib-for-small-cell-lung-cancer
#14
REVIEW
Deepa S Subramaniam, Eiran A Warner, Giuseppe Giaccone
Heat shock proteins (Hsps) are part of a complex network of chaperone proteins that are critically involved in the conformational maturation of intracellular proteins and regulate their degradation via the proteasome system Hsps (especially Hsp70 and Hsp90) are upregulated in many cancers and are potentially attractive therapeutic targets. Ganetespib is a potent non-geldanamycin analogue, and avoids the toxicities associated with older analogues due to its small molecular weight, lipophilicity and the absence of the benzoquinone moiety; strong pre-clinical data support its evaluation in lung cancer, especially small cell lung cancer (SCLC)...
January 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/27894818/supt20-is-required-for-development-of-the-axial-skeleton
#15
Sunita Warrier, Samer Nuwayhid, Julia A Sabatino, Kelsey F Sugrue, Irene E Zohn
Somitogenesis and subsequent axial skeletal development is regulated by the interaction of pathways that determine the periodicity of somite formation, rostrocaudal somite polarity and segment identity. Here we use a hypomorphic mutant mouse line to demonstrate that Supt20 (Suppressor of Ty20) is required for development of the axial skeleton. Supt20 hypomorphs display fusions of the ribs and vertebrae at lower thoracic levels along with anterior homeotic transformation of L1 to T14. These defects are preceded by reduction of the rostral somite and posterior shifts in Hox gene expression...
January 15, 2017: Developmental Biology
https://www.readbyqxmd.com/read/27882195/design-and-synthesis-of-tesirine-a-clinical-antibody-drug-conjugate-pyrrolobenzodiazepine-dimer-payload
#16
Arnaud C Tiberghien, Jean-Noel Levy, Luke A Masterson, Neki V Patel, Lauren R Adams, Simon Corbett, David G Williams, John A Hartley, Philip W Howard
Pyrrolobenzodiazepine dimers are an emerging class of warhead in the field of antibody-drug conjugates (ADCs). Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics. One of the reactive imines was capped with a cathepsin B-cleavable valine-alanine linker. A robust synthetic route was developed to allow the production of tesirine on clinical scale, employing a flexible, convergent strategy...
November 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27782828/spatial-transcriptome-analysis-reveals-notch-pathway-associated-prognostic-markers-in-idh1-wild-type-glioblastoma-involving-the-subventricular-zone
#17
Christine Jungk, Andreas Mock, Janina Exner, Christoph Geisenberger, Rolf Warta, David Capper, Amir Abdollahi, Sara Friauf, Bernd Lahrmann, Niels Grabe, Philipp Beckhove, Andreas von Deimling, Andreas Unterberg, Christel Herold-Mende
BACKGROUND: The spatial relationship of glioblastoma (GBM) to the subventricular zone (SVZ) is associated with inferior patient survival. However, the underlying molecular phenotype is largely unknown. We interrogated an SVZ-dependent transcriptome and potential location-specific prognostic markers. METHODS: mRNA microarray data of a discovery set (n = 36 GBMs) were analyzed for SVZ-dependent gene expression and process networks using the MetaCore™ workflow...
October 26, 2016: BMC Medicine
https://www.readbyqxmd.com/read/27520484/chemotherapy-enhances-tumor-vascularization-via-notch-signaling-mediated-formation-of-tumor-derived-endothelium-in-breast-cancer
#18
COMPARATIVE STUDY
Peng Zhang, Dongxu He, Zhen Chen, Qiongxi Pan, Fangfang Du, Xian Zang, Yan Wang, Chunlei Tang, Hong Li, He Lu, Xiaoqiang Yao, Jian Jin, Xin Ma
It is believed that tumor cells can give rise to endothelial cells and tumor endothelium has a neoplastic origin. Yet, the stimuli and underlying mechanism remain unclear. Here, we demonstrate that adriamycin or paclitaxel, first-line chemotherapy agent, induced breast cancer cells to generate morphological, phenotypical and functional features of endothelial cells in vitro. In xenografts models, challenges from adriamycin or paclitaxel induced cancer cells to generate the majority of microvessels. Importantly, in breast cancer specimens from patients with neoadjuvant anthracycline-based or taxane-based chemotherapy, tumor-derived endothelial microvessels, lined by EGFR-amplified or/and TP53(+)-CD31(+) endothelial cells, was significantly higher in patients with progressive or stable disease (PD/SD) than in those with a partial or complete response (PR/CR)...
October 15, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27472720/five-known-tagging-dll3-snps-are-not-associated-with-congenital-scoliosis-a-case-control-association-study-in-a-chinese-han-population
#19
Yong Yang, Bing-Qiang Wang, Zhi-Hong Wu, Hai-Yan Zhang, Gui-Xing Qiu, Jian-Xiong Shen, Jian-Guo Zhang, Yu Zhao, Yi-Peng Wang, Qi Fei
Genetic etiology hypothesis is widely accepted in the development of congenital scoliosis (CS). The delta-like 3 (DLL3) gene, a member of the Notch signaling pathway, was implicated to contribute to human CS. In this study, a case-control association study was conducted to determine the association of single nucleotide polymorphism (SNP) in the DLL3 gene with CS in a Chinese Han Population. Five known tagging SNPs of the DLL3 gene were genotyped among 270 Chinese Han subjects (128 nonsyndromic CS patients and 142 matched controls)...
July 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/27452466/ascl1-and-neurod1-reveal-heterogeneity-in-pulmonary-neuroendocrine-tumors-and-regulate-distinct-genetic-programs
#20
Mark D Borromeo, Trisha K Savage, Rahul K Kollipara, Min He, Alexander Augustyn, Jihan K Osborne, Luc Girard, John D Minna, Adi F Gazdar, Melanie H Cobb, Jane E Johnson
Small cell lung carcinoma (SCLC) is a high-grade pulmonary neuroendocrine tumor. The transcription factors ASCL1 and NEUROD1 play crucial roles in promoting malignant behavior and survival of human SCLC cell lines. Here, we find that ASCL1 and NEUROD1 identify heterogeneity in SCLC, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1, but not NEUROD1, is present in mouse pulmonary neuroendocrine cells, and only ASCL1 is required in vivo for tumor formation in mouse models of SCLC. ASCL1 targets oncogenic genes including MYCL1, RET, SOX2, and NFIB while NEUROD1 targets MYC...
August 2, 2016: Cell Reports
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