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Cancer discovery

Ya Chen, Yong Tang, Beibei Mao, Wenchao Li, Hongwei Jin, Liangren Zhang, Zhenming Liu
Any type of breast cancer not expressing genes of the estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) is referred to as triple-negative breast cancer (TNBC). Accordingly, TNBCs do not respond to hormonal therapies or medicines targeting the ER, PR, or HER2. Systemic chemotherapy is therefore the only treatment option available today and prognoses remain poor. We report the discovery and characterization of N-(naphtho[1,2-b]furan-5-yl)benzenesulfonamides as selective inhibitors of TNBCs...
March 16, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Chen Chi, Leigh C Murphy, Pingzhao Hu
Breast cancer diagnosis in young women has emerged as an independent prognostic factor with higher recurrence risk and death than their older counterparts. We aim to find recurrent somatic copy number alteration (CNA) regions identified from breast cancer microarray data and associate the CNA status of the genes harbored in the regions to the survival of young women with breast cancer. By using the interval graph-based algorithm we developed, and the CNA data consisting of a Discovery set with 130 young women and a Validation set with 125 young women, we identified 38 validated recurrent CNAs containing 39 protein encoding genes...
February 20, 2018: Oncotarget
Daniela Cecconi, Luca Dalle Carbonare, Antonio Mori, Samuele Cheri, Michela Deiana, Jessica Brandi, Vincenzo Degaetano, Valentina Masiero, Giulio Innamorati, Monica Mottes, Giovanni Malerba, Maria Teresa Valenti
Melanoma is an aggressive skin cancer; an early detection of the primary tumor may improve its prognosis. Despite many genes have been shown to be involved in melanoma, the full framework of melanoma transformation has not been completely explored. The characterization of pathways involved in tumor restraint in in vitro models may help to identify oncotarget genes. We therefore aimed to probe novel oncotargets through an integrated approach involving proteomic, gene expression and bioinformatic analysis We investigated molecular modulations in melanoma cells treated with ascorbic acid, which is known to inhibit cancer growth at high concentrations...
February 20, 2018: Oncotarget
Qianqian Wang, Jiahui Xu, Ying Li, Jumin Huang, Zebo Jiang, Yuwei Wang, Liang Liu, Elaine Lai Han Leung, Xiaojun Yao
Protein arginine methyltransferase 5 (PRMT5) is able to regulate gene transcription by catalyzing the symmetrical dimethylation of arginine residue of histone, which plays a key role in tumorigenesis. Many efforts have been taken in discovering small-molecular inhibitors against PRMT5, but very few were reported and most of them were SAM-competitive. EPZ015666 is a recently reported PRMT5 inhibitor with a new binding site, which is different from S-adenosylmethionine (SAM)-binding pocket. This new binding site provides a new clue for the design and discovery of potent and specific PRMT5 inhibitors...
2018: Frontiers in Pharmacology
Fleur M Ferguson, Nathanael S Gray
Receptor tyrosine kinase signalling pathways have been successfully targeted to inhibit proliferation and angiogenesis for cancer therapy. However, kinase deregulation has been firmly demonstrated to play an essential role in virtually all major disease areas. Kinase inhibitor drug discovery programmes have recently broadened their focus to include an expanded range of kinase targets and therapeutic areas. In this Review, we provide an overview of the novel targets, biological processes and disease areas that kinase-targeting small molecules are being developed against, highlight the associated challenges and assess the strategies and technologies that are enabling efficient generation of highly optimized kinase inhibitors...
March 16, 2018: Nature Reviews. Drug Discovery
Irini A Doytchinova, Darren R Flower
Cancer kills 8 million annually worldwide. Although survival rates in prevalent cancers continue to increase, many cancers have no effective treatment, prompting the search for new and improved protocols. Immunotherapy is a new and exciting addition to the anti-cancer arsenal. The successful and accurate identification of aberrant host proteins acting as antigens for vaccination and immunotherapy is a key aspiration for both experimental and computational research. Here we describe key elements of in silico prediction, including databases of cancer antigens and bleeding-edge methodology for their prediction...
March 15, 2018: BMC Immunology
Matthew G K Benesch, Iain T K MacIntyre, Todd P W McMullen, David N Brindley
A quarter-century after the discovery of autotaxin in cell culture, the autotaxin-lysophosphatidate (LPA)-lipid phosphate phosphatase axis is now a promising clinical target for treating chronic inflammatory conditions, mitigating fibrosis progression, and improving the efficacy of existing cancer chemotherapies and radiotherapy. Nearly half of the literature on this axis has been published during the last five years. In cancer biology, LPA signaling is increasingly being recognized as a central mediator of the progression of chronic inflammation in the establishment of a tumor microenvironment which promotes cancer growth, immune evasion, metastasis, and treatment resistance...
March 15, 2018: Cancers
Yanchun Ma, Kun Chen, Zhenhua Yang, Ming Guan
Lung cancer is the most common type of malignancy to metastasize to the brain, with the median survival time of patients being 6-11 months. In the present study, the aim was to compare the actionable gene mutation profiles of primary lung adenocarcinoma (LC) samples and LC brain metastasis (LCBM) samples through targeted sequencing. Next generation sequencing (NGS) of 13 formalin-fixed, paraffin-embedded LC samples and 15 LCBM samples was performed using a customized OncoAim™ cancer panel and OncoAim™ RNA fusion panel on the MiSeq platform...
April 2018: Oncology Letters
Dong-Wook Kim, Keun-Cheol Kim, Kee-Beom Kim, Colin T Dunn, Kwon-Sik Park
The discovery of recurrent alterations in genes encoding transcription regulators and chromatin modifiers is one of the most important recent developments in the study of the small cell lung cancer (SCLC) genome. With advances in models and analytical methods, the field of SCLC biology has seen remarkable progress in understanding the deregulated transcription networks linked to the tumor development and malignant progression. This review will discuss recent discoveries on the roles of RB and P53 family of tumor suppressors and MYC family of oncogenes in tumor initiation and development...
February 2018: Translational Lung Cancer Research
Kun Qian, Hao Hu, Hui Xu, Y George Zheng
Protein arginine methyltransferases (PRMTs) are crucial epigenetic regulators in eukaryotic organisms that serve as histone writers for chromatin remodeling. PRMTs also methylate a variety of non-histone protein substrates to modulate their function and activity. The development of potent PRMT inhibitors has become an emerging and imperative research area in the drug discovery field to provide novel therapeutic agents for treating diseases and as tools to investigate the biological functions of PRMTs. PRMT1 is the major type I enzyme that catalyzes the formation of asymmetric dimethyl arginine, and PRMT1 plays important regulatory roles in signal transduction, transcriptional activation, RNA splicing, and DNA repair...
2018: Signal Transduction and Targeted Therapy
Brunella Costanza, Andrei Turtoi, Akeila Bellahcène, Touko Hirano, Olivier Peulen, Arnaud Blomme, Vincent Hennequière, Eugene Mutijima, Jacques Boniver, Marie-Alice Meuwis, Claire Josse, Benjamin Koopmansch, Karin Segers, Takehiko Yokobori, Karim Fahmy, Marc Thiry, Carla Coimbra, Nancy Garbacki, Alain Colige, Dominique Baiwir, Vincent Bours, Edouard Louis, Olivier Detry, Philippe Delvenne, Masahiko Nishiyama, Vincent Castronovo
The identification of diagnostic and prognostic biomarkers from early lesions, measurable in liquid biopsies remains a major challenge, particularly in oncology. Fresh human material of high quality is required for biomarker discovery but is often not available when it is totally required for clinical pathology investigation. Hence, all OMICs studies are done on residual and less clinically relevant biological samples. Here after, we present an innovative, simple, and non-destructive, procedure named EXPEL that uses rapid, pressure-assisted, interstitial fluid extrusion, preserving the specimen for full routine clinical pathology investigation...
February 13, 2018: Oncotarget
Mohamed E M Saeed, Nuha Mahmoud, Yoshikazu Sugimoto, Thomas Efferth, Heba Abdel-Aziz
For decades, natural products represented a significant source of diverse and unique bioactive lead compounds in drug discovery field. In Clinical oncology, complete tumors remission is hampered by the development of drug-resistance. Therefore, development of cytotoxic agents that may overcome drug resistance is urgently needed. Here, the natural benzophenanthridine alkaloid sanguinarine has been studied for its cytotoxic activity against multidrug resistance (MDR) cancer cells. We investigated the role of the ATP-binding cassette (ABC) transporters BCRP/ABCG2, P-glycoprotein/ABCB1 and its close relative ABCB5 in drug resistance...
2018: Frontiers in Pharmacology
Michal J Dabrowski, Michal Draminski, Klev Diamanti, Karolina Stepniak, Magdalena A Mozolewska, Paweł Teisseyre, Jacek Koronacki, Jan Komorowski, Bozena Kaminska, Bartosz Wojtas
In order to find clinically useful prognostic markers for glioma patients' survival, we employed Monte Carlo Feature Selection and Interdependencies Discovery (MCFS-ID) algorithm on DNA methylation (HumanMethylation450 platform) and RNA-seq datasets from The Cancer Genome Atlas (TCGA) for 88 patients observed until death. The input features were ranked according to their importance in predicting patients' longer (400+ days) or shorter (≤400 days) survival without prior classification of the patients. Interestingly, out of the 65 most important features found, 63 are methylation sites, and only two mRNAs...
March 13, 2018: Scientific Reports
Nathalie Harder, Maria Athelogou, Harald Hessel, Nicolas Brieu, Mehmet Yigitsoy, Johannes Zimmermann, Martin Baatz, Alexander Buchner, Christian G Stief, Thomas Kirchner, Gerd Binnig, Günter Schmidt, Ralf Huss
Tissue Phenomics is the discipline of mining tissue images to identify patterns that are related to clinical outcome providing potential prognostic and predictive value. This involves the discovery process from assay development, image analysis, and data mining to the final interpretation and validation of the findings. Importantly, this process is not linear but allows backward steps and optimization loops over multiple sub-processes. We provide a detailed description of the Tissue Phenomics methodology while exemplifying each step on the application of prostate cancer recurrence prediction...
March 13, 2018: Scientific Reports
Mariarosaria Conte, Raffaele De Palma, Lucia Altucci
In recent years, anti-tumor immunotherapy has shown promising results, and immune-oncology is now emerging as the fourth major wave in the treatment of tumors after radiotherapy, chemotherapy and molecular targeted therapy. Understanding the impact of the immune system on neoplastic cells is crucial to improve its effectiveness against cancer. The stratification of patients who might benefit from immunotherapy as well as the personalization of medicine have contributed to the discovery of new immunotherapeutic targets and molecules...
March 10, 2018: International Journal of Biochemistry & Cell Biology
Peng Wu, Jia-Li Liu, Shi-Mei Pei, Chang-Peng Wu, Kai Yang, Shu-Peng Wang, Song Wu
BACKGROUND: Renal cell carcinoma (RCC) account for over 80% of renal malignancies. The most common type of RCC can be classified into three subtypes including clear cell, papillary and chromophobe. ccRCC (the Clear Cell Renal Cell Carcinoma) is the most frequent form and shows variations in genetics and behavior. To improve accuracy and personalized care and increase the cure rate of cancer, molecular typing for individuals is necessary. METHODS: We adopted the genome, transcriptome and methylation HMK450 data of ccRCC in The Cancer Genome Atlas Network in this research...
March 13, 2018: BMC Cancer
Azam Peyvandipour, Nafiseh Saberian, Adib Shafi, Michele Donato, Sorin Draghici
Motivation: Identification of novel therapeutic effects for existing U.S. Food and Drug Administration (FDA)-approved drugs, drug repurposing, is an approach aimed to dramatically shorten the drug discovery process, which is costly, slow and risky. Several computational approaches use transcriptional data to find potential repurposing candidates. The main hypothesis of such approaches is that if gene expression signature of a particular drug is opposite to the gene expression signature of a disease, that drug may have a potential therapeutic effect on the disease...
March 9, 2018: Bioinformatics
Lei Xu, Guangmin Liang, Longjie Wang, Changrui Liao
Cancer is a serious health issue worldwide. Traditional treatment methods focus on killing cancer cells by using anticancer drugs or radiation therapy, but the cost of these methods is quite high, and in addition there are side effects. With the discovery of anticancer peptides, great progress has been made in cancer treatment. For the purpose of prompting the application of anticancer peptides in cancer treatment, it is necessary to use computational methods to identify anticancer peptides (ACPs). In this paper, we propose a sequence-based model for identifying ACPs (SAP)...
March 13, 2018: Genes
Chunlong Zhao, Jie Zang, Qin'ge Ding, Elizabeth S Inks, Wenfang Xu, C James Chou, Yingjie Zhang
In the past decade, although research and development of histone deacetylase (HDAC) inhibitors as therapeutic agents have achieved great accomplishments, especially in oncology field, there is still an urgent need for the discovery of isoform-selective HDAC inhibitors considering the side effects caused by nonselective HDAC inhibitors. HDAC8, a unique class I zinc-dependent HDAC, is becoming a potential target in cancer and other diseases. In the current study, a novel series of N-hydroxy-3-sulfamoylbenzamide-based HDAC8 selective inhibitors (12a-12p) were designed and synthesized, among which compounds 12a, 12b and 12c exhibited potent HDAC8 inhibition with two-digit nanomolar IC50 values, and considerable selectivity over HDAC2 (>180-fold) and HDAC6 (∼30-fold) which was confirmed by western blot analysis...
March 6, 2018: European Journal of Medicinal Chemistry
Patrick Kwok-Shing Ng, Jun Li, Kang Jin Jeong, Shan Shao, Hu Chen, Yiu Huen Tsang, Sohini Sengupta, Zixing Wang, Venkata Hemanjani Bhavana, Richard Tran, Stephanie Soewito, Darlan Conterno Minussi, Daniela Moreno, Kathleen Kong, Turgut Dogruluk, Hengyu Lu, Jianjiong Gao, Collin Tokheim, Daniel Cui Zhou, Amber M Johnson, Jia Zeng, Carman Ka Man Ip, Zhenlin Ju, Matthew Wester, Shuangxing Yu, Yongsheng Li, Christopher P Vellano, Nikolaus Schultz, Rachel Karchin, Li Ding, Yiling Lu, Lydia Wai Ting Cheung, Ken Chen, Kenna R Shaw, Funda Meric-Bernstam, Kenneth L Scott, Song Yi, Nidhi Sahni, Han Liang, Gordon B Mills
The functional impact of the vast majority of cancer somatic mutations remains unknown, representing a critical knowledge gap for implementing precision oncology. Here, we report the development of a moderate-throughput functional genomic platform consisting of efficient mutant generation, sensitive viability assays using two growth factor-dependent cell models, and functional proteomic profiling of signaling effects for select aberrations. We apply the platform to annotate >1,000 genomic aberrations, including gene amplifications, point mutations, indels, and gene fusions, potentially doubling the number of driver mutations characterized in clinically actionable genes...
March 12, 2018: Cancer Cell
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