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Molecular Cancer Therapeutics

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https://www.readbyqxmd.com/read/30446586/induction-of-mnk-kinases-dependent-eif4e-phosphorylation-by-inhibitors-targeting-bet-proteins-limits-efficacy-of-bet-inhibitors
#1
Thao N Pham, Krishan Kumar, Brian T DeCant, Meng Shang, Samad Z Munshi, Maria Matsangou, Kazumi Ebine, Hidayatullah G Munshi
BET inhibitors (BETis), which target transcription of key oncogenic genes, are currently being evaluated in early-phase clinical trials. However, since BETis show limited single agent activity, there is increasing interest in identifying signaling pathways to enhance the efficacy of BETis. Here, we demonstrate increased MNK kinases-dependent eIF4E phosphorylation following treatment with BETis, indicating activation of a pro-survival feedback mechanism in response to BETis. BET PROTACs, which promote degradation of BET proteins, also induced eIF4E phosphorylation in cancer cells...
November 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30446585/akt-inhibition-modulates-h3k4-demethylase-levels-in-pten-null-prostate-cancer
#2
Mohammad Imran Khan, Abid Hamid, Suvasmita Rath, Bushra Ateeq, Qateeb Khan, Imtiaz A Siddiqui, Vaqar Mustafa Adhami, Hani Choudhry, Mazin A Zamzami, Hasan Mukhtar
Hyperactivated AKT kinase due to loss of its negative regulator PTEN influences many aspects of cancer biology including chromatin. AKT primarily regulates acetyl-CoA production and phosphorylates many histone modulating enzymes resulting in their activation or inhibition. Therefore, understanding the therapeutic impact of AKT inhibition on chromatin related events is essential. Here, we report that AKT inhibition in prostate specific PTEN knockout mice significantly induces di- and tri-methylation of H3K4 with concomitant reduction in H3K9 acetylation...
November 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30425132/the-t197a-knock-in-model-of-cdkn1b-gene-to-study-the-effects-of-p27-restoration-in-vivo
#3
Carmela De Marco, Nicola Rinaldo, Fernanda De Vita, Floriana Forzati, Elvira Caira, Valentina Iovane, Orlando Paciello, Donatella Montanaro, Sara D'Andrea, Gustavo Baldassarre, Serenella Papparella, Donatella Malanga, Alfonso Baldi, Giuseppe Viglietto
The CDK inhibitor, p27kip1, encoded by the Cdkn1b gene can negatively modulate cell proliferation. The control of p27 activity during the cell cycle is regulated at multiple levels including transcription, translation and protein stability. The last residue of p27 (threonine 198 in human, threonine 197 in mouse) is involved in the control of protein stability. We have generated a murine knock-in model (Cdkn1bT197A) in which threonine 197 is replaced by alanine, which renders p27 protein highly unstable due to a high rate of proteasomal degradation...
November 13, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30425131/mtorc1-2-inhibition-as-a-therapeutic-strategy-for-pik3ca-mutant-cancers
#4
Stephanie L Fricke, Susan N Payne, Peter F Favreau, Jeremy D Kratz, Cheri A Pasch, Tyler M Foley, Alexander E Yueh, Dana R Van De Hey, Mitchell G Depke, Demetra P Korkos, Gioia Chengcheng Sha, Rebecca A DeStefanis, Linda Clipson, Mark E Burkard, Kayla K Lemmon, Benjamin M Parsons, Paraic A Kenny, Kristina A Matkowskyj, Michael A Newton, Melissa C Skala, Dustin A Deming
PIK3CA mutations are common in clinical molecular profiling, yet an effective means to target these cancers has yet to be developed. MTORC1 inhibitors are often used off-label for patients with PIK3CA mutant cancers with only limited data to support this approach. Here we describe a cohort of patients treated with cancers possessing mutations activating the PI3K signaling cascade with minimal benefit to treatment with the MTORC1 inhibitor everolimus. Previously, we demonstrated that dual PI3K/mTOR inhibition could decrease proliferation, induce differentiation, and result in a treatment response in APC and PIK3CA mutant colorectal cancer (CRC)...
November 13, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30420565/predicting-novel-therapies-and-targets-regulation-of-notch3-by-the-bromodomain-protein-brd4
#5
Alejandro Villar-Prados, Sherry Y Wu, Karem A Court, Shaolin Ma, Christopher LaFargue, Mamur A Chowdhury, Margaret I Engelhardt, Cristina Ivan, Prahlad T Ram, Ying Wang, Keith Baggerly, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Shyh-Ming Yang, David J Maloney, Makoto Yoshioka, Jeffrey W Strovel, Jason Roszik, Anil K Sood
BACKGROUND: Systematic approaches for accurate re-purposing of targeted therapies are needed. We developed and aimed to biologically validate our Therapy Predicting Tool (TPT) for the re-purposing of targeted therapies for specific tumor types by testing the role of Bromodomain and Extra-Terminal motif inhibitors (BETis) in inhibiting BRD4 function and downregulating Notch3 signaling in ovarian cancer. METHODS: Utilizing established ovarian cancer pre-clinical models, we carried out in vitro and in vivo studies using clinically relevant BETis to determine their therapeutic effect and impact on Notch3 signaling...
November 12, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30413650/mir-454-3p-is-an-exosomal-biomarker-and-functions-as-a-tumor-suppressor-in-glioma
#6
Naiyuan Shao, Lian Xue, Rong Wang, Kaiming Luo, Feng Zhi, Qing Lan
Glioma is the most common type of primary malignant brain tumor in adults. Our previous work discovered that plasma miR-454-3p may have some advantages in glioma prognosis, but the clinical significance and the regulatory mechanism of miR-454-3p in glioma have not been systematically investigated, especially regarding the relationship between circulating and tissue miR-454-3p. The expression level of miR-454-3p in glioma serum and tissues was analysed through quantitative real-time PCR (qRT-PCR). Cell-Counting Kit 8 (CCK-8), wound healing, transwell invasion, apoptosis and immunofluorescence assays were employed to assess the role of miR-454-3p in glioma cancer cells...
November 9, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30413649/pleiotropic-action-of-novel-bruton-s-tyrosine-kinase-inhibitor-bgb-3111-in-mantle-cell-lymphoma
#7
Carrie J Li, Changying Jiang, Yang Liu, Taylor Bell, Wencai Ma, Yin Ye, Shengjian Huang, Hui Guo, Hui Zhang, Lai Wang, Jing Wang, Krystle Nomie, Liang Zhang, Michael Wang
Bruton's tyrosine kinase (BTK) is a key mediator of BCR-dependent cell growth signaling and a clinically effective therapeutic target in mantle cell lymphoma (MCL). The molecular impact of BTK inhibition remains unclear particularly in hematopoietic malignancies. We analyzed the molecular mechanisms of BTK inhibition with the novel inhibitor BGB-3111 (zanubrutinib) in MCL models. The efficacy of BGB-3111 was investigated using growth proliferation/cell viability and apoptosis assays in MCL cell lines and patient-derived xenograft (PDX) MCL cells...
November 9, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30413648/apomab%C3%A2-antibody-drug-conjugates-targeting-dead-tumor-cells-are-effective-in-vivo
#8
Alexander H Staudacher, Yanrui Li, Vasilios Liapis, Jeff Jia Cheng Hou, David Chin, Olan Dolezal, Timothy E Adams, Patrick H van Berkel, Michael P Brown
Antibody-drug conjugates (ADC) have revolutionized the field of cancer therapy. ADCs combine the high specificity of tumor-targeting monoclonal antibodies with potent cytotoxic drugs, which cannot be used alone because of their high toxicity. Up until now, all ADCs have either targeted cell membrane proteins on tumors or the tumor vasculature and microenvironment. Here, we investigate ADCs of APOMAB® (DAB4, or its chimeric derivative, chDAB4), which is a monoclonal antibody targeting the La/SSB protein which is only accessible for binding in dying or dead cancer cells...
November 9, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30404927/urolithin-a-a-novel-natural-compound-to-target-pi3k-akt-mtor-pathway-in-pancreatic-cancer
#9
Tulasigeri M Totiger, Supriya Srinivasan, Venkatakrishna R Jala, Purushottam Lamichhane, Austin R Dosch, Alexander A Gaidarski, Chandrashekar Joshi, Shobith Rangappa, Jason Castellanos, Praveen Kumar Vemula, Xi Chen, Deukwoo Kwon, Nilesh Kashikar, Michael VanSaun, Nipun B Merchant, Nagaraj S Nagathihalli
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and is highly resistant to standard treatment regimens. Targeted therapies against KRAS, a mutation present in an overwhelming majority of PDAC cases, have been largely ineffective. However, inhibition of downstream components in the KRAS signaling cascade provide promising therapeutic targets in the management of PDAC and warrant further exploration. Here, we investigated Urolithin A (Uro A), a novel natural compound derived from pomegranates, which targets numerous kinases downstream of KRAS, in particular the PI3K/AKT/mTOR signaling pathways...
November 7, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30401696/circulating-tumor-cells-with-stemness-and-epithelial-to-mesenchymal-transition-features-are-chemoresistant-and-predictive-of-poor-outcome-in-metastatic-breast-cancer
#10
Maria A Papadaki, Giannis Stoupis, Panayiotis A Theodoropoulos, Dimitris Mavroudis, Vassilis Georgoulias, Sofia Agelaki
Circulating tumor cells (CTCs) bearing stemness and epithelial-to-mesenchymal transition (EMT) characteristics have been identified in breast cancer, however their clinical significance is not clear. In the current study we investigated the prognostic relevance of single CSC+/partial-EMT+ CTCs in patients with metastatic breast cancer and the effect of first-line chemotherapy on their incidence. For this purpose, triple immunofluorescence against Cytokeratin, ALDH1 and TWIST1 was performed in peripheral blood mononuclear cell (PBMC) cytospins from 130 patients before and after first-line chemotherapy...
November 6, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30401695/combining-dna-vaccine-and-aim2-in-h1-nanoparticles-exert-anti-renal-carcinoma-effects-via-enhancing-tumor-specific-multi-functional-cd8-t-cell-responses
#11
Dafei Chai, Hongjian Shan, Gang Wang, Qing Zhang, Huizhong Li, Lin Fang, Jingyuan Song, Nianli Liu, Qian Zhang, Hong Yao, Junnian Zheng
Renal carcinoma presents a rapid progression in patients with high metastasis with no effective therapeutic strategy. In this study, we designed a folate grafted PEI600-CyD (H1) nanoparticle-mediated DNA vaccine containing an adjuvant of absent in melanoma 2 (AIM2) and a tumor-specific antigen of carbonic anhydrase IX (CAIX) for renal carcinoma therapy. Mice bearing subcutaneous human CAIX (hCAIX)-Renca tumor were intramuscularly immunized with H1-pAIM2/pCAIX, H1-pCAIX, H1-pAIM2, or Mock vaccine, respectively...
November 6, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30401694/intestinal-toxicity-in-rats-following-administration-of-cdk4-6-inhibitors-is-independent-of-primary-pharmacology
#12
Stephane Thibault, Wenyue Hu, Brad Hirakawa, Dalia Kalabat, Tania Franks, Tae Sung, Su Khoh-Reiter, Shuyan Lu, Martin Finkelstein, Bart Jessen, Aida I Sacaan
Recently three different cyclin-dependent kinase 4 and 6 (CDK4/6) dual inhibitors were approved for the treatment of breast cancer (palbociclib, ribociclib and abemaciclib), all of which offer comparable therapeutic benefits. Their safety profiles however are different. For example, neutropenia is observed at varying incidences in patients treated with these drugs; however it is the most common adverse event for palbociclib and ribociclib, whereas diarrhea is the most common adverse event observed in patients treated with abemaciclib...
November 6, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30401693/necuparanib-a-multi-targeting-heparan-sulfate-mimetic-targets-tumor-and-stromal-compartments-in-pancreatic-cancer
#13
Silva Krause, Amanda MacDonald, Michelle Priess, Jennifer Curran, Jamey Guess, Victor Farutin, Ilse Oosterom, Chia Lin Chu, Edward Cochran, Lynn Zhang, Kristen Getchell, Martijn Lolkema, Birgit C Schultes
Pancreatic cancer has an abysmal five year survival rate of 8 %, making it a deadly disease with a need for novel therapies. Here we describe a multi-targeting heparin-based mimetic, necuparanib, and its anti-tumor activity in both in vitro and in vivo models of pancreatic cancer. Necuparanib reduced tumor cell proliferation and invasion in a 3-dimensional (3D) culture model; in vivo it extended survival and reduced metastasis. Furthermore, proteomic analysis demonstrated that necuparanib altered the expression levels of multiple proteins involved in cancer-driving pathways including organ development, angiogenesis, proliferation, genomic stability, cellular energetics, and invasion & metastasis...
November 6, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30381448/cd3-bispecific-antibody-therapy-turns-solid-tumors-into-inflammatory-sites-but-does-not-install-protective-memory
#14
Hreinn Benonisson, Işıl Altıntaş, Marjolein Sluijter, Sandra Verploegen, Aran Labrijn, Danita H Schuurhuis, Mischa A Houtkamp, J Sjef Verbeek, Janine Schuurman, Thorbald van Hall
Immunotherapy of cancer with CD3-targeting bispecific antibodies (CD3 bsAb) is a fast developing field and multiple tumor-associated antigens (TAA) are evaluated for hematological and solid malignancies. The efficacy of these CD3 bsAb is usually examined in xenograft mouse tumor models with human T cells or in genetically engineered mouse models, where human TAA are introduced. These models often fail to fully recapitulate the natural tumor environment, especially for solid cancers, because of interspecies differences...
October 31, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30381447/combined-cellular-and-biochemical-profiling-to-identify-predictive-drug-response-biomarkers-for-kinase-inhibitors-approved-for-clinical-use-between-2013-and-2017
#15
Joost C M Uitdehaag, Jeffrey J Kooijman, Jeroen A D M de Roos, Martine B W Prinsen, Jelle Dylus, Nicole Willemsen-Seegers, Yusuke Kawase, Masaaki Sawa, Jos de Man, Suzanne J C van Gerwen, Rogier C Buijsman, Guido J R Zaman
Kinase inhibitors form the largest class of precision medicine. From 2013-2017, seventeen have been approved, with eight different mechanisms. We present a comprehensive profiling study of all seventeen inhibitors on a biochemical assay panel of 280 kinases and proliferation assays of 108 cancer cell lines. Drug responses of the cell lines were related to the presence of frequently recurring point mutations, insertions, deletions, and amplifications in 15 well- known oncogenes and tumor suppressor genes. Additionally, drug responses were correlated with basal gene expression levels with a focus on 383 clinically actionable genes...
October 31, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30381446/identification-of-the-novel-role-of-cd24-as-an-oncogenesis-regulator-and-therapeutic-target-for-triple-negative-breast-cancer
#16
Shih-Hsuan Chan, Kuo-Wang Tsai, Shu-Yi Chiu, Wen-Hung Kuo, Heng-Yi Chen, Shih Sheng Jiang, King-Jen Chang, Wen-Chun Hung, Lu-Hai Wang
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with unfavorable prognosis and 5-year survival. The purpose of this study was to investigate the underlying mechanisms involved in TNBC progression. We determined that CD24 expression was elevated in highly lung and lymph node metastatic TNBC cells. CD24 depletion inhibited primary tumor growth and lymph node and lung metastasis and reduced the number of blood and lymphatic vessels in the tumor microenvironment. CD24 knockdown impaired EGFR/Met-mediated signaling and reduced lymphangiogenesis- and angiogenesis-related molecules, including vascular endothelial growth factors A and C, by promoting EGFR and Met protein instability via the lysosomal degradation pathway...
October 31, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30381445/glycoprotein-130-expression-is-associated-with-aggressive-bladder-cancer-and-is-a-potential-therapeutic-target
#17
Darryl T Martin, Hongliang Shen, Jill M Steinbach-Rankins, Xi Zhu, Katelyn K Johnson, Jamil Syed, W Mark Saltzman, Robert M Weiss
Predicting bladder cancer progression is important in selecting the optimal treatment for bladder cancer. Since current diagnostic factors regarding progression are lacking, new factors are needed to further stratify the curative potential of bladder cancer. Glycoprotein-130 (GP130), a transmembrane protein, is central to a number of signal transduction pathways involved in tumor aggressiveness, making it an attractive target. We hypothesize that if GP130 is found in an aggressive population of bladder tumors then blocking GP130 expression may inhibit bladder cancer growth...
October 31, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30373932/traf2-cooperates-with-focal-adhesion-signaling-to-regulate-cancer-cell-susceptibility-to-anoikis
#18
Sabrina Daniela Silva, Bin Xu, Mariana Maschietto, Fabio Albuquerque Marchi, Maisa I Alkailani, Krikor Bijian, Dingzhang Xiao, Moulay A Alaoui-Jamali
TRAF2, a RING finger adaptor protein, plays an important function in Tumor Necrosis Factor (TNF)- and TNF-like weak inducer of apoptosis (TWEAK)-dependent signaling, in particular during inflammatory and immune responses. We identified a functional interaction of TRAF2 with focal adhesion (FA) signaling involving the focal adhesion kinase (FAK) in the regulation of cell susceptibility to anoikis. Comparison of TRAF2-proficient (TRAF2+/+) versus TRAF2-deficient (TRAF2-/-), and FAK-proficient (FAK+/+) versus FAK-deficient (FAK-/-) mouse embryonic fibroblasts and their matched reconstituted cells demonstrated that TRAF2 interacts physically with the N-terminal portion of FAK and co-localizes to cell membrane protrusions...
October 29, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30361332/anti-met-vhh-pool-overcomes-met-targeted-cancer-therapeutic-resistance
#19
Zhipeng Su, Yuchun Han, Qichen Sun, Xiaoxiao Wang, Ting Xu, Wei Xie, Xing Huang
Receptor tyrosine kinase MET and its ligand HGF play crucial roles in many human malignancies. Numerous drugs have been developed against kinase center of MET or HGF-mediated activation, however, the outcomes in patients are not so promising. Increasing evidences show that MET has kinase-independent effects on tumorigenesis and dissemination, which explains the low efficacy in kinase inhibition-based strategy. VHH is the recombinant variable region of Camelid heavy-chain antibody. As a nanoscale antigen-binding unit, VHH has become an appealing drug candidate in cancer therapy...
October 25, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/30352802/targeting-of-hematologic-malignancies-with-ptc299-a-novel-potent-inhibitor-of-dihydroorotate-dehydrogenase-with-favorable-pharmaceutical-properties
#20
Liangxian Cao, Marla Weetall, Christopher Trotta, Katherine Cintron, Jiyuan Ma, Min Jung Kim, Bansri Furia, Charles Romfo, Jason D Graci, Wencheng Li, Joshua Du, Josephine Sheedy, Jean Hedrick, Nicole Risher, Shirley Yeh, Hongyan Qi, Tamil Arasu, Seongwoo Hwang, William Lennox, Ronald Kong, Janet Petruska, Young-Choon Moon, John Babiak, Thomas W Davis, Allan Jacobson, Neil G Almstead, Art Branstrom, Joseph M Colacino, Stuart W Peltz
PTC299 was identified as an inhibitor of VEGFA mRNA translation in a phenotypic screen and evaluated in the clinic for treatment of solid tumors. To guide precision cancer treatment, we performed extensive biological characterization of the activity of PTC299 and demonstrated that inhibition of VEGF production and cell proliferation by PTC299 is linked to a decrease in uridine nucleotides by targeting dihydroorotate dehydrogenase (DHODH), a rate limiting enzyme for de novo pyrimidine nucleotide synthesis. Unlike previously reported DHODH inhibitors that were identified using in vitro enzyme assays, PTC299 is a more potent inhibitor of DHODH in isolated mitochondria suggesting that mitochondrial membrane lipid engagement in the DHODH conformation in situ is required for its optimal activity...
October 23, 2018: Molecular Cancer Therapeutics
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