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Molecular Cancer Therapeutics

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https://www.readbyqxmd.com/read/28637716/modulation-of-plasma-metabolite-biomarkers-of-mapk-pathway-with-the-mek-inhibitor-ro4987655-pharmacodynamic-and-predictive-potential-in-metastatic-melanoma
#1
Joo Ern Ang, Akos Pal, Yasmin J Asad, Alan T Henley, Melanie Valenti, Gary Box, Alexis de Haven Brandon, Victoria Revell, Debra J Skene, Miro Venturi, Ruediger Rueger, Valerie Meresse, Suzanne A Eccles, Johann S de Bono, Stanley B Kaye, Paul Workman, Udai Banerji, Florence I Raynaud
<p>MAPK pathway activation is frequently observed in human malignancies, including melanoma, and is associated with sensitivity to MEK inhibition and changes in cellular metabolism. Using quantitative mass spectrometry-based metabolomics, we identified in preclinical models 21 plasma metabolites including amino acids, propionylcarnitine, phosphatidylcholines and sphingomyelins that were significantly altered in two B-RAF mutant melanoma xenografts and that were reversed following a single dose of the potent and selective MEK inhibitor RO4987655...
June 21, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28637715/tyrosine-kinase-inhibitors-protect-the-salivary-gland-from-radiation-damage-by-inhibiting-activation-of-protein-kinase-c-%C3%AE
#2
Sten M Wie, Elizabeth Wellberg, Sana D Karam, Mary E Reyland
In patients undergoing irradiation therapy, injury to non-tumor tissues can result in debilitating, and sometimes permanent, side effects. We have defined Protein Kinase C-delta (PKCδ) as a regulator of DNA damage induced apoptosis and have shown that phosphorylation of PKCδ by c-Abl and c-Src activates its pro-apoptotic function.  Here we have explored the use of tyrosine kinase inhibitors (TKIs) of c-Src and c-Abl to block activation of PKCδ for radioprotection of the salivary gland.  Dasatinib, imatinib, and bosutinib all suppressed tyrosine phosphorylation of PKCδ and inhibited IR-induced apoptosis in vitro  To determine if TKIs can provide radioprotection of salivary gland function in vivo, mice were treated with TKIs and a single or fractionated doses of irradiation...
June 21, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28626084/optimization-of-ras-braf-mutational-analysis-confirms-improvement-in-patient-selection-for-clinical-benefit-to-anti-egfr-treatment-in-metastatic-colorectal-cancer
#3
Cristina Santos, Daniel Azuara, Rocio Garcia-Carbonero, Pilar García Alfonso, Alfredo Carrato, Elena Elez, Auxiliadora Gómez, Ferran Losa, Clara Montagut, Bartomeu Massuti, Valenti Navarro, Mar Varela, Adriana López-Doriga, Victor Moreno, Manuel Valladares, Jose Luis Manzano, José Maria Viéitez, Enrique Aranda, Xavier Sanjuan, Josep Tabernero, Gabriel Capella, Ramon Salazar
In metastatic colorectal cancer (mCRC) recent studies have shown the importance to accurately quantify low-abundance mutations of RAS pathway because anti-EGFR therapy may depend on certain mutation thresholds. We aimed to evaluate the added predictive value of extended RAS panel testing using two commercial assays and a highly sensitive and quantitative digital PCR (dPCR). Tumor samples from 583 mCRC patients treated with anti-EGFR (n=255) or bevacizumab (n=328) based therapies from several clinical trials and retrospective series from the TTD/RTICC Spanish network were analyzed by cobas®, therascreen® and dPCR...
June 16, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28619760/fbw7-dependent-mcl-1-degradation-mediates-the-anticancer-effect-of-hsp90-inhibitors
#4
Jingshan Tong, Shuai Tan, Zaneta Nikolovska-Coleska, Jian Yu, Fangdong Zou, Lin Zhang
Heat shock protein 90 (Hsp90) is widely overexpressed in cancer cells and necessary for maintenance of malignant phenotypes. Hsp90 inhibition induces tumor cell death through degradation of its client oncoproteins, and has shown promises in preclinical studies. However, the mechanism by which Hsp90 inhibitors kill tumor cells is not well understood. Biomarkers associated with differential sensitivity and resistance to Hsp90 inhibitors remain to be identified. In this study, we found that colorectal cancer (CRC) cells containing inactivating mutations of FBW7, a tumor suppressor and E3 ubiquitin ligase, are intrinsically insensitive to Hsp90 inhibitors...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28619759/modelling-therapy-resistance-in-brca1-2-mutant-cancers
#5
Amy Dréan, Chris T Williamson, Rachel Brough, Inger Brandsma, Malini Menon, Asha Konde, Isaac Garcia-Murillas, Helen N Pemberton, Jessica Frankum, Rumana Rafiq, Nicholas Badham, James Campbell, Aditi Gulati, Nicholas C Turner, Stephen J Pettitt, Alan Ashworth, Christopher J Lord
Although PARP inhibitors target BRCA1 or BRCA2 mutant tumour cells, drug resistance is a problem. PARP inhibitor resistance is sometimes associated with the presence of secondary or "revertant" mutations in BRCA1 or BRCA2 Whether secondary mutant tumour cells are selected for in a Darwinian fashion by treatment is unclear. Furthermore, how PARP inhibitor resistance might be therapeutically targeted is also poorly understood. Using CRISPR-mutagenesis, we generated isogenic tumour cell models with secondary BRCA1 or BRCA2 mutations...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28619758/co-targeting-of-mek-and-pdgfr-stat3-pathways-to-treat-pancreaticductal-adenocarcinoma
#6
Nisebita Sahu, Emily Chan, Felix Chu, Thinh Pham, Hartmut Koeppen, William Forrest, Mark Merchant, Jeff Settleman
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal human diseases and remains largely refractory to available drug treatments.  Insufficient targeting of the known oncogenic drivers and activation of compensatory feedback loops and inability to prevent metastatic spread contribute to poor prognosis for this disease. The KRAS-driven MEK pathway is mutationally activated in most pancreatic cancers and is an important target for therapeutics. Using a 2-dimensional monolayer culture system as well as 3-dimensional spheroid culture system, we conducted a screen of a large panel of anti-cancer agents, and found that MEK inhibitors were most effective in targeting PDAC spheroids in comparison to monolayer cultures...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28619757/cdk4-6-inhibitors-sensitize-rb-positive-sarcoma-cells-to-wee1-kinase-inhibition-through-reversible-cell-cycle-arrest
#7
Ashleigh M Francis, Angela Alexander, Yanna Liu, Smruthi Vijayaraghavan, Kwang Hui Low, Dong Yang, Tuyen Bui, Neeta Somaiah, Vinod Ravi, Khandan Keyomarsi, Kelly K Hunt
Research into the biology of soft tissue sarcomas has uncovered very few effective treatment strategies that improve upon the current standard of care which usually involves surgery, radiation, and chemotherapy. Many patients with large (>5cm), high-grade sarcomas develop recurrence, and at that point have limited treatment options available. One challenge is the heterogeneity of genetic drivers of sarcomas, and many of these are not validated targets. Even when such genes are tractable targets, the rarity of each subtype of sarcoma makes advances in research slow...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28619756/alpha-particle-enhanced-blood-brain-tumor-barrier-permeabilization-in-glioblastomas-using-integrin-alpha-v-beta-3-targeted-liposomes
#8
Anirudh Sattiraju, Xiaobing Xiong, Darpan N Pandya, Thaddeus J Wadas, Ang Xuan, Yao Sun, Youngkyoo Jung, Kiran Kumar Solingapuram Sai, Jay F Dorsey, King C Li, Akiva Mintz
<span style="font-size: 11.0pt; line-height: 200%; color: windowtext;">Glioblastoma (GBM) is the most common primary malignant astrocytoma characterized by extensive invasion, angiogenesis, hypoxia and micrometastasis. Despite the relatively leaky nature of GBM blood vessels, effective delivery of anti-tumor therapeutics has been a major challenge due to the complications caused by the blood brain barrier (BBB) and the highly torturous nature of newly formed tumor vasculature (blood tumor barrier-BTB)...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28619755/epidermal-growth-factor-receptor-egfr-targeted-photoimmunotherapy-pit-for-the-treatment-of-egfr-expressing-bladder-cancer
#9
Reema Railkar, L Spencer Krane, Q Quentin Li, Thomas Sanford, Mohammad Rashid Siddiqui, Diana Haines, Srinivas Vourganti, Sam J Brancato, Peter L Choyke, Hisataka Kobayashi, Piyush K Agarwal
The use of light as a means of therapy for bladder cancer (BC) has a long history but has been hampered by a lack of tumor specificity and therefore, damage to the normal bladder mucosa. Here, we describe a targeted form of photo-therapy called photoimmunotherapy (PIT) which targets EGFR-expressing BC. Anti-EGFR antibody panitumumab (pan) was labeled with the photo-absorber (PA), IRDye 700Dx (IR700), to create a pan IR700 antibody-PA conjugate which is activated by near-infrared radiation (NIR). BC tissue microarray (TMA) and BC cell lines were analyzed for expression of EGFR...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28619754/antitumor-effect-of-the-atypical-retinoid-st1926-in-acute-myeloid-leukemia-and-nanoparticle-formulation-prolongs-lifespan-and-reduces-tumor-burden-of-xenograft-mice
#10
Leeanna El-Houjeiri, Walid Saad, Berthe Hayar, Patrick Aouad, Nadim Tawil, Rana Abdel-Samad, Rita Hleihel, Maguy Hamie, Angelo Mancinelli, Claudio Pisano, Hiba El Hajj, Nadine Darwiche
Acute myeloid leukemia (AML) is one of the most frequent types of blood malignancies. It is a complex disorder of undifferentiated hematopoietic progenitor cells. The majority of patients generally respond to intensive therapy. Nevertheless, relapse is the major cause of death in AML, warranting the need for novel treatment strategies. Retinoids have demonstrated potent differentiation and growth regulatory effects in normal, transformed and hematopoietic progenitor cells. All-trans retinoic acid (ATRA) is the paradigm of treatment in acute promyelocytic leukemia, an AML subtype...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28619753/inhibition-of-hsp90-suppresses-pi3k-akt-mtor-signaling-and-has-antitumor-activity-in-burkitt-lymphoma
#11
Lisa Giulino-Roth, Herman J Van Besien, Tanner Dalton, Jennifer E Totonchy, Anna Rodina, Tony Taldone, Alexander Bolaender, Hediye Erdjument-Bromage, Jouliana Sadek, Amy Chadburn, Matthew J Barth, Filemon S Dela Cruz, Allison Rainey, Andrew L Kung, Gabriela Chiosis, Ethel Cesarman
Heat shock protein 90 (Hsp90) is a molecular chaperone that protects proteins, including oncogenic signaling complexes, from proteolytic degradation.  PU-H71 is a next-generation Hsp90 inhibitor that preferentially targets the functionally distinct pool of Hsp90 present in tumor cells.  Tumors that are driven by the MYC oncoprotein may be particularly sensitive to PU-H71 due to the essential role of Hsp90 in the epichaperome which maintains the malignant phenotype in the setting of MYC.  Burkitt lymphoma (BL) is an aggressive B-cell lymphoma characterized by MYC dysregulation...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28619752/the-met-axl-fgfr-inhibitor-s49076-impairs-aurora-b-activity-and-improves-the-antitumor-efficacy-of-radiotherapy
#12
Céline Clémenson, Cyrus Chargari, Winchygn Liu, Michele Mondini, Charles Ferté, Mike F Burbridge, Valérie Cattan, Anne Jacquet-Bescond, Eric Deutsch
Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non-small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefinitib in NSCLC patients whose tumors show resistance to EGFR inhibitors...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28619751/synthesis-and-profiling-of-a-novel-potent-selective-inhibitor-of-chk1-kinase-possessing-unusual-n-trifluoromethylpyrazole-pharmacophore-resistant-to-metabolic-n-dealkylation
#13
Pounami Samadder, Tereza Suchanková, Ondrej Hylse, Prashant Khirsariya, Fedor Nikulenkov, Stanislav Drápela, Nicol Straková, Petr Vaňhara, Kateřina Vašíčková, Hana Kolářová, Lucia Binó, Miroslava Bittová, Petra Ovesná, Peter Kollar, Radek Fedr, Milan Ešner, Josef Jaroš, Aleš Hampl, Lumír Krejčí, Kamil Paruch, Karel Soucek
Checkpoint-mediated dependency of tumor cells can be deployed to selectively kill them without substantial toxicity to normal cells. Specifically, loss of CHK1, a serine threonine kinase involved in the surveillance of the G2/M checkpoint in the presence of replication stress inflicted by DNA damaging drugs, has been reported to dramatically influence the viability of tumor cells. CHK1's pivotal role in maintaining genomic stability offers attractive opportunity for increasing the selectivity, effectivity and reduced toxicity of chemotherapy...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28615299/ormeloxifene-suppresses-prostate-tumor-growth-and-metastatic-phenotypes-via-inhibition-of-oncogenic-%C3%AE-catenin-signaling-and-emt-progression
#14
Bilal Bin Hafeez, Aditya Ganju, Mohammed Sikander, Vivek K Kashyap, Zubair Bin Hafeez, Neeraj Chauhan, Shabnam Malik, Andrew E Massey, Manish K Tripathi, Fathi T Halaweish, Nadeem Zafar, Man M Singh, Murali M Yallapu, Meena Jaggi, Subhash C Chauhan
Ormeloxifene (ORM), is a clinically approved selective estrogen receptor modulator, which has also shown excellent anti-cancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ORM on prostate cancer (PrCa) and elucidate a novel molecular mechanism of its anti-cancer activity. ORM treatment inhibited epithelial to mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, and vimentin, MMPs (MMP2 and MMP3), β-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3β...
June 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28615298/combination-treatment-with-orlistat-containing-nanoparticles-and-taxanes-is-synergistic-and-enhances-microtubule-stability-in-taxane-resistant-prostate-cancer-cells
#15
Joshua J Souchek, Amanda L Davis, Tanner K Hill, Megan B Holmes, Bowen Qi, Pankaj K Singh, Steven J Kridel, Aaron M Mohs
Taxane-based therapy provides a survival benefit in patients with metastatic prostate cancer, yet the median survival is less than 20 months in this setting due in part to taxane-associated resistance. Innovative strategies are required to overcome chemoresistance for improved patient survival. Here, NanoOrl, a new experimental nanoparticle formulation of the FDA-approved drug, orlistat, was investigated for its cytotoxicity in taxane-resistant prostate cancer utilizing two established taxane-resistant (TxR) cell lines...
June 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28615297/disruption-of-aneuploidy-and-senescence-induced-by-aurora-inhibition-promotes-intrinsic-apoptosis-in-double-hit-or-double-expressor-diffuse-large-b-cell-lymphomas
#16
Daruka Mahadevan, Shariful Islam, Wenqing Qi, Carla Morales, Laurence Cooke, Catherine Spier, Eric Weterings
Double Hit (DH) or Double Expressor (DE) diffuse large B-cell lymphoma (DLBCL) are aggressive Non-Hodgkin's Lymphomas (NHLs) with translocations and/or over-expressions of MYC and BCL-2, that are difficult to treat. Aurora kinase (AK) inhibition with alisertib in DH/DE-DLBCL induces cell death in ~30%, while ~70% are aneuploid and senescent cells (AASCs), a mitotic escape mechanism contributing to drug resistance. These AASCs elaborated a high metabolic rate by increased AKT/mTOR and ERK/MAPK activity via BTK signaling through the chronic active B-cell receptor (BCR) pathway...
June 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28611109/an-in-vivo-functional-screen-identifies-jnk-signaling-as-a-modulator-of-chemotherapeutic-response-in-breast-cancer
#17
Matthew Ashenden, Antoinette van Weverwijk, Nirupa Murugaesu, Antony Fearns, James Campbell, Qiong Gao, Marjan Iravani, Clare M Isacke
Chemotherapy remains the mainstay of treatment for advanced breast cancer, however, resistance is an inevitable event for the majority of patients with metastatic disease. Moreover, there is little information available to guide stratification of first line chemotherapy, crucial given the common development of multidrug resistance. Here we describe an in vivo screen to interrogate the response to anthracycline-based chemotherapy in a syngeneic metastatic breast cancer model, and identify JNK signaling as a key modulator of chemotherapy response...
June 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28611108/wnt-%C3%AE-catenin-signaling-contributes-to-tumor-malignancy-and-is-targetable-in-gastrointestinal-stromal-tumor
#18
Shan Zeng, Adrian M Seifert, Jennifer Q Zhang, Michael J Cavnar, Teresa S Kim, Vinod P Balachandran, Juan A Santamaria-Barria, Noah A Cohen, Michael J Beckman, Benjamin Medina, Ferdinand Rossi, Megan H Crawley, Jennifer K Loo, Joanna H Maltbaek, Peter Besmer, Cristina R Antonescu, Ronald P DeMatteo
Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma and usually harbors either a KIT or PDGFRA mutation. However, the molecular basis for tumor malignancy is not well defined. While the Wnt/b-catenin signaling pathway is important in a variety of cancers, its role in GIST is uncertain. Through analysis of nearly 150 human GIST specimens, we found that some human GISTs expressed b-catenin and contained active, dephosphorylated nuclear b-catenin. Furthermore, advanced human GISTs expressed reduced levels of the Wnt antagonist DKK4...
June 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28611107/il-6-receptor-blockade-enhances-chemotherapy-efficacy-in-pancreatic-ductal-adenocarcinoma
#19
Kristen B Long, Graham Tooker, Evan Tooker, Santiago Lombo Luque, Jae W Lee, Xiaoqing Pan, Gregory L Beatty
Inflammation mediated by activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling is a major cause of chemotherapy resistance in cancer. We studied the impact of selectively blocking the IL-6 receptor (IL6R) as a strategy to inhibit IL-6-induced STAT activation and to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). To do this, STAT activation was investigated in tumors arising spontaneously in LSL-Kras(G12D/+);LSL-Trp53(R172H/+);Pdx-1Cre (KPC) mice...
June 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28611106/a-novel-combination-treatment-targeting-bcl-xl-and-mcl1-for-kras-braf-mutated-and-bcl2l1-amplified-colorectal-cancers
#20
Sung-Yup Cho, Jee Yun Han, Deukchae Na, Wonyoung Kang, Ahra Lee, Jooyoung Kim, Jieun Lee, Seoyeon Min, Jinjoo Kang, Jeesoo Chae, Jong-Il Kim, Hansoo Park, Won-Suk Lee, Charles Lee
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world, and exhibits heterogeneous characteristics in terms of genomic alterations, expression signature and drug responsiveness. Although there have been considerable efforts to classify this disease based on high-throughput sequencing techniques, targeted treatments for specific subgroups has been limited. KRAS and BRAF mutations are prevalent genetic alterations in CRCs, and patients with mutations in either of these genes have a worse prognosis and are resistant to anti-EGFR treatments...
June 13, 2017: Molecular Cancer Therapeutics
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