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Molecular Cancer Therapeutics

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https://www.readbyqxmd.com/read/28729403/autophagy-inhibition-improves-sunitinib-efficacy-in-pancreatic-neuroendocrine-tumors-via-a-lysosome-dependent-mechanism
#1
Tabea Wiedmer, Annika Blank, Sophia Pantasis, Lea Normand, Ruben Bill, Philippe Krebs, Mario P Tschan, Ilaria Marinoni, Aurel Perren
Increasing the efficacy of approved systemic treatments in metastasized pancreatic neuroendocrine tumors (PanNETs) is an unmet medical need. The anti-angiogenic tyrosine kinase inhibitor sunitinib is approved for PanNET treatment. Additionally, sunitinib is a lysosomotropic drug and such drugs can induce lysosomal membrane permeabilization as well as autophagy. We investigated sunitinib-induced autophagy as a possible mechanism of PanNET therapy resistance. Sunitinib accumulated in lysosomes and induced autophagy in PanNET cell lines...
July 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28729402/wilms-tumor-ncam-expressing-cancer-stem-cells-as-potential-therapeutic-target-for-polymeric-nanomedicine
#2
Ela Markovsky, Einav Vax, Dikla Ben-Shushan, Anat Eldar-Boock, Rachel Shukrun, Eilam Yeini, Iris Barshack, Revital Caspi, Orit Harari-Steinberg, Naomi Pode-Shakked, Benjamin Dekel, Ronit Satchi-Fainaro
Cancer stem cells (CSC) form a specific population within the tumor that has been shown to have self-renewal and differentiation properties, increased ability to migrate and form metastases, and increased resistance to chemotherapy. Consequently, even a small number of cells remaining after therapy can repopulate the tumor and cause recurrence of the disease. CSCs in Wilms tumor, a pediatric renal cancer, were previously shown to be characterized by neural cell adhesion molecule (NCAM) expression. Therefore, NCAM provides a specific biomarker through which the CSC population in this tumor can be targeted...
July 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28729401/jak1-stat3-activation-through-a-proinflammatory-cytokine-pathway-leads-to-resistance-to-molecularly-targeted-therapy-in-non-small-cell-lung-cancer
#3
Kazuhiko Shien, Vassiliki A Papadimitrakopoulou, Dennis Ruder, Carmen Behrens, Li Shen, Neda Kalhor, Juhee Song, J Jack Lee, Jing Wang, Ximing Tang, Roy S Herbst, Shinichi Toyooka, Luc Girard, John D Minna, Jonathan M Kurie, Ignacio I Wistuba, Julie G Izzo
Molecularly targeted drugs have yielded significant therapeutic advances in oncogene-driven non-small cell lung cancer (NSCLC), but a majority of patients eventually develop acquired resistance. Recently, the relation between proinflammatory cytokine interleukin-6 (IL6) and resistance to targeted drugs has been reported. We investigated the functional contribution of IL6 and the other members of IL6 family proinflammatory cytokine pathway to resistance to targeted drugs in NSCLC cells. In addition, we examined the production of these cytokines by cancer cells and cancer-associated fibroblasts (CAFs)...
July 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28729400/vessel-targeted-chemophototherapy-with-cationic-porphyrin-phospholipid-liposomes
#4
Dandan Luo, Jumin Geng, Nasi Li, Kevin A Carter, Shuai Shao, G Ekin Atilla-Gokcumen, Jonathan F Lovell
Cationic liposomes have been used for targeted drug delivery to tumor blood vessels, via mechanisms that are not fully elucidated. Doxorubicin (Dox)-loaded liposomes were prepared that incorporate a cationic lipid; 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), along with a small amount of porphyrin-phospholipid (PoP). Near infrared (NIR) light induced release of entrapped Dox via PoP-mediated DOTAP photo-oxidation. The formulation was optimized to enable extremely rapid NIR light-triggered Dox release (i...
July 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28729399/decitabine-priming-enhances-mucin-1-inhibition-mediated-disruption-of-redox-homeostasis-in-cutaneous-t-cell-lymphoma
#5
Salvia Jain, Abigail Washington, Rebecca Karp Leaf, Parul Bhargava, Rachael A Clark, Thomas S Kupper, Dina Stroopinsky, Athalia Pyzer, Leandra Cole, Myrna Nahas, Arie Apel, Jacalyn Rosenblatt, Jon Arnason, Donald Kufe, David Avigan
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous neoplasm and patients with relapsed/refractory disease exhibit resistance to standard therapies. We have previously demonstrated that the MUC1-C oncoprotein plays a critical role in protection from oxidative stress in CTCL cells. Targeting of MUC1-C with a pharmacologic inhibitor, GO-203, was associated with apoptosis in CTCL. However, disease responses were incomplete underscoring the need for combinatorial strategies that could exploit the vulnerability of CTCL cells to oxidative signals...
July 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28729398/quercetin-targets-hnrnpa1-to-overcome-enzalutamide-resistance-in-prostate-cancer-cells
#6
Ramakumar Tummala, Wei Lou, Allen C Gao, Nagalakshmi Nadiminty
Prostate cancer remains dependent on androgen receptor signaling even after castration. Aberrant androgen receptor signaling in castration resistant prostate cancer is mediated by mechanisms such as alterations in the androgen receptor and activation of interacting signaling pathways. Clinical evidence confirms that resistance to the next generation anti-androgen, enzalutamide, may be mediated to a large extent by alternative splicing of the androgen receptor to generate constitutively active splice variants such as AR-V7...
July 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28729397/the-igf1r-insr-inhibitor-bi-885578-selectively-inhibits-growth-of-igf2-overexpressing-colorectal-cancer-tumors-and-potentiates-the-efficacy-of-anti-vegf-therapy
#7
Michael P Sanderson, Marco H Hofmann, Pilar Garin-Chesa, Norbert Schweifer, Andreas Wernitznig, Stefan Fischer, Astrid Jeschko, Reiner Meyer, Jurgen Moll, Thomas Pecina, Heribert Arnhof, Ulrike Weyer-Czernilofsky, Stephan K Zahn, Günther R Adolf, Norbert Kraut
Clinical studies of pharmacological agents targeting the insulin like growth factor (IGF) pathway in unselected cancer patients have so far demonstrated modest efficacy outcomes, with objective responses being rare. As such, the identification of selection biomarkers for enrichment of potential responders represents a high priority for future trials of these agents. Several reports have described high IGF2 expression in a subset of colorectal cancers (CRC), with focal IGF2 amplification being responsible for some of these cases...
July 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28716817/pi3k-gamma-delta-and-notch1-cross-regulate-pathways-that-define-the-t-cell-acute-lymphoblastic-leukemia-disease-signature
#8
Evgeni Efimenko, Utpal P Davé, Irina V Lebedeva, Yao Shen, Maria J Sanchez-Quintero, Daniel Diolaiti, Andrew Kung, Brian J Lannutti, Jianchung Chen, Ronald Realubit, Zoya Niatsetskiya, Vadim Ten, Charles Karan, Xi Chen, Andrea Califano, Thomas G Diacovo
PI3K/AKT and NOTCH1 signaling pathways are frequently dysregulated in T-cell acute lymphoblastic leukemias (T-ALL). Although we have shown that the combined activities of the class I PI3K isoforms p110γ and p110δ play a major role in the development and progression of PTEN null T-ALL, it has yet to be determined whether their contribution to leukemogenic programing is unique from that associated with NOTCH1 activation. Using a Lmo2-driven mouse model of T-ALL in which both the PI3K/AKT and NOTCH1 pathways are aberrantly upregulated, we now demonstrate that the combined activities of PI3Kγ/δ have both overlapping and distinct roles from NOTCH1 in generating T-ALL disease signature and in promoting tumor cell growth...
July 17, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28716816/sphingosine-1-phosphate-receptor-1-promotes-environment-induced-and-acquired-chemoresistance
#9
Veronica Lifshitz, Saul J Priceman, Wenzhao Li, Gregory Cherryholmes, Heehyoung Lee, Adar Makovski-Silverstein, Lucia Borriello, Yves A DeClerck, Hua Yu
Drug resistance is a major barrier for the development of effective and durable cancer therapies. Overcoming this challenge requires further defining the cellular and molecular mechanisms underlying drug resistance, both acquired and environment-mediated drug resistance (EMDR). Here, using neuroblastoma (NB), a childhood cancer with high incidence of recurrence due to resistance to chemotherapy, as a model we show that human bone marrow-mesenchymal stromal cells induce tumor expression of sphingosine-1-phosphate receptor-1 (S1PR1) leading to their resistance to chemotherapy...
July 17, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28716815/exposure-response-analyses-of-ramucirumab-from-two-randomized-phase-iii-trials-of-second-line-treatment-for-advanced-gastric-or-gastroesophageal-junction-cancer
#10
Josep Tabernero, Atsushi Ohtsu, Kei Muro, Eric Van Cutsem, Sang Cheul Oh, György Bodoky, Yasuhiro Shimada, Shuichi Hironaka, Jaffer A Ajani, Jiri Tomasek, Howard Safran, Kumari Chandrawansa, Yanzhi Hsu, Michael Heathman, Azhar Khan, Lan Ni, Allen S Melemed, Ling Gao, David Ferry, Charles S Fuchs
Ramucirumab is an IgG1 monoclonal antibody specific for the vascular endothelial growth factor receptor-2. Ramucirumab, 8 mg/kg every two weeks, administered as monotherapy (REGARD) or in combination with paclitaxel (RAINBOW), was safe and effective in patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer. We evaluated exposure-efficacy and exposure-safety relationships of ramucirumab from two randomized, placebo-controlled phase III trials. Sparse pharmacokinetic samples were collected and a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady-state (Cmin,ss)...
July 17, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28716814/potency-matched-dual-cytokine-antibody-fusion-proteins-for-cancer-therapy
#11
Roberto De Luca, Alex Soltermann, Francesca Pretto, Catherine Pemberton-Ross, Giovanni Pellegrini, Sarah Wulhfard, Dario Neri
A novel biopharmaceutical, consisting of the F8 monoclonal antibody (specific to a splice isoform of fibronectin) simultaneously fused to both tumor necrosis factor and interleukin-2, was found to react with the majority of solid tumors and hematological malignancies in mouse and man, but not with healthy adult tissues. The product selectively localized to neoplastic lesions in vivo, as evidenced by quantitative biodistribution studies using radioiodinated protein preparations. When the potency of the cytokine payloads was matched by a single-point mutation, the resulting fusion protein (IL2-F8-TNF(mut)) eradicated soft-tissue sarcomas in immunocompetent mice, which did not respond to individual antibody-cytokine fusion proteins or by standard doxorubicin treatment...
July 17, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28716813/inhibition-of-heparanase-in-pediatric-brain-tumor-cells-attenuates-their-proliferation-invasive-capacity-and-in-vivo-tumor-growth
#12
Argyris Spyrou, Soumi Kundu, Lulu Haseeb, Di Yu, Tommie Olofsson, Keith Dredge, Edward Hammond, Uri Barash, Israel Vlodavsky, Karin Forsberg-Nilsson
Curative therapy for medulloblastoma and other pediatric embryonal brain tumors has improved, but the outcome still remains poor and current treatment causes long-term complications. Malignant brain tumors infiltrate the healthy brain tissue and, thus despite resection, cells that have already migrated cause rapid tumor regrowth. Heparan sulfate proteoglycans (HSPG), major components of the extracellular matrix (ECM), modulate the activities of a variety of proteins. The major enzyme that degrades HS, heparanase (HPSE), is an important regulator of the ECM...
July 17, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28698199/mir-125b-increases-nasopharyngeal-carcinoma-radioresistance-by-targetinga20-nf-%C3%AE%C2%BAb-signaling-pathway
#13
Li-Na Li, Ta Xiao, Hong-Mei Yi, Zhen Zheng, Jia-Quan Qu, Wei Huang, Xu Ye, Hong Yi, Shan-Shan Lu, Xin-Hui Li, Zhi-Qiang Xiao
Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment, but little is known about how miRNA regulates this phenomenon. In this study, we investigated the function and mechanism of miR-125b in NPC radioresistance, one of upregulated miRNAs in the radioresistant NPC cells identified by our previous microarray analysis. We observed that miR-125b was frequently upregulated in the radioresistant NPCs, and its increment was significantly correlated with NPC radioresistance, and was an independent predictor for poor patient survival...
July 11, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28698198/abcb1-mediates-cabazitaxel-docetaxel-cross-resistance-in-advanced-prostate-cancer
#14
Alan P Lombard, Chengfei Liu, Cameron M Armstrong, Vito Cucchiara, Xinwei Gu, Wei Lou, Christopher P Evans, Allen C Gao
in research have added several new therapies for castration-resistant prostate cancer (CRPC), greatly augmenting our ability to treat patients. However, CRPC remains an incurable disease due to the development of therapeutic resistance and the existence of cross-resistance between available therapies. Understanding the interplay between different treatments will lead to improved sequencing and the creation of combinations which overcome resistance and prolong survival. Whether there exists cross-resistance between docetaxel and the next-generation taxane cabazitaxel is poorly understood...
July 11, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28663269/inactivation-of-the-kinase-domain-of-cdk10-prevents-tumor-growth-in-a-preclinical-model-of-colorectal-cancer-and-is-accompanied-by-downregulation-of-bcl-2
#15
Louis-Bastien Weiswald, Mohammad R Hasan, John Ct Wong, Clarissa C Pasiliao, Mahbuba Rahman, Jianhua Ren, Yaling Yin, Samuel Gusscott, Sophie Vacher, Andrew P Weng, Hagen F Kennecke, Ivan Bièche, David F Schaeffer, Donald T Yapp, Isabella T Tai
Cyclin dependent kinase 10 (CDK10), a CDC2 related kinase, is highly expressed in colorectal cancer (CRC). Its role in the pathogenesis of CRC is unknown. This study examines the function of CDK10 in CRC, and demonstrates its role in suppressing apoptosis and in promoting tumor growth in vitro and in vivo Modulation of CDK10 expression in CRC cell lines demonstrates that CDK10 promotes cell growth, reduces chemosensitivity and inhibits apoptosis by upregulating the expression of Bcl-2. This effect appears to depend on its kinase activity, as kinase-defective mutant CRC cell lines have an exaggerated apoptotic response and reduced proliferative capacity...
June 29, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28659432/a-novel-theranostic-strategy-for-mmp-14-expressing-glioblastomas-impacts-survival
#16
Suchismita Mohanty, Zixin Chen, Kai Li, Goreti Ribeiro Morais, Jessica Klockow, Ketan Yerneni, Laura Pisani, Frederick T Chin, Siddhartha Mitra, Samuel Cheshier, Edwin Chang, Sanjiv Sam Gambhir, Jianghong Rao, Paul M Loadman, Robert A Falconer, Heike E Daldrup-Link
Glioblastoma (GBM) has a dismal prognosis. Evidence from preclinical tumor models and human trials indicates the role of GBM initiating cells (GIC) in GBM drug resistance. Here, we propose a new treatment option with tumor enzyme-activatable, combined therapeutic and diagnostic (theranostic) nanoparticles, which caused specific toxicity against GBM tumor cells and GICs. The theranostic cross-linked iron oxide nanoparticles (CLIO) were conjugated to a highly potent vascular disrupting agent (ICT) and secured with a matrix-metalloproteinase (MMP-14) cleavable peptide...
June 28, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28655785/a-small-molecule-inhibitor-of-wee1-azd1775-synergizes-with-olaparib-by-impairing-homologous-recombination-and-enhancing-dna-damage-and-apoptosis-in-acute-leukemia
#17
Tamara B Garcia, Jonathan C Snedeker, Dmitry Baturin, Lori Gardner, Susan P Fosmire, Chengjing Zhou, Craig T Jordan, Sujatha Venkataraman, Rajeev Vibhakar, Christopher C Porter
Although some patients with acute leukemia have good prognoses, the prognosis of adult and pediatric patients who relapse or cannot tolerate standard chemotherapy is poor. Inhibition of WEE1 with AZD1775 has been shown to sensitize cancer cells to genotoxic chemotherapies including cytarabine in AML and T-ALL. Inhibition of WEE1 impairs homologous recombination by indirectly inhibiting BRCA2. Thus, we sought to determine if AZD1775 could sensitize cells to the PARP1/2 inhibitor olaparib. We found that combined treatment with AZD1775 and olaparib was synergistic in AML and ALL cells, and this combination impaired proliferative capacity upon drug withdrawal...
June 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28655784/inhibition-of-megakaryocyte-differentiation-by-antibody-drug-conjugates-adcs-is-mediated-by-macropinocytosis-implications-for-adc-induced-thrombocytopenia
#18
Hui Zhao, Sara Gulesserian, Sathish Kumar Ganesan, Jimmy Ou, Karen Morrison, Zhilan Zeng, Veronica Robles, Josh Snyder, Lisa Do, Hector Aviña, Sher Karki, David R Stover, Fernando Doñate
Thrombocytopenia is a common adverse event in cancer patients treated with antibody-drug conjugates (ADCs), including AGS-16C3F, an ADC targeting ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase-3) and Trastuzumab emtansine (T-DM1). This study aims to elucidate the mechanism of action of ADC-induced thrombocytopenia. ENPP3 expression in platelets and megakaryocytes (MKs) was investigated and shown to be negative. The direct effect of AGS-16C3F on platelets was evaluated using platelet rich plasma following the expression of platelet activation markers...
June 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28655783/inhibition-of-androgen-receptor-nuclear-localization-and-castration-resistant-prostate-tumor-growth-by-pyrroloimidazole-based-small-molecules
#19
Khalid Z Masoodi, Yadong Xu, Javid A Dar, Kurtis Eisermann, Laura E Pascal, Erica Parrinello, Junkui Ai, Paul A Johnston, Joel B Nelson, Peter Wipf, Zhou Wang
The androgen receptor (AR) is a ligand-dependent transcription factor that controls the expression of androgen-responsive genes.  A key step in androgen action, which is amplified in castration resistant prostate cancer (CRPC), is AR nuclear translocation. Small molecules capable of inhibiting AR nuclear localization could be developed as novel therapeutics for CRPC. We developed a high throughput screen and identified two structurally-related pyrroloimidazoles that could block AR nuclear localization in CRPC cells...
June 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28655782/ada-07-suppresses-solar-ultraviolet-induced-skin-carcinogenesis-by-directly-inhibiting-topk
#20
Ge Gao, Tianshun Zhang, Qiushi Wang, Kanamata Reddy, Hanyong Chen, Ke Yao, Keke Wang, Eunmiri Roh, Tatyana Zykova, Weiya Ma, Joohyun Ryu, Clara Curiel-Lewandrowski, David Alberts, Sally E Dickinson, Ann M Bode, Ying Xing, Zigang Dong
Cumulative exposure to solar ultraviolet (SUV) irradiation is regarded as the major etiologic factor in the development of skin cancer. The activation of the mitogen-activated protein kinase (MAPK) cascades occurs rapidly and is vital in the regulation of SUV-induced cellular responses. The T-LAK cell-originated protein kinase (TOPK), an upstream activator of MAPKs, is heavily involved in inflammation, DNA damage, and tumor development. However, the chemopreventive and therapeutic effects of specific TOPK inhibitors in SUV-induced skin cancer have not yet been elucidated...
June 27, 2017: Molecular Cancer Therapeutics
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