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Molecular Cancer Therapeutics

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https://www.readbyqxmd.com/read/28292941/preclinical-anti-tumor-efficacy-of-bay-1129980-a-novel-auristatin-based-anti-c4-4a-lypd3-antibody-drug-conjugate-for-the-treatment-of-non-small-cell-lung-cancer
#1
Jörg Willuda, Lars Linden, Hans-Georg Lerchen, Charlotte Kopitz, Beatrix Stelte-Ludwig, Carol Pena, Claudia Lange, Sven Golfier, Christoph Kneip, Patricia E Carrigan, Kirk Mclean, Joachim Schuhmacher, Oliver von Ahsen, Jörg Müller, Frank Dittmer, Rudolf Beier, Sherif El-Sheikh, Jan Tebbe, Gabriele Leder, Heiner Apeler, Rolf Jautelat, Karl Ziegelbauer, Bertolt Kreft
C4.4A (LYPD3) has been identified as a cancer- and metastasis-associated internalizing cell surface protein that is expressed in non-small cell lung cancer (NSCLC), with particularly high prevalence in the squamous cell carcinoma (SCC) subtype. With the exception of skin keratinocytes and esophageal endothelial cells, C4.4A expression is scarce in normal tissues, presenting an opportunity to selectively treat cancers with a C4.4A-directed antibody-drug conjugate (ADC). We have generated BAY 1129980 (C4.4A-ADC), an ADC consisting of a fully human C4...
March 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28292940/optimising-therapeutic-effect-of-aurora-b-inhibition-in-acute-myeloid-leukemia-with-azd2811-nanoparticles
#2
Nicolas Floc'h, Susan Ashton, Paula Taylor, Dawn Trueman, Emily Harris, Rajesh Odedra, Kim Maratea, Nicola Derbyshire, Jacqueline Caddy, Vivien N Jacobs, Maureen Hattersley, Shenghua Wen, Nicola J Curtis, James E Pilling, Elizabeth J Pease, Simon T Barry
Barasertib (AZD1152), a highly potent and selective aurora kinase B inhibitor, gave promising clinical activity in elderly AML patients. However clinical utility was limited by the requirement for a 7 day infusion. Here we assessed the potential of a nanoparticle formulation of the selective Aurora kinase B inhibitor AZD2811 (formerly known as AZD1152-hQPA) in pre-clinical models of AML. When administered to HL-60 tumor xenografts at a single dose between 25mg/kg and 98.7mg/kg, AZD2811 nanoparticle treatment delivered profound inhibition of tumour growth, exceeding the activity of AZD1152...
March 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28292939/a-fas-ligand-fasl-fused-humanized-antibody-against-tumor-associated-glycoprotein-72-selectively-exhibits-the-cytotoxic-effect-against-oral-cancer-cells-with-a-low-fasl-fas-ratio
#3
Ming-Hsien Chien, Wei-Min Chang, Wei-Jiunn Lee, Yu-Chan Chang, Tsung-Ching Lai, Derek V Chan, Rahul Sharma, Yuan-Feng Lin, Michael Hsiao
Altered expression of the Fas ligand (FasL)/Fas ratio exhibits a direct impact on the prognosis of cancer patients and its impairment in cancer cells may lead to apoptosis resistance. Thus, the development of effective therapies targeting the FasL/Fas system may play an important role in the fight against cancer. In this study, we evaluated whether fusion of a protein (hcc49scFv-FasL) of the cytotoxicity domain of the FasL to a humanized antibody (CC49) against tumor-associated glycoprotein 72, which is expressed on oral squamous cell carcinoma (OSCC), can selectively kill OSCC cells with different FasL/Fas ratios...
March 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28292938/combinatorial-screening-of-pancreatic-adenocarcinoma-reveals-sensitivity-to-drug-combinations-including-bromodomain-inhibitor-plus-neddylation-inhibitor
#4
Casey G Langdon, James T Platt, Robert E Means, Pinar Iyidogan, Ramanaiah Mamillapalli, Michael Klein, Matthew A Held, Jong Woo Lee, Ja Seok Koo, Christos Hatzis, Howard S Hochster, David F Stern
Pancreatic adenocarcinoma (PDAC) is the fourth most common cause of cancer death in the United States. PDAC is difficult to manage effectively, with a five-year survival rate of only 5%. PDAC is largely driven by activating KRAS mutations, and as such, cannot be directly targeted with therapeutic agents that affect the activated protein. Instead, inhibition of downstream signaling and other targets will be necessary to effectively manage PDAC. Here, we describe a tiered single-agent and combination compound screen to identify targeted agents that impair growth of a panel of PDAC cell lines...
March 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28292937/disruption-of-tcf-%C3%AE-catenin-binding-impairs-wnt-signalling-and-induces-apoptosis-in-soft-tissue-sarcoma-cells
#5
Esther Martinez-Font, Irene Felipe-Abrio, Silvia Calabuig-Fariñas, Rafael F Ramos, Josefa Terrasa, Oliver Vögler, Regina Alemany, Javier Martín-Broto, Antònia Obrador-Hevia
Soft tissue sarcomas (STS) are malignant tumours of mesenchymal origin and represent around 1% of adult cancers, being a very heterogeneous group of tumours with more than 50 different subtypes. The Wnt signalling pathway is involved in the development and in the regulation, self-renewal and differentiation of mesenchymal stem cells and plays a role in sarcomagenesis. In this study we have tested pharmacological inhibition of Wnt signalling mediated by disruption of TCF/β-catenin binding and AXIN stabilization, being the first strategy more efficient in reducing cell viability and downstream effects...
March 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28292936/synthesis-and-evaluation-of-the-novel-prostamide-15-deoxy-%C3%AE-12-14-prostamide-j2-as-a-selective-anti-tumor-therapeutic
#6
Daniel A Ladin, Eman Soliman, Rene Escobedo, Timothy L Fitzgerald, Li V Yang, Colin Burns, Rukiyah Van Dross
15-deoxy, Δ12,14-prostaglandin J2-ethanolamide, also known as 15-deoxy, Δ12,14-prostamide J2 (15d-PMJ2) is a novel product of the metabolism of arachidonoyl ethanolamide (AEA) by cyclooxygenase-2 (COX-2). 15d-PMJ2 preferentially induced cell death and apoptosis in tumorigenic A431 keratinocytes and B16F10 melanoma cells compared to non-tumorigenic HaCaT keratinocytes and Melan-A melanocytes. Activation of the ER stress execution proteins, PERK and CHOP10, was evaluated to determine if this process was involved in 15d-PMJ2 cell death...
March 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28292935/selective-killing-of-smarca2-and-smarca4-deficient-small-cell-carcinoma-of-the-ovary-hypercalcemic-type-cells-by-inhibition-of-ezh2-in-vitro-and-in-vivo-preclinical-models
#7
Elayne Chan-Penebre, Kelli Armstrong, Allison Drew, Alexandra R Grassian, Igor Feldman, Sarah K Knutson, Kristy Kuplast-Barr, Maria Roche, John Campbell, Peter Ho, Robert A Copeland, Richard Chesworth, Jesse J Smith, Heike Keilhack, Scott A Ribich
The SWI/SNF complex is a major regulator of gene expression and is increasingly thought to play an important role in human cancer, as evidenced by the high frequency of subunit mutations across virtually all cancer types. We previously reported that in preclinical models, malignant rhabdoid tumors, which are deficient in the SWI/SNF core component INI1 (SMARCB1), are selectively killed by inhibitors of the H3K27 histone methyltransferase EZH2. Given the demonstrated antagonistic activities of the SWI/SNF complex and the EZH2-containing PRC2 complex, we investigated whether additional cancers with SWI/SNF mutations are sensitive to selective EZH2 inhibition...
March 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28292934/maltotriose-conjugation-to-a-chlorin-derivative-enhances-the-antitumor-effects-of-photodynamic-therapy-in-peritoneal-dissemination-of-pancreatic-cancer
#8
Akihisa Kato, Hiromi Kataoka, Shigenobu Yano, Kazuki Hayashi, Noriyuki Hayashi, Mamoru Tanaka, Itaru Naitoh, Tesshin Ban, Katsuyuki Miyabe, Hiromu Kondo, Michihiro Yoshida, Yasuaki Fujita, Yasuki Hori, Makoto Natsume, Takashi Murakami, Atsushi Narumi, Akihiro Nomoto, Aya Naiki-Ito, Satoru Takahashi, Takashi Joh
Peritoneal dissemination is a major clinical issue associated with dismal prognosis and poor quality of life for patients with pancreatic cancer; however, no effective treatment strategies have been established. Herein, we evaluated the effects of photodynamic therapy (PDT) with maltotriose-conjugated chlorin (Mal3-chlorin) in culture and in a peritoneal disseminated mice model of pancreatic cancer. The Mal3-chlorin was prepared as a water-soluble chlorin derivative conjugated with four Mal3 molecules to improve cancer selectivity...
March 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28270436/focal-adhesion-kinase-as-a-potential-target-in-aml-and-mds
#9
Bing Z Carter, Po Yee Mak, Xiangmeng Wang, Hui Yang, Guillermo Garcia-Manero, Duncan Mak, Hong Mu, Vivian Ruvolo, Yihua Qiu, Kevin Coombes, Nianxiang Zhang, Brittany Ragon, David T Weaver, Jonathan A Pachter, Steven Kornblau, Michael Andreeff
Although overexpression/activation of focal adhesion kinase (FAK) is widely known in solid tumors to control cell growth, survival, invasion, metastasis, gene expression, and stem cell self-renewal, its expression and function in myeloid leukemia are not well investigated. Using reverse-phase protein arrays in large cohorts of newly diagnosed acute myeloid leukemia (AML) and myeloid dysplastic syndrome (MDS) samples, we found that high FAK expression was associated with unfavorable cytogenetics (P = 2 x 10-4) and relapse (P = 0...
March 7, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28265009/preclinical-mammalian-safety-studies-of-epharna-dopc-nanoliposomal-epha2-targeted-sirna
#10
Michael J Wagner, Rahul Mitra, Mark J McArthur, Wallace Baze, Kirstin Barnhart, Sherry Wu, Cristian Rodriguez-Aguayo, Xinna Zhang, Robert L Coleman, Gabriel Lopez-Berestein, Anil K Sood
To address the need for efficient and biocompatible delivery systems for systemic siRNA delivery, we developed 1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine (DOPC) nanoliposomal EphA2-targeted therapeutic (EPHARNA). Here, we performed safety studies of EPHARNA in murine and primate models. Single dosing of EPHARNA was tested at 5 concentrations in mice (N=15 per group) and groups were sacrificed on days 1, 14, and 28 for evaluation of clinical pathology and organ toxicity. Multiple dosing of EPHARNA was tested in mice and Rhesus macaques twice weekly at two dose levels in each model...
March 6, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28265008/histone-methyltransferase-g9a-drives-chemotherapy-resistance-by-regulating-the-glutamate-cysteine-ligase-catalytic-subunit-in-head-and-neck-squamous-cell-carcinoma
#11
Chia-Wen Liu, Kuo-Tai Hua, Kai-Chun Li, Hsiang-Fong Kao, Ruey-Long Hong, Jenq-Yuh Ko, Michael Hsiao, Min-Liang Kuo, Ching-Ting Tan
Transient chemotherapeutic response is a major obstacle to treating head and neck squamous cell carcinomas (HNSCC). Histone methyltransferase G9a has recently been shown to be abundantly expressed in HNSCC, and is required to maintain the malignant phenotype. In this study, we found that high G9a expression is significantly associated with poor chemotherapeutic response and disease-free survival in HNSCC patients. Similarly, G9a expression and enzymatic activity were elevated in cisplatin-resistant HNSCC cells...
March 6, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28265007/the-btk-inhibitor-ibrutinib-pci-32765-overcomes-paclitaxel-resistance-in-abcb1-and-abcc10-overexpressing-cells-and-tumors
#12
Hui Zhang, Atish S Patel, Yi-Jun Wang, Yun-Kai Zhang, Rishil J Kathawala, Long-Hui Qiu, Bhargav A Patel, Li-Hua Huang, Suneet Shukla, Dong-Hua Yang, Suresh V Ambudkar, Liwu Fu, Zhe-Sheng Chen
Paclitaxel is one of the most widely used antineoplastic drugs in clinic. Unfortunately, the occurrence of cellular resistance has limited its efficacy and application. The ATP- Binding Cassette Subfamily B member 1 (ABCB1/P-gp) and Subfamily C member 10 (ABCC10/MRP7) are the major membrane protein transporters responsible for the efflux of paclitaxel, constituting one of the most important mechanisms of paclitaxel resistance. Here we demonstrated that the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, significantly enhanced the antitumor activity of paclitaxel by antagonizing the efflux function of ABCB1 and ABCC10 in cells overexpressing these transporters...
March 6, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28265006/characterization-of-the-anti-pd-1-antibody-regn2810-and-its-antitumor-activity-in-human-pd-1-knock-in-mice
#13
Elena Burova, Aynur Hermann, Janelle Waite, Terra Potocky, Venus Lai, Seongwon Hong, Matt Liu, Omaira Allbritton, Amy Woodruff, Qi Wu, Amanda D'Orvilliers, Elena Garnova, Ashique Rafique, William Poueymirou, Joel Martin, Tammy Huang, Dimitris Skokos, Joel Kantrowitz, Jon Popke, Markus Mohrs, Douglas MacDonald, Ella Ioffe, William Olson, Israel Lowy, Andrew Murphy, Gavin Thurston
The Programmed Death-1 (PD-1) receptor delivers inhibitory checkpoint signals to activated T cells upon binding to its ligands PD-L1 and PD-L2 expressed on antigen presenting cells and cancer cells, resulting in suppression of T cell effector function and tumor immune evasion. Clinical antibodies blocking the interaction between PD-1 and PD-L1 restore the cytotoxic function of tumor antigen-specific T cells, yielding durable objective responses in multiple cancers. This report describes the preclinical characterization of REGN2810, a fully human hinge-stabilized IgG4 (S228P) high-affinity anti-PD-1 antibody that potently blocks PD-1 interactions with PD-L1 and PD-L2...
March 6, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28258165/fluorinated-n-n-diarylureas-as-novel-therapeutic-agents-against-cancer-stem-cells
#14
Dasha E Kenlan, Piotr Rychahou, Vitaliy M Sviripa, Heidi L Weiss, Chunming Liu, David S Watt, B Mark Evers
Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality in the United States. Over 50% of patients with CRC will develop local recurrence or distant organ metastasis. Cancer stem cells play a major role in the survival and metastasis of cancer cells. In this study, we examined the effects of novel AMP-activated protein kinase (AMPK) activating compounds on CRC metastatic and stem cell lines as potential candidates for chemotherapy. We found that activation of AMPK by all fluorinated N,N-diarylureas (FND) compounds at micromolar levels significantly inhibited the cell cycle progression and subsequent cellular proliferation...
March 3, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28258164/highly-potent-anthracycline-based-antibody-drug-conjugates-generated-by-enzymatic-site-specific-conjugation
#15
Nikolas Stefan, Rémy Gébleux, Lorenz Waldmeier, Tamara Hell, Marie Escher, Fabian I Wolter, Ulf Grawunder, Roger R Beerli
Antibody drug conjugates (ADCs) are highly potent and specific anti-tumor drugs, combining the specific targeting of monoclonal antibodies (mAbs) with the potency of small molecule toxic payloads. ADCs generated by conventional chemical conjugation yield heterogeneous mixtures with variable pharmacokinetics, stability, safety and efficacy profiles. In order to address these issues, numerous site-specific conjugation technologies are currently being developed allowing the manufacturing of homogeneous ADCs with pre-determined drug-to-antibody ratios...
March 3, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28258163/g-1-inhibits-breast-cancer-cell-growth-via-targeting-colchicine-binding-site-of-tubulin-to-interfere-with-microtubule-assembly
#16
Xiangmin Lv, Chunbo He, Cong Huang, Guohua Hua, Zhengfeng Wang, Steven W Remmenga, Kerry J Rodabaugh, Adam R Karpf, Jixin Dong, John S Davis, Cheng Wang
G-protein coupled estrogen receptor 1 (GPER1) has been reported to play a significant role in mediating the rapid estrogen actions in a wide range of normal and cancer cells. G-1 was initially developed as a selective agonist for GPER. However, the molecular mechanisms underlying the actions of G-1 are unknown and recent studies report inconsistent effects of G-1 on the growth of breast cancer cells. By employing high-resolution laser scanning confocal microscopy and time-lapse imaging technology, as well as biochemical analyses, in the present study, we provide convincing in vitro and in vivo evidence that G-1 is able to suppress the growth of breast cancer cells independent of the expression status of GPERs and classic estrogen receptors...
March 3, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28255027/akt-activation-mediates-acquired-resistance-to-fibroblast-growth-factor-receptor-inhibitor-bgj398
#17
Jharna Datta, Senthilkumar Damodaran, Hannah Parks, Cristina Ocrainiciuc, Jharna Miya, Lianbo Yu, Elijah P Gardner, Eric Samorodnitsky, Michele R Wing, Darshna Bhatt, John Hays, Julie W Reeser, Sameek Roychowdhury
Activation of FGFR signaling through mutations, amplifications, or fusions involving FGFR1, 2, 3, or 4 is seen in multiple tumors, including lung, bladder, and cholangiocarcinoma. Currently, several clinical trials are evaluating the role of novel FGFR inhibitors in solid tumors. As we move forward with FGFR inhibitors clinically, we anticipate the emergence of resistance with treatment. Consequently, we sought to study the mechanism(s) of acquired resistance to FGFR inhibitors using annotated cancer cell lines...
March 2, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28246302/acquired-resistance-with-epigenetic-alterations-under-long-term-anti-angiogenic-therapy-for-hepatocellular-carcinoma
#18
Yoshiteru Ohata, Shu Shimada, Yoshimitsu Akiyama, Kaoru Mogushi, Keisuke Nakao, Satoshi Matsumura, Arihiro Aihara, Yusuke Mitsunori, Daisuke Ban, Takanori Ochiai, Atsushi Kudo, Shigeki Arii, Minoru Tanabe, Shinji Tanaka
Anti-angiogenic therapy is initially effective for several solid tumors including hepatocellular carcinoma (HCC); however, they finally relapse and progress, resulting in poor prognosis. We here established in vivo drug-tolerant subclones of human HCC cells by long-term treatment with vascular endothelial growth factor receptor (VEGFR) inhibitor and serial transplantation in immunocompromised mice (total 12 months), and then compared them with the parental cells in molecular and biological features. Gene expression profiles elucidated a G-actin monomer binding protein thymosin β 4 (Tβ4) as one of the genes enriched in the resistant cancer cells relative to the initially sensitive ones...
February 28, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28223427/calcium-dependent-enhancement-by-extracellular-acidity-of-the-cytotoxicity-of-mitochondrial-inhibitors-against-melanoma
#19
Fumihito Noguchi, Shigeki Inui, Clare Fedele, Mark Shackleton, Satoshi Itami
Extracellular acidity is a hallmark of cancers and is independent of hypoxia. Since acidity potentiates malignant phenotypes, therapeutic strategies that enhance the targeting of oncogenic mechanisms in an acidic microenvironment should be effective. We report here that drugs which abrogate mitochondrial respiration show enhanced cytotoxicity against melanoma cells in a normoxic but acidic extracellular pH, independent from P53 mutations, BRAF (V600E) mutations and/or resistance against BRAF inhibitors. Conversely, the cytotoxicity against melanoma cells of mitochondrial inhibitors is impaired by a neutral or alkaline extracellular pH and in vivo systemic alkalinization with NaHCO3 enhanced subcutaneous tumor growth and lung metastasis of B16F10 cells in mice treated with the mitochondrial inhibitor phenformin...
February 21, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28223426/resistance-mechanism-against-trastuzumab-in-her2-positive-cancer-cells-and-its-negation-by-src-inhibition
#20
Mei Hua Jin, Ah-Rong Nam, Ji Eun Park, Ju-Hee Bang, Yung-Jue Bang, Do-Youn Oh
Trastuzumab in combination with chemotherapy is the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancers. Several resistance mechanisms against anti-HER2 therapy have been proposed. Src activation has been suggested to be responsible for the resistance of HER2-positive breast cancer. In our study, we generated four trastuzumab-resistant (HR) cancer cell lines from HER2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773)...
February 21, 2017: Molecular Cancer Therapeutics
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