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Investigational New Drugs

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https://www.readbyqxmd.com/read/29139009/lfm-a13-a-potent-inhibitor-of-polo-like-kinase-inhibits-breast-carcinogenesis-by-suppressing-proliferation-activity-and-inducing-apoptosis-in-breast-tumors-of-mice
#1
Kazim Sahin, Mehmet Tuzcu, Mehmet Yabas, Cemal Orhan, Nurhan Sahin, Ibrahim H Ozercan
The goals of the present study were to define the anticancer activity of LFM-A13 (α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)-propenamide), a potent inhibitor of Polo-like kinase (PLK), in a mouse mammary cancer model induced by 7,12-dimethylbenz(a)anthracene (DMBA) in vivo and explore its anticancer mechanism(s). We also examined whether the inhibition of PLK by LFM-A13 would improve the efficiency of paclitaxel in breast cancer growth in vivo. To do this, female BALB/c mice received 1 mg of DMBA once a week for 6 weeks with oral gavage...
November 15, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29134432/phase-iii-study-of-dulanermin-recombinant-human-tumor-necrosis-factor-related-apoptosis-inducing-ligand-apo2-ligand-combined-with-vinorelbine-and-cisplatin-in-patients-with-advanced-non-small-cell-lung-cancer
#2
Xuenong Ouyang, Meiqi Shi, Fangwei Jie, Yuxian Bai, Peng Shen, Zhuang Yu, Xiuwen Wang, Cheng Huang, Min Tao, Zhehai Wang, Conghua Xie, Qi Wu, Yongqian Shu, Baohui Han, Fengchun Zhang, Yiping Zhang, Chunhong Hu, Xitao Ma, Yongjie Liang, Anlan Wang, Bing Lu, Yi Shi, Jinfei Chen, Zhixiang Zhuang, Jiejun Wang, Jianjin Huang, Changhui Wang, Chunxue Bai, Xin Zhou, Qiang Li, Feng Chen, Hao Yu, Jifeng Feng
Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25 mg/m(2) on days 1 and 8 and cisplatin 30 mg/m(2) on days 2 to 4) for up to six cycles plus dulanermin (75 μg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent...
November 14, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29127533/a-phase-2-study-of-ontuxizumab-a-monoclonal-antibody-targeting-endosialin-in-metastatic-melanoma
#3
Sandra P D'Angelo, Omid A Hamid, Ahmad Tarhini, Dirk Schadendorf, Bartosz Chmielowski, Frances A Collichio, Anna C Pavlick, Karl D Lewis, Susan C Weil, John Heyburn, Charles Schweizer, Daniel J O'Shannessy, Richard D Carvajal
Objectives Ontuxizumab (MORAB-004) is a first-in-class monoclonal antibody that interferes with endosialin function, which is important in tumor stromal cell function, angiogenesis, and tumor growth. This Phase 2 study evaluated the 24-week progression-free survival (PFS) value, pharmacokinetics, and tolerability of 2 doses of ontuxizumab in patients with metastatic melanoma. Patients and methods Patients with metastatic melanoma and disease progression after receiving at least 1 prior systemic treatment were randomized to receive ontuxizumab (2 or 4 mg/kg) weekly, without dose change, until disease progression...
November 11, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29119276/phase-ib-ii-study-of-gemcitabine-nab-paclitaxel-and-pembrolizumab-in-metastatic-pancreatic-adenocarcinoma
#4
Glen J Weiss, Lisa Blaydorn, Julia Beck, Kirsten Bornemann-Kolatzki, Howard Urnovitz, Ekkhard Schütz, Vivek Khemka
Background A single center phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab (GNP) to evaluate the safety and efficacy in metastatic pancreatic adenocarcinoma (PDAC) was conducted (NCT02331251). Methods PDAC patients (pts) with measurable disease, biopsy proven metastasis, adequate laboratory tests, and KPS ≥ 70% received GNP until progression or toxicity. Safety monitoring, RECIST 1.1, and irRECIST assessments were conducted. Response imaging was performed prior to cycle 4, then every 3 months...
November 8, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29116478/cyclodextrin-polymers-as-nanocarriers-for-sorafenib
#5
Valentina Giglio, Maurizio Viale, Vittorio Bertone, Irena Maric, Rita Vaccarone, Graziella Vecchio
Polymeric nanoparticles based on cyclodextrins are currently undergoing clinical trials as new promising nanotherapeutics. In light of this interest, we investigated cyclodextrin cross-linked polymers with different lengths as carriers for the poorly water-soluble drug sorafenib. Both polymers significantly enhanced sorafenib solubility, with shorter polymers showing the most effective solubilizing effect. Inclusion complexes between sorafenib and the investigated polymers exhibited an antiproliferative effect in tumor cells similar to that of free sorafenib...
November 8, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29116477/4egi-1-represses-cap-dependent-translation-and-regulates-genome-wide-translation-in-malignant-pleural-mesothelioma
#6
Arpita De, Blake A Jacobson, Mark S Peterson, Joe Jay-Dixon, Marian G Kratzke, Ahad A Sadiq, Manish R Patel, Robert A Kratzke
Deregulation of cap-dependent translation has been implicated in the malignant transformation of numerous human tissues. 4EGI-1, a novel small-molecule inhibitor of cap-dependent translation, disrupts formation of the eukaryotic initiation factor 4F (eIF4F) complex. The effects of 4EGI-1-mediated inhibition of translation initiation in malignant pleural mesothelioma (MPM) were examined. 4EGI-1 preferentially inhibited cell viability and induced apoptosis in MPM cells compared to normal mesothelial (LP9) cells...
November 8, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29116476/contribution-of-reactive-oxygen-species-to-the-anticancer-activity-of-aminoalkanol-derivatives-of-xanthone
#7
Daniel Sypniewski, Natalia Szkaradek, Tomasz Loch, Anna M Waszkielewicz, Agnieszka Gunia-Krzyżak, Daria Matczyńska, Dagna Sołtysik, Henryk Marona, Ilona Bednarek
Reactive oxygen species (ROS) are critically involved in the action of anticancer agents. In this study, we investigated the role of ROS in the anticancer mechanism of new aminoalkanol derivatives of xanthone. Most xanthones used in the study displayed significant pro-oxidant effects similar to those of gambogic acid, one of the most active anticancer xanthones. The pro-oxidant activity of our xanthones was shown both directly (by determination of ROS induction, effects on the levels of intracellular antioxidants, and expression of antioxidant enzymes) and indirectly by demonstrating that the overexpression of manganese superoxide dismutase decreases ROS-mediated cell senescence...
November 8, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29110173/combination-treatment-with-docetaxel-and-histone-deacetylase-inhibitors-downregulates-androgen-receptor-signaling-in-castration-resistant-prostate-cancer
#8
Sang Eun Park, Ha-Gyeong Kim, Dong Eun Kim, Yoo Jung Jung, Yunlim Kim, Seong-Yun Jeong, Eun Kyung Choi, Jung Jin Hwang, Choung-Soo Kim
Backgrounds Since most patients with castration-resistant prostate cancer (CRPC) develop resistance to its standard therapy docetaxel, many studies have attempted to identify novel combination treatment to meet the large clinical unmet need. In this study, we examined whether histone deacetylase inhibitors (HDACIs) enhanced the effect of docetaxel on AR signaling in CRPC cells harboring AR and its splice variants. Methods HDACIs (vorinostat and CG200745) were tested for their ability to enhance the effects of docetaxel on cell viability and inhibition of AR signaling in CRPC 22Rv1 and VCaP cells by using CellTiter-Glo™ Luminescent cell viability assay, synergy index analysis and Western blotting...
November 7, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29101518/phase1-study-of-cisplatin-plus-pemetrexed-with-erlotinib-and-bevacizumab-for-chemotherapy-na%C3%A3-ve-advanced-non-squamous-non-small-cell-lung-cancer-with-egfr-mutations
#9
Motohiro Tamiya, Akihiro Tamiya, Takayuki Shiroyama, Sawa Takeoka, Yujiro Naito, Naoki Omachi, Yohei Kimura, Naoko Morishita, Hidekazu Suzuki, Norio Okamoto, Kyoichi Okishio, Tomoya Kawaguchi, Shinji Atagi, Tomonori Hirashima
Background Cisplatin and pemetrexed are very effective against advanced non-squamous non-small cell lung cancer (NSCLC) without EGFR mutations. Erlotinib plus bevacizumab are highly effective against advanced NSCLCs with activating EGFR mutations. We performed this phase I 'Quartet Trial' to determine the safety and efficacy of all 4 agents as a first-line treatment for non-squamous NSCLC patients harboring activating EGFR mutations. Patients and Methods Patients received escalating quartet-agent doses every 3 weeks for 4 cycles...
November 4, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29094232/phase-i-trial-of-bortezomib-daily-dose-safety-pharmacokinetic-profile-biological-effects-and-early-clinical-evaluation-in-patients-with-advanced-solid-tumors
#10
Rastislav Bahleda, Marie-Cécile Le Deley, Apexa Bernard, Shalini Chaturvedi, Michael Hanley, Audrey Poterie, Anas Gazzah, Andreea Varga, Mehdi Touat, Eric Deutsch, Christophe Massard, Helgi Van De Velde, Antoine Hollebecque, Magali Sallansonnet-Froment, Damien Ricard, Hervé Taillia, Eric Angevin, Vincent Ribrag, Jean-Charles Soria
Purpose This phase I study investigated bortezomib in solid tumors used as a daily subcutaneous regimen. Previous regimens showed only modest activity in solid tumors which was potentially related to sub-optimal tumor penetration. We aimed at exploring if daily low dose administration of bortezomib may allow a greater and tolerable pharmacokinetic exposure which might be required for antitumor activity in solid tumors. Patients and methods This 3 + 3 design, dose escalation, monocentric study aimed at defining the maximum tolerated dose of daily low dose schedule of bortezomib...
November 2, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29082457/systematic-analysis-reveals-a-lncrna-mrna-co-expression-network-associated-with-platinum-resistance-in-high-grade-serous-ovarian-cancer
#11
Lei Fang, Hao Wang, Peiling Li
Resistance to platinum-based chemotherapy is the major barrier to treating high-grade serous ovarian cancer (HGS-OvCa). To improve HGS-OvCa patient prognosis, it is critical to identify the underlying mechanisms that promote platinum resistance. The goal of the present study was to identify a lncRNA-mRNA co-expression network and key lncRNAs that predict resistance to platinum-based chemotherapy in ovarian cancer patients. By systematically analyzing the expression profiles of lncRNAs and mRNAs in HGS-OvCa samples from the Cancer Genome Atlas (TCGA), we revealed that lncRNAs play important roles in platinum resistance in HGS-OvCa patients and delineate a lncRNA-mRNA co-expression network in HGS-OvCa patients who exhibit platinum resistance...
October 30, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29081024/ganoderic-acid-lanostanoid-triterpene-a-key-player-in-apoptosis
#12
REVIEW
Balraj Singh Gill, Navgeet, Richa Mehra, Vicky Kumar, Sanjeev Kumar
Cancer is a multifactorial disease, causing behavioral and metabolic alterations, leading to uncontrolled cell proliferation with collateral weakening of immune system. Crucial balance between cell proliferation and cell death determines the fate of a cell, which might progress towards survival or apoptosis. Apoptosis is a complex, programmed, and highly regulated process causing dramatic morphological and biochemical perturbations in the cellular machinery. Ganoderma lucidum is a basidiomycetes, polypore mushroom known for its pharmacological properties in cancer...
October 28, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29081023/combined-treatment-with-pemetrexed-and-vinflunine-in-patients-with-metastatic-urothelial-cell-carcinoma-after-prior-platinum-containing-chemotherapy-results-of-an-exploratory-phase-i-study
#13
H Pappot, H von der Maase, A Ullén, M Agerbæk
Vinflunine is to date the only registered agent for second-line treatment of metastatic urothelial cell carcinoma (UCC) in Europe. However, the effect is modest. Pemetrexed has demonstrated some single-agent activity in this disease entity. In order to improve treatment possibilities for UCC patients, a phase I trial (VINTREX) was undertaken to assess the safety of vinflunine and pemetrexed in metastatic UCC patients. A dose escalation design was planned to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a vinflunine/pemetrexed combination...
October 28, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29075985/radiomics-to-predict-immunotherapy-induced-pneumonitis-proof-of-concept
#14
Rivka R Colen, Takeo Fujii, Mehmet Asim Bilen, Aikaterini Kotrotsou, Srishti Abrol, Kenneth R Hess, Joud Hajjar, Maria E Suarez-Almazor, Anas Alshawa, David S Hong, Dunia Giniebra-Camejo, Bettzy Stephen, Vivek Subbiah, Ajay Sheshadri, Tito Mendoza, Siqing Fu, Padmanee Sharma, Funda Meric-Bernstam, Aung Naing
We present the first reported work that explores the potential of radiomics to predict patients who are at risk for developing immunotherapy-induced pneumonitis. Despite promising results with immunotherapies, immune-related adverse events (irAEs) are challenging. Although less common, pneumonitis is a potentially fatal irAE. Thus, early detection is critical for improving treatment outcomes; an urgent need to identify biomarkers that predict patients at risk for pneumonitis exists. Radiomics, an emerging field, is the automated extraction of high fidelity, high-dimensional imaging features from standard medical images and allows for comprehensive visualization and characterization of the tissue of interest and corresponding microenvironment...
October 27, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29067537/posterior-reversible-encephalopathy-syndrome-pres-induced-by-pazopanib-a-multi-targeting-tyrosine-kinase-inhibitor-in-a-patient-with-soft-tissue-sarcoma-case-report-and-review-of-the-literature
#15
Shoichi Deguchi, Koichi Mitsuya, Yoko Nakasu, Nakamasa Hayashi, Hirohisa Katagiri, Hideki Murata, Junji Wasa, Mitsuru Takahashi, Masahiro Endo
Posterior reversible encephalopathy syndrome (PRES) is a clinical entity characterized by acute neurological symptoms such as severe headache, seizures, and visual disturbance, and by typical reversible lesion on brain magnetic resonance (MR) images. Since PRES is thought to be caused by vascular endothelial injury due to cytotoxic agents or acute systemic hypertension, the number of reports on PRES associated with angiogenesis inhibitors has been increasing. Although five cases that developed PRES due to pazopanib for renal cell carcinoma have already been reported, none of PRES due to pazopanib for soft-tissue sarcoma has been reported thus far...
October 25, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29047029/phase-i-study-of-the-combination-of-crizotinib-as-a-met-inhibitor-and-dasatinib-as-a-c-src-inhibitor-in-patients-with-advanced-cancer
#16
Shumei Kato, Denis L Jardim, Faye M Johnson, Vivek Subbiah, Sarina Piha-Paul, Apostolia M Tsimberidou, Gerald S Falchook, Daniel Karp, Ralph Zinner, Jennifer Wheler, Filip Janku, Siqing Fu, JoAnn Lim, Stacie Bean, Ly Nguyen, Susan Urban, Elsa Browne, Funda Meric-Bernstam, David S Hong
Background Both MET and c-SRC are important mediators of cancer progression and there is cross talk between the two molecules. Preclinical studies have demonstrated combination of MET and c-SRC inhibitors is effective in multiple cancer types. Methods We analyzed the safety and efficacy of administering a c-SRC inhibitor (dasatinib) in combination with a MET inhibitor (crizotinib) in a two-arm concurrent phase I study. Arm A consisted of crizotinib fixed at 250 mg twice per day with escalation of dasatinib...
October 19, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29027591/clinical-toxicity-of-antibody-drug-conjugates-a-meta-analysis-of-payloads
#17
REVIEW
Joanna C Masters, Dana J Nickens, Dawei Xuan, Ronald L Shazer, Michael Amantea
Background Antibody drug conjugates (ADCs) utilize a monoclonal antibody to deliver a cytotoxic payload specifically to tumor cells, limiting exposure to healthy tissues. Major clinical toxicities of ADCs include hematologic, hepatic, neurologic, and ophthalmic events, which are often dose-limiting. These events may be off-target effects caused by premature release of payload in circulation. A meta-analysis was performed to summarize key clinical safety data for ADCs by payload, and data permitting, establish a dose-response model for toxicity incidence as a function of payload, dose/regimen, and cancer type...
October 13, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29018997/gastrointestinal-perforation-related-to-lenvatinib-an-anti-angiogenic-inhibitor-that-targets-multiple-receptor-tyrosine-kinases-in-a-patient-with-metastatic-thyroid-cancer
#18
Emi Date, Kunio Okamoto, Souichi Fumita, Hiroyasu Kaneda
Lenvatinib, a novel potent multikinase inhibitor, was approved for the treatment of radioiodine-refractory differentiated thyroid cancer based on results from phase III trial (SELECT study). Thyroid cancer is a diverse disease that includes anaplastic thyroid cancer (ATC), which the most aggressive form of the disease, although it accounts for <2% of all thyroid cancers. Current treatments for ATC have limited efficacy. We report the case of a woman with recurrent well-differentiated papillary carcinoma of the thyroid that had transformed into ATC who developed a perforation of the small intestine secondary to a marked effect of lenvatinib...
October 11, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28990119/dual-src-and-egfr-inhibition-in-combination-with-gemcitabine-in-advanced-pancreatic-cancer-phase-i-results-a-phase-i-clinical-trial
#19
Dana B Cardin, Laura W Goff, Emily Chan, Jennifer G Whisenant, G Dan Ayers, Naoko Takebe, Lori R Arlinghaus, Thomas E Yankeelov, Jordan Berlin, Nipun Merchant
Pancreatic adenocarcinoma remains a major therapeutic challenge, as the poor (<8%) 5-year survival rate has not improved over the last three decades. Our previous preclinical data showed cooperative attenuation of pancreatic tumor growth when dasatinib (Src inhibitor) was added to erlotinib (EGFR inhibitor) and gemcitabine. Thus, this study was designed to determine the maximum-tolerated dose of the triplet combination. Standard 3 + 3 dose escalation was used, starting with daily oral doses of 70 mg dasatinib and 100 mg erlotinib with gemcitabine on days 1, 8, and 15 (800 mg/m(2)) of a 28-day cycle (L0)...
October 9, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28983766/hersintuzumab-a-novel-humanized-anti-her2-monoclonal-antibody-induces-potent-tumor-growth-inhibition
#20
Mohammad Mehdi Amiri, Forough Golsaz-Shirazi, Tahereh Soltantoyeh, Reza Hosseini-Ghatar, Tannaz Bahadori, Jalal Khoshnoodi, Shadi Sadat Navabi, Samira Farid, Mohammad Hossein Karimi-Jafari, Mahmood Jeddi-Tehrani, Fazel Shokri
Humanized monoclonal antibodies (mAbs) against HER2 including trastuzumab and pertuzumab are widely used to treat HER2 overexpressing metastatic breast cancers. These two mAbs recognize distinct epitopes on HER2 and their combination induces a more potent blockade of HER2 signaling than trastuzumab alone. Recently, we have reported characterization of a new chimeric mAb (c-1T0) which binds to an epitope different from that recognized by trastuzumab and significantly inhibits proliferation of HER2 overexpressing tumor cells...
October 6, 2017: Investigational New Drugs
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