bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hemorrhagic and thrombotic events in oncology patients treated with antiangiogenic therapy: Impact of study design on the results assessed by meta-analysis.
Authors: Trone Jane-Chloe , Chapelle Céline , Ollier Edouard , Bertoletti Laurent , Cucherat Michel , Mismetti Patrick , Magné Nicolas , Laporte Silvy 
Published: September 2018

e14058 Background: Antiangiogenic (AA) therapies emerge as a new cornerstone for cancer treatment, but carry their own particular risk profile. Several previous meta-analyses have showed increasing risk of bleeding and paradoxically thrombosis in cancer patients receiving antiangiogenic. The aim of the meta-analysis is to investigate the impact of studies design (open or double blind (DB)), on the incidence and the occurrence of bleeding, venous thrombotic events (VTE) and arterial thrombotic events (ATE) in cancer patients treated by AA therapies. Methods: We searched Medline, Cochrane, ClinicalTrial databases, meeting abstracts of the American Society of Clinical Oncology and the European Society of Medical Oncology for relevant clinical trials. We included prospective phase II and III clinical trials that randomly assigned patients with solid cancer to AA therapy or control. Statistical analyses were conducted to calculate the summary incidence, ORs, and 95% CIs, using random-effects or fixed-effects models based on the heterogeneity of included studies. Results: A total of 166 trials (72,024 patients) were included. For bleeding events, comparison on AA treatment versus control yielded an OR of 2.41 (95% CI 2.07 to 2.71; p < 0.001) with an exaggeration of treatment effects by 68% (95% CI, 33 to 113) in open-label studies compared with DB trials. Concerning VTE, an OR of 1.18 (95% CI 1.04 to 1.35; p = 0.0115) was noted, with a significant enhancement of 53% (95% CI, 19 to 96) of treatment side effects with open trials compared with DB trials. AA don’t increase significantly the frequency of VTE when considering only DB trials. For ATE, an OR of 1.59 (95% CI 1.30 to 1.94; p < 0.001) was observed, associated with a significant exaggeration of 65% (95% CI, 13 to 143) with open trials compared with DB trials. Conclusions: The present meta-analysis showed a significant interaction of study design for the tolerance assessment in the AA therapies in cancers. The increasing risk of hemorrhagic events, VTE and ATE appear to have been overestimated in the previous meta-analyses. In the future, meta-analyses should be restricted to DB trials for analysis of toxicity profile.
SMK/SM88 toxicity, efficacy, and patient reported outcomes in metastatic pancreas cancer.
Authors: Hoffman Steve , Stega Jeanetta , Del Priore Giuseppe , Rothman John 
Published: September 2018

e14060 Background: SMK/SM-88 is a combination of novel tyrosine isomer ( TI) and 3 low dose repurposed agents that are generally recognized as safe for typical use. Its mechanism of action is based on the Warburg effect. It has previously been reported to have clinical benefit with little toxicity in a variety of cancers (J. Clin. Oncol. 2013 31: e22095). We now report on a subset of subjects with pancreas cancer. Methods: Retrospective chart review. Results: Subjects received all four SMK/SM-88 components orally and subcutaneously, consisting of a proprietary altered TI, CYP3a4 inducer, mTOR inhibitor and mitochondrial oxidative stress catalyst, five days per week for a period of six weeks (1 cycle). A total of 11 pancreatic cancers cases were identified. The average age was 63.2 (44-81), 36.4% (4/11) were female. Prior treatment included surgery only (n = 3); chemo only (n = 4); multi-modality therapy (n = 2) and unknown or none (n = 2). Duration on study regimen was 3-57 weeks (mean = 28.5). Clinical benefits documented for all subjects included: 1-3 points improvement in ECOG performance status; 1-5 point mean improvement on EORTC questionnaire (scale 1-7); weight gain (1-5 lbs.); and reduction in pain levels (1-9 points/10 scale) with cessation of all analgesics by the end of cycle 1 in 36% (4/11). Overall reduction in tumor size was seen in 27.3% (3/11) including one CR with PFS of at least 6 months duration, and 2 PRs with one known PFS of 15wks. 72.7% (8/11) had stable disease for 6-61wks. One patient had an overall survival of 23.3 months with no further treatment, and one had an overall survival of 43.2 months. All subjects developed hyperpigmentation. Overall, all subjects tolerated the SMK/SM-88 compounds well. No serious or unexpected adverse events related to the agent have been reported. Conclusions: SMK/SM-88 is a promising treatment for metastatic pancreatic cancer with no significant toxicity. Additional studies are on going in other cancers and confirmatory pancreas investigations are planned.
Antibiotics target MCF-7 breast cancer stem cells in hypoxic environment.
Authors: Miftakhova Regina R. , Akhunzyanov Almaz , Filina Julia V , Khaiboullina Svetlana F , Rizvanov Albert A 
Published: September 2018

e14068 Background: Deregulated cellular metabolism is characteristic for cancer cells which heavily rely on glycolysis to meet metabolic demands. Studies have shown that increased glucose metabolism promotes tumor cell survival through mechanisms related to mitochondrial activities. Recently, mitochondrial inhibitors have been proposed as a potential anticancer therapeutics. In 2015 Lamb et al. presented anti-cancer activity of several antibiotics targeting mitochondrial function. Interestingly, these drugs have the highest inhibitory effect on cancer stem cells (CSCs), a small population of cancer initiating cells. It is believed that tumor microenvironment plays significant role in maintaining CSC population. The hypoxia is a major feature of the tumor microenvironment contributing into CSC phenotype, tumorigenicity and metastasis. Therefore, we sought to determine the effect of five antibiotics targeting mitochondrial function on CSC survival in hypoxia conditions. Methods: MCF-7 cells were cultured in normoxic (20% O2) and hypoxic (4% O2) conditions for 14 days in a presence of azithromycin, doxycycline, tetracycline, erythromycin and chloramphenicol. The ability to form mammospheres was used to determine CSC survival. Results: Incubation of CSCs with erythromycin, doxycycline, tetracycline and chloramphenicol reduced the number of mammospheres, the decrease in mammosphere number was comparable for MCF-7 cells incubated under normoxic and hypoxic conditions [erythromycin (62.5 % ± 10.8% vs. 58.9% ± 2.2% ), doxycycline (75.2% ± 5.9% vs. 68.5% ± 5.4% ), tetracycline (56.0% ± 3.2% vs. 65.0% ± 15.0%) and chloramphenicol (71.5% ± 6.7% vs. 73.7% ± 5.5%)]. Interestingly, azithromycin did not show inhibiting activity on sphere formation under hypoxic condition, while number of spheres was reduced in normoxic conditions Conclusions: These data indicate that four out of five antibiotics in our study can be potentially applied for targeted eradication of breast CSCs in hypoxiс conditions. Acknowledgements: The study was funded by RFBR, according to the research project No. 16-34-60210 mol_а_dk, and by Russian Government Program of Competitive Growth of Kazan Federal University.
Camouflaging iRGD-EGFR anchored human cytotoxic T-lymphocyte membranes to the surface of nanoparticles combined with low-dose irradiation: New approach to enhance drug-delivery targeting in gastric cancer.
Authors: Zhang Lianru , Sha Huizi , Li Rutian , Wei Jia , Liu Baorui 
Published: September 2018

e14076 Background: We report a biomimetic delivery platform based on human cytotoxic T-lymphocyte membranes. In this platform, T-lymphocyte membranes were camouflaged to the surface of poly-lactic-co-glycolic acid nanoparticles, with local low-dose irradiation (LDI) as a chemoattractant. These carriers were further anchored with the recombinant protein anti-EGFR-iRGD, improving tumor accumulation, facilitating tumor uptake. Methods: The T-lymphocyte membrane coating was verified by dynamic light scattering, transmission electron microscopy and confocal laser scanning microscopy. The particle phagocytosis study was performed using a human phagocytic cell line. In vivo NIR fluorescence imaging was performed to monitor the route of nanoparticles. EGFR expression of tumor cells was tested before and after LDI. Results: This new platform reduced phagocytosis of macrophages by 23.99% (p = 0.002). iRGD-EGFR anchored T-lymphocyte membrane-encapsulated nanoparticles accumulated in tumor site more than unfunctionalized groups, while LDI significantly enhanced the targeting ability. LDI could up-regulate EGFR expression on tumor cells, which was important in the process of localization of iRGD-EGFR anchored T-lymphocyte membrane-encapsulated nanoparticles in tumors. Conclusions: This new platform included both the long circulation time and tumor sites accumulation ability while LDI could significantly enhance the tumor accumulation ability.
Efficacy and toxicity of HLX07 as a new anti-EGFR monoclonal antibody for epithelial cancers.
Authors: Liu Hsingjin Eugene , Tseng Chi-Ling , Liu Scott , Jiang Weidong 
Published: September 2018

e14078 Background: EGFR is a validated target for anti-cancer drug development. Several anti-EGFR monoclonal antibodies (mAb) are used in clinics, but associated with a variety of toxicities. A new anti-EGFR mAb might offer better efficacy with less toxicities. Methods: we have developed a new humanized anti-EGFR mAb, HLX07, through engineering of Fab portion and improvement of glycosylation profile and tested in in vitro assays, in vivo xenograft animal models and primate pharmacokinetic (PK) and toxicokinetic (TK) studies. Results: HLX07 exerted potent antibody-dependent, cell-mediated cytotoxicity in vitro. It specifically binds to monkey and human but not rodent EGFR. HLX07 has better binding affinity to human EGFR, compared with cetuximab (KD 1.43x10-10 vs. 2.62x10-10). HLX07 completely inhibited the phosphorylation of EGFR in H292 cells at ≥0.1 nM, The IC50 of HLX07 for DiFi and H292 cells were 54.2 and 23.9 ng/mL, respectively, compared with 63.7 and 37.2 ng/mL by cetuximab, respectively. In vivo xenogenic studies also demonstrated that HLX07 significantly inhibited the growth of H292, A432 and WiDi cells in a dose-dependent manner. Xenogenic studies also showed that HLX07 used with gemcitabine and/or cisplatin was more active than either agent alone. HLX07 was more effective than cetuximab in inhibiting the growth of FaDu cells when used with local radiotherapy in vivo. Single-dose and 13-week repeat-dose GLP pharmacokinetic and toxicokinetic studies in cynomulgus monkeys up to 60 mg/kg/wk shows minimal-to-mild toxicities (see table). Conclusions: The detailed preclinical characterization indicates that HLX07 has better efficacy and less toxicity than cetuximab. A phase 1 first-in-human study is ongoing (NCT02648490). [Table: see text]
A phase I, open-label, nonrandomized, pharmacokinetic study of trifluridine/tipiracil (TAS-102) in Chinese patients with solid tumors.
Authors: Wang Xicheng , Zhou Jianfeng , Li Yan , Ge Yuping , Zhou Yanping , Shen Lin , Bai Chunmei 
Published: September 2018

e14079 Background: Trifluridine/tipiracil (TAS-102) is an oral combination of an antineoplastic thymidine-based nucleoside analog, trifluridine (FTD), and the thymidine phosphorylase inhibitor, tipiracil (TPI). Trifluridine/tipiracil is demonstrated as a valid treatment choice for Asian and Western patients (pts) with metastatic colorectal cancer refractory or intolerant to standard chemotherapies in earlier studies. Its pharmacokinetic (PK) profile was also investigated in American and Japanese phase 1 studies, but never in Chinese pts. This study was conducted to investigate the PK profile of Trifluridine/tipiracil in a Chinese population with solid tumors. Methods: Pts who has responded poorly to existing standard treatment received Trifluridine/tipiracil (35 mg/m2/dose), orally BID, on days 1-5 and days 8-12 every 4 weeks until one of discontinuation criteria was met. Blood samples for PK analysis of FTD (the active compound), fluorothymine (FTY, inactive metabolite) and TPI were collected after single and multiple doses of Trifluridine/tipiracil on days 1 and 12 of cycle 1. The safety, tolerability, and antitumor activity of Trifluridine/tipiracil were also assessed as secondary endpoints. Results: A total of 15 pts were administered Trifluridine/tipiracil and analyzed for PKs. The PKs of FTD, FTY, and TPI in Chinese pts were comparable to those in Japanese pts. Compared with American pts, although the AUC0-t of TPI on day 12 was significantly lower in Chinese pts, the Cmax and AUC0-t of FTD were not significantly different. Thirteen (86.7%) pts reported treatment-emergent adverse events (TEAEs), and eight (53.3%) pts experienced grade 3 TEAEs, of which anemia and fatigue were most frequently (≥10% of patients) reported. Grade 4 or 5 TEAEs were not observed. Conclusions: The PKs of Trifluridine/tipiracil in Chinese pts were comparable to those in Japanese pts. The exposure of FTD was showed without significant difference between Chinese, Japanese and American pts. Trifluridine/tipiracil was well-tolerated in Chinese pts and had the similar safety profile in comparison with previous studies. Clinical trial information: NCT02261532.
Pharmacogenomic determinants of cetuximab and oxaliplatin pharmacokinetics during combined intravenous cetuximab (IV-Cet) and triplet hepatic artery chronomodulated infusion in patients (pts) with initially unresectable liver metastases from colorectal cancer (uLM-CRC) (EU OPTILIV trial).
Authors: Karaboue Abdoulaye , Saffroy Raphael , Desterke Christophe , Bouchahda Mohamed , Innominato Pasquale , Focan C. N. J. , Chatelut Etienne , Paintaud Gilles , Milano Gerard A. , Lemoine Antoinette , Levi Francis 
Published: September 2018

e14082 Background: Triplet HAI with IV-Cet achieved 29.7% complete uLM-CRC resections (R0+R1) and an overall median survival (OS) of 25.7 months in previously treated pts. While the high antitumour efficacy of this new regimen involved direct exposure of LM to the HAI drugs and their potentiation by cetuximab, haematological and intestinal toxicities mostly related to systemic exposure (Lévi, Ann Oncol 2016; Clin Pharmacokin 2016). Methods: To identify potential pharmacogenomics (PG) determinants of toxicity-related systemic exposure to the HAI drugs, 207 single nucleotide polymorphisms (SNPs) from 34 pharmacology genes were analysed in blood mononuclear cells (ADME PGx, MassArray platform, Sequenom, USA) from 11 pts undergoing a first course of chronomodulated triplet HAI and iv-CET (Levi et al. Clin Pharmacokinet 2016). Relations between SNPs and main pharmacokinetics parameters and toxicities were determined using ANOVA or Fisher Exact test. Results: Nine toxicity-related polymorphic genes were identified in the 52 pts of the PG study (ASCO, submitted). Here we investigated whether any of these polymorphic genes modified PK in 4F and 7M (33-72 yo) with WHO performance status 0-1. ABCB1 (rs1045642) was the only polymorphic gene that was significantly associated with both pharmacokinetics and toxicity in this study population. Conclusions: ABCB1 polymorphisms might contribute to the systemic hematologic toxicity of the combined IV-HAI regimen through altering cetuximab and oxaliplatin disposition, yet without affecting efficacy. Consideration of ABCB1 polymorphism could help optimize OPTILIV delivery in individual patients. Clinical trial information: NCT00852228. [Table: see text]
Inhibition of hypoxia-inducible factor-1α by PX-478 as a potential targeted therapy in ESCC.
Authors: Zhu Yingming , Zang Yuanwei , Li Minghuan , Yu Jinming 
Published: September 2018

e14083 Background: Hypoxia is a unique microenvironment in solid tumors, including ESCC. We aim to investigate the interaction between hypoxia-inducible factor-1α (HIF-1α), COX-2 and programmed cell death ligand-1 (PD-L1) and uncover the role of HIF-1α inhibitor PX-478 as a potential targeted therapy in ESCC. Methods: Immunohistochemical staining was performed to investigate the levels of HIF-1α, COX-2 and PD-L1 from 133 pT3N0M0 ESCC patients after radical resection. The prognostic value of the expression of HIF-1α, COX-2 and PD-L1 and the correlation with clinicopathologic features was evaluated. Knockdown assay, CCK-8 assay, Western blot, real-time polymerase chain reaction (RT-PCR), flow cytometry and Transwell migration assays were used in cells experiment. Results: HIF-1α and PD-L1 are independent prognostic factors in pT3N0M0 ESCC. Further data showed that HIF-1α plays an important role in regulation of COX-2 and PD-L1 expression. Our in vitro studies demonstrated that HIF-1α inhibitor, PX-478, induced G2 phase arrest, increased apoptosis, and inhibited migration and invasion of esophageal carcinoma cells, and thus significantly inhibit ESCC cells proliferation. Conclusions: Our results provide new insight into the potential role of HIF-1α inhibitors, PX-478 and open up the possibility of PX-478 for targeted therapy of ESCC.
Preclinical in vitro and in vivo evaluation of antitumor activity of UD-017, a novel selective and orally available CDK7 inhibitor, in colorectal cancer.
Authors: Ogi Sayaka , Aga Yasuhiro , Onuma Kazuhiro , Sunamoto Hidetoshi , Matsushita Takashi , Ogawa Ayumi , Hasegawa Tohru , Kono Shigeyuki , Iwase Noriaki , Tokunaga Yasunori , Ushiyama Shigeru 
Published: September 2018

e14085 Background: Cyclin dependent kinase 7 (CDK7) is an attractive target for cancer drugs due to its dual roles, cell cycle regulation and gene transcription/RNA procession. We synthesized UD-017, a small molecule, highly selective CDK7 inhibitor with a novel chemotype. In this study, we characterize antitumor activity of UD-017 in vitro and in vivo, and try to elucidate underlying mechanisms by which CDK7 inhibition contributes to the antitumor efficacy in colorectal cancer cells. Methods: We examined CDK7 selectivity of UD-017 against the other CDKs and kinases. We evaluated the antitumor activity in a variety of human cancer cell lines including colorectal cancer cells. We investigated the mechanism of antitumor activity of UD-017 using a human colorectal cancer cell line, HCT-116. In vivo antitumor efficacy of UD-017 was assessed in HCT-116 xenograft models and patient derived xenograft (PDX) model. Results:UD-017 inhibited CDK7 enzyme (IC50 = 16 nM), which is at least 300-fold more selective against other CDKs. In a panel of 313 kinases assay, UD-017 inhibited CDK7 almost mono-specifically. UD-017 potently inhibited the growth of human cancer cells including the patient-derived colorectal cancer cells.In the mechanism study, UD-017 inhibited phosphorylation of CDK1, 2 and retinoblastoma, which was followed by cell-cycle arrest. Inhibition of both RNA polymerase II phosphorylation and c-Myc expression was observed followed by apoptosis induction. HCT-116 xenograft model and PDX model demonstrated the potent antitumor activity of UD-017 with dose-dependence by daily oral administration for 2 weeks. Furthermore, UD-017 showed the combination effect with 5-FU without further affecting the side effects of the chemotherapy. Conclusions:UD-017 is a potent and highly selective CDK7 inhibitor, and significantly inhibits the growth of human cancer cell lines with cell-cycle arrest and apoptosis induction. UD-017 showed potent and dose-dependent antitumor response in the HCT-116 xenograft model and PDX model. Further investigation towards clinical development is warranted.
Efficacy of a single-dose injection of CLR 131 (1-131-CLR1404) in a Caki-2 athymic nude mouse model.
Authors: Longcor Jarrod , Oliver Katherine , Kandela Irawati 
Published: September 2018

e14087 Background: CLR 131 is a novel radioiodinated therapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Study was to evaluate the therapeutic effect of CLR 131 when administered as a single dose intravenous injection in Caki-2 tumor bearing mice. Caki-2 cells are a human clear cell renal cell carcinoma (CCRCC). Methods: The Caki-2 cell line (human clear cell carcinoma) was purchased from American Type Culture Collection (ATCC, Rockville, MD) and maintained in McCoy’s 5a media supplemented with 10% fetal bovine serum. Female athymic nude mice (Hsd: Athymic Nude-Foxn1nu); 4-5 weeks of age, 16-18 g (Harlan, Indianapolis, IN) were injected subcutaneously with 1x106 viable cells (in 100 µL Dulbecco’s PBS) into the right flank. The study was initiated when tumor size had reached a pre-determined size (100-250 mm3). The mice were given potassium iodide at a concentration of 0.1% in their drinking water to block possible free iodide in the drug formulation. A single dose of ~110µCi of CLR 131 was given at Day 0 (N = 6 per group). A control dose of I-127-CLR1404 was given at ~110 µCi dose and was injected via tail vein on Day 0. Results: Tumor growth of the treatment group was significantly inhibited. The control group showed exponential growth after day 20 post-injection while the treatment group maintained the initial tumor volume up to day 75 post injection. By day 65, the control group increased 10.75-fold compared to the treatment group in average tumor volume. CLR 131 provides survival benefit for Caki-2 bearing mice. Kaplan Meier survival showed significant survival benefit with this model. Conclusions: The results of the study indicate that a single dose of CLR 131 on Caki-2 tumor bearing model showed a significant inhibition of tumor growth as well as significant survival benefit.
Efficacy of repeated injections of CLR 131 (I-131-CLR1404) in a MES SA/Dx5 athymic nude mouse model.
Authors: Oliver Katherine , Longcor Jarrod , Kandela Irawati 
Published: September 2018

e14091 Background: CLR 131 is a novel radioiodinated therapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Uterine sarcoma (MES SA/Dx5) cells express high levels of P-gp and are known to be a doxorubicin resistant cell line. The cells exhibit a marked cross resistance to several chemotherapy drugs including vinblastine, Taxol®, vincristine, etc. This study evaluates the effect of repeated injections of CLR 131 in MES SA/Dx5 tumor bearing mice and evaluate the ability of CLR 131 to overcome resistance caused by over-expression of the P-gp Multi Drug Resistance (MDR) ‘pump’. Methods: The MES SA/Dx5 cell line (human uterine sarcoma) was purchased from American Type Culture Collection (Rockville, MD) and maintained in McCoy’s 5a media supplemented with 10% fetal bovine serum. Female athymic nude mice (Crl: NU-Foxn1nu); approximately 4-5 weeks of age and between 16-18 g (Charles River, Portage, MI) were injected subcutaneously with 2x106 viable cells (in ~100 µL Dulbecco’s PBS) into the right flank. The study was initiated when tumor size had reached a pre-determined size (approximately 50-150 mm3). The mice were given potassium iodide at a concentration of 0.1% in their drinking water to block possible free iodide in the drug formulation. Doses of ~130 µCi and ~145 µCi of CLR 131were given at Day 0 and Day 7 (N = 6 in treatment group, N = 5 in control group). A single control dose of ~130 µCi of I-127-CLR1404 was given via tail vein injection on Day 0. Results: Tumor growth of the treatment group was significantly inhibited. The control group showed exponential growth throughout the study, increasing in volume by an average 21 fold from baseline to day 22 (all control mice died day 23). This compared with a 6 fold increase from baseline in the treatment group. Conclusions: The results of the study indicated that multiple injections of CLR 131 on human uterine sarcoma (MES SA/Dx5) tumor bearing model showed a significant inhibition of tumor growth as well as significant survival benefit. The implication is that in this clinically predictive in vivo model CLR 131 is not susceptible to the MDR “pump” and thus CLR 131 might show clinical efficacy in patients with MDR cancer due to P-gp overexpression.