bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Effect of amplification of xenobiotic detoxification pathways genes on survival in lung adenocarcinoma versus squamous cell carcinoma bases on the Cancer Genome Atlas provisional database.
Authors: Shanshal Mohamed , Tijani Lukman Aderoju , Hardwicke Fred L. , Kaleem Hassan , D'Cunha Nicholas C. , Igid Henry Palangdao , Khan Muhammad Saad , Jones Catherine , Awasthi Sanjay , Radhi Saba
Published: September 2018

e14093

Background: Ral interacting protein (RLIP76) is a stress-responsive anti-apoptotic efflux transporter of the mercapturic acid pathway (MPy). The MPy enzymes are an essential component of the broader xenobiotic detoxification pathways (XDP) that are regulated by p53 (TP53) in response to xenobiotic/oxidative stress. Homozygous Rlip knockout (Rlip-/-) mice are resistant to benzopyrene induced adenocarcinoma and have constitutive activation of p53. The cancer-resistant phenotype of Rlip-/- mice is the diametric opposite of p53 homozygous knockout mice (p53-/-) mice, which die before the age of 24 weeks of spontaneous malignancy. Methods: Our preliminary studies show that creating Rlip deficiency through pharmacological or genetic methods caused all p53-/- mice to remain cancer-free at an unprecedented age of 32 weeks. This degree of cancer prevention has never been observed with any previous pharmacological or genetic intervention in p53-/- mice. Transcriptomic and epigenomic profiling of the cancer-free p53-/- mice revealed that the direction of change in expression of a network of Rlip-linked XDP enzymes and signaling proteins was identical to that in the cancer-resistant Rlip-/- mice. Results: We hypothesized that the activity of this Rlip-linked subset of the XDP enzymes/signaling proteins (designated XMN1) is a determinant of carcinogenic susceptibility caused by p53 loss. To examine this possibility, we queried the TCGA (The Cancer Genome Atlas) database to determine whether components of XMN1 were differentially expressed in human malignancy, and whether this was associated with overall survival. We focused on non-small cell lung cancer because of the high incidence of p53 mutations in these cancers. To our surprise, we found amplification or upregulation of XMN1 components conferred a reduced survival in lung adenocarcinoma but prolonged survival in squamous cell carcinoma. Conclusions: The mechanisms underlying this remarkable diametrically opposite effect on prognosis of are unknown and suggest opposed functions of XMN1 in Squamous verses Adenocarcinoma.
Pediatric oncology phase 1 trial efficiency in the era of targeted and biological therapies.
Authors: Cooney Tabitha , Tran Duy C , Onar-Thomas Arzu , Norris Robin Elizabeth
Published: September 2018

e14100

Background: Prior reviews have assessed the conduct and efficiency of pediatric phase 1 trials evaluating conventional chemotherapy. Additional analyses are now needed to evaluate the conduct and design of pediatric phase 1 trials of targeted and biologic agents. Methods: A systematic review of pediatric oncology phase 1 trials published between 2000-2015 was performed. Patient characteristics, study design, and trial endpoints were evaluated. When available, the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) was compared to the adult MTD/RP2D. Results: 166 pediatric phase 1 trials meeting pre-defined selection criteria were identified. Sixty-six trials evaluated conventional chemotherapeutic agents and 100 evaluated biologic agents. Of the 4,763 enrolled patients, 1933 were female and 2487 were male (ratio 1:1.3). Race or ethnicity data was included in only 31.3% of published articles. Seventy-five percent of trials used a 3+3 dose escalation strategy. Eight percent of studies used an adaptive/Bayesian strategy and 7% used the rolling six design. Eighty-eight percent of trials cited the MTD as their primary endpoint and 10.8% of studies did not define an MTD/RP2D. The median (range) ratio of pediatric to adult RP2D for small molecule phase studies (n = 41) was 1.13 (0.45-11.9). The median (range) ratio for phase 1 studies of biologic agents (n = 6) was 1.15 (0.6-1.6). Conclusions: Consistent with prior reports, more males than females were enrolled on pediatric phase 1 studies and racial and ethnic characteristics continued to be underreported. The majority of trials used the MTD as the primary endpoint. While there was some variability based on evaluated agent, the pediatric RP2D of the small molecule and biologic agent was similar to that determined in the adult population. These results are consistent with similar evaluations of pediatric phase 1 studies of conventional chemotherapy.
Phase I/II, first in human trial of the Bruton’s tyrosine kinase inhibitor (BTKi) M7583 in patients with B cell malignancies.
Authors: Rule Simon , Tucker David , Kalapur Anup , Sarholz Barbara , Scheele Jürgen , Zinzani Pier Luigi
Published: September 2018

e14101

Background: BTK is a cytoplasmic tyrosine kinase expressed in cells of hematopoietic origin that is involved in innate and adaptive immunity. BTK inhibition blocks B-cell functions including proliferation, antigen presentation, antibody production, and cell migration. The B-cell receptor pathway is implicated in the pathogenesis of B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and B-cell chronic lymphocytic leukemia (CLL). Small molecule BTKis are a new class of agent against B-cell malignancies; ibrutinib has recently been approved for the treatment of resistant/refractory CLL, MCL, and Waldenström’s macroglobulinemia (WM). This ongoing phase I/II clinical trial (NCT02825836) is designed to determine the safety, tolerability, PK, BTK occupancy, and preliminary antitumor activity of the highly selective BTKi M7583 in patients (pts) with refractory/resistant B cell malignancies. Methods: The trial is in two parts: a dose-escalation part for which pts with refractory/resistant B cell malignancies are eligible; and a dose-expansion part for which pts with DLBCL (ABC subtype) or MCL who have failed 1-3 prior lines of therapy are eligible. Pts in the dose-escalation part will be enrolled to sequential dose escalation, with ascending once-daily M7583 doses starting at 80 mg (3 initial days)/160 mg (full 28-day cycle) and increasing according to an adaptive Bayesian design. Results: Three pts have been enrolled to treatment with M7583 80/160 mg (Table). All 3 patients have had an objective response or stable disease and relevant clinical benefit.Conclusions: M7583 appears to have a favorable benefit:risk profile, with an efficacy signal at a dose of 80 mg (3 initial days)/160 mg (full cycle) with objective response or clinical benefit. Clinical trial information: NCT02825836. [Table: see text]
Targeting polo-like kinase 1 and TRAIL to enhance apoptosis in non-small cell lung cancer (NSCLC) cells.
Authors: Noor Alfiah , Umelo Ijeoma Adaku , Kronenberger Peter , Teugels Erik , De Greve Jacques
Published: September 2018

e14104

Background: TNF-related apoptosis-ligand (TRAIL) can selectively induce apoptosis in cancer cells without causing damage to normal cells. However, some tumors are resistant to TRAIL monotherapy and clinical studies assessing targeted agents towards the TRAIL receptor have failed to show robust therapeutic activity. A number of studies have reported that the combination of targeted agents against the TRAIL receptor with standard systemic therapy and another targeted therapy considerably increased anti-tumor activity in experimental NSCLC models. Polo like kinase 1 (PLK1) is an emerging anti-mitotic target for NSCLC with high selectivity. Depleting PLK1 has been shown to reduce cell proliferation and induce apoptosis in NSCLC cells but not in normal cells. Both PLK1 and TRAIL-induced apoptosis pathways are important in supporting the malignant phenotype. We postulated that inhibiting PLK1 could enhance TRAIL-induced apoptosis. We therefore combined human recombinant TRAIL (rhTRAIL) and the PLK1 inhibitor RO3280, and studied the effect of combinatorial treatment on NSCLC cells. Methods: Cell growth was assessed by MTS assay and apoptotic activity by FACS and western blot analysis. The effect of combinatorial treatment on MAPK/ERK, PI3K/Akt and JAK/STAT signaling pathways that play an essential role in the survival of NSCLC cells were investigated by western blot analysis. Results: In this study, we demonstrate that the combination of a rhTRAIL with RO3280 synergistically reduces cell growth and strongly increases apoptotic activity in NSCLC cells. In response to RO3280 treatment, STAT3 activity is inhibited, possibly contributing to the sensitization of NSCLC cells to TRAIL-induced apoptosis. Blockade of STAT3 activity with a STAT3 inhibitor (stattic) and siRNA-mediated knockdown of STAT3 significantly enhances TRAIL-induced apoptosis in NSCLC cells. Conclusions: Our results suggest that this synergistic effect might occur through the inhibition of STAT3 activity which in turn may further contribute to the sensitization of the NSCLC cells to TRAIL therapy. Taken together, our results support the further exploration of PLK1 inhibitors in combination with TRAIL therapy in the treatment of NSCLC.
A novel function of SMC1 as a transporter of xenobiotics.
Authors: Yendala Rachana , Tijani Lukman , Thein Kyaw Zin , Igid Henry Palangdao , Shanshal Mohamed , Awasthi Sanjay , Hardwicke Fred L.
Published: September 2018

e14107

Background: Structural Maintenance of Chromosome 1 (SMC1) is a component of the cohesin complex involved in the DNA-damage repair. Studies have shown that it is overexpressed in Colon Ca, Glioblastoma ,Triple-negative breast cancer (TNBC) and contributes to their characteristic drug resistance. Because of its structural homology to the ABC-membrane transporter proteins (mediate multi-drug resistance in cancer cells by catalyzing ATP-dependent efflux of many structurally unrelated amphiphilic xenobiotics) and because of its marked over-expression in tissues of knockout mice lacking the other known transporter RLIP76 (RALBP1), the present studies were directed at determining whether SMC1 was present in plasma membrane and could function as a multi-drug transporter capable of mediating multi-drug resistance. Methods: The intracellular localization of SMC1 was performed by immunocytochemistry in fixed and live H358 cells (human non small cell lung cancer cells). We demonstrated, for the first time that SMC1 can be purified to apparent homogeneity using a GS-E affinity chromatography method. Transport activity of SMC1 was tested by reconstituting purified SMC1 into artificial liposomes, later transfected into H358 and TNBC cells with confirmed SMC1 overexpression. Accumulation and efflux of amphiphilic chemo drugs were compared to control cells. Results: Immunofixation studies demonstrated no detectable immunological cross-reactivity between SMC1 and Ralbp1.SMC1 was found in the plasma membrane ,cytosol and nucleus.The uptake of Doxorubicin and Vinblastine in transfected cells was significantly lower and were two-fold resistant to DOX as compared with controls. These cells, when treated with SMC1 antibody/antisense also confirmed increased drug cytotoxicity as well as apoptosis. Conclusions: This study provides convincing evidence for the distribution of SMC1 in the plasma membrane, cytosol, and nucleus. It functions as a drug-transporter reducing intracellular accumulation of chemotherapy drugs in cancer cells.These findings indicate a dual role in defending these from apoptosis and suggest that strategies aimed at inhibiting SMC1 could be useful in reversing intrinsic or acquired drug-resistance of cancer cells.
Tracking the interplay between circulating and tumor-infiltrating T cells using AmpliSeq-based Ion Torrent TCRβ immune repertoire sequencing.
Authors: Looney Timothy , Lowman Geoffrey , Linch Elizabeth , Topacio Denise , Miller Lauren , Lin Lifeng , Pankov Aleksandr , Au-Young Janice , Andersen Mark , Mongan Ann , Hyland Fiona
Published: September 2018

e14518

Background: TCRβ immune repertoire analysis by next-generation sequencing is emerging as a valuable tool for research studies of the tumor microenvironment and potential immune responses to future cancer immunotherapy. Here we describe a multiplex PCR-based TCRβ sequencing assay that takes advantage of the exceptionally low base-call error rate and long read capability of the Ion S5 530 chip. The S530 chip provides > 15M reads, allowing for sample sequencing in multiplex. The research assay utilizes AmpliSeq technology and Framework 1 and Constant gene targeting primers to provide comprehensive coverage of TCRβ CDR 1, 2 and 3 from RNA input with a hands-on time of less than 30 minutes. CDR region sequences reveal the antigen specificity of the receptor and may be genetically modified to increase TCR affinity for tumor antigen. Methods: We evaluated assay performance by sequencing TCRβ rearrangements from normal donor peripheral blood leukocyte (PBL) cDNA that had been spiked with 30 reference rearrangements taken from the literature. We then used our assay to evaluate the extent of clonal overlap between matched tumor infiltrating lymphocyte (TIL) and peripheral blood leukocyte repertoires in an individual with squamous cell carcinoma of lung. Results: Results from sequencing of spike-in reference rearrangements indicate that the assay is accurate and sensitive over 5 logs of input template amount while showing minimal amplification bias. Sequencing of matched PBL and TIL repertoires revealed that a subset of the PBL repertoire (8%) consisted of clones also found in TIL. Technical replicates showed high concordance (r > .96) in the frequency of detected clones, indicating that the results were reproducible and samples were sequenced to an appropriate depth. Conclusions: In summary, these data suggest that AmpliSeq-based multiplex PCR and Ion Torrent sequencing provide unbiased, reproducible, scalable, complete, and accurate information for immune repertoire research sequencing applications.
Hyponatraemia as an unrecognised risk factor in non-small cell lung cancer (NSCLC) treatment with nivolumab.
Authors: Grohe Christian , Gwynn Simon , Evans Richard
Published: September 2018

e14526

Background: The investigation, diagnosis and management of hyponatraemia is often inadequate in cancer patients. In a retrospective analysis of 3,357 cancer patients hyponatraemia was noted in up to 47%. A strong and independent association between hyponatremia and longer length of stay with higher mortality was highlighted and associated with standard chemotherapy. No pooled data, however are available on the effect of immuno-oncology (IO) treatment options such as nivolumab on HN in lung cancer patients. Methods: Key publications and data registries concerning the incidence, evaluation and management of hyponatraemia in patients with NSCLC and treated with nivolumab were analysed. Our data show that hyponatraemia is a common side effect and around 5.2% of patients treated with nivolumab progressed from baseline to a Grade 3 / 4 adverse event. Results: The aetiology of hyponatraemia in cancer patients is complex, appearing to be a negative prognostic indicator. Existing data show that effective treatment of hyponatraemia in cancer patients may be associated with reduced mortality. In addition, the role of sodium on the cancer cell cycle requires further investigation. It has been shown in vitro that a hypotonic environment is pro-tumorigenic, whereas a slightly hypertonic environment may have a negative impact on clonogenicity in prostate cancer cells. This may suggest a more complex interaction impacting on cancer patients other than a simplistic mortality association with hyponatraemia. Nivolumab treatment is associated with HN and particular attention should be paid to the correction of symptomatic HN in these patients. Conclusions: Hyponatraemia is the most commonly occurring electrolyte disturbance in cancer patients and may represent a modifiable risk factor impacting patient survival. The clinician should be aware of the potential for IO therapies to precipitate hyponatraemia. Consideration of the correct diagnosis and management of hyponatraemia may further enhance the prognosis of NSCLC patients treated with IO agents.
Hyponatraemia as a risk factor in renal cell carcinoma treatment with nivolumab.
Authors: Grohe Christian , Gwynn Simon , Evans Richard
Published: September 2018

e14528

Background: In the general hospital population, the incidence of hyponatraemia is reported at varying levels up to 40%. In a retrospective analysis of 3,357 cancer patients (4,702 admissions) hyponatraemia was noted in 47%. A strong and independent association between hyponatraemia and longer length of stay with higher mortality was highlighted. The investigation, diagnosis and management of hyponatraemia is often inadequate in cancer patients. This poster offers recommendations for the improved diagnosis and management of hyponatraemia patients with renal cell carcinoma treated with nivolumab. Hyponatraemia occurs in 20% of patients with renal cell carcinoma and is associated with reduced survival. Patients with hyponatraemia before treatment had a median overall survival of 5.5 months compared with 18.6 months for those with normal sodium values. Methods: Key publications concerning the incidence, evaluation and management of hyponatraemia in patients with RCC as well as unpublished data from Phase III registration studies were reviewed and the data examined to consider impacts on current oncology practice Results: Hyponatraemia is a negative prognostic indicator in cancer. Data show that effective treatment of hyponatraemia in cancer patients reduces mortality. It has been shown in vitro that a hypotonic environment is pro-tumorigenic, whereas a slightly hypertonic environment may have a negative impact on clonogenicity. This may suggest a more complex impact on outcomes in cancer patients than simply the mortality associated with hyponatraemia. The presentation of hyponatraemia in cancer patients is complex and may be caused by the direct impacts of disease, iatrogenic factors or different treatment approaches Conclusions: Hyponatraemia is the most commonly occurring electrolyte disturbance in cancer patients, potentially representing a modifiable risk factor, with resultant impact on patient survival. The clinician should be aware of the potential for Immuno-oncology agents to precipitate hyponatraemia and consider that the correct diagnosis and management of hyponatraemia may further enhance efficacy and survival.
Correlation of QNBC immune and basal signature to targeted therapies and race.
Authors: Hughley Raymond Wesley , Dean-Colomb Windy Marie , Tripathi Shweta , Davis Melissa , Yates Clayton Clopton
Published: September 2018

e14537

Background: Triple Negative Breast Cancer has been identified as one of the most aggressive breast cancer subtypes. We previously identified a subtype of TNBC, which lacks the androgen receptor (AR), which we coined quadriple negative breast cancer (QNBC). We have shown that women with QNBC have a worse prognosis compared to those with just TNBC. Additionally, we have noted that African American (AA) women with TNBC have a greater chance of having QNBC (28%) and a higher rate of disease progression (25%) vs Caucasian Americans (CA). We also found these QNBC patients have a unique immune signature that correlates to the more aggressive basal subtype. Here, we explore individual genes and their correlation to race and immune therapies. Methods: We analyzed mRNA expression in 925 tumors from CA or AA women from The Cancer Genome Atlas. Samples were dichotomized as positive or negative using mean gene expression cutoff. Gene expression comparisons among groups were determined using standard t-tests, ANOVA, and odds ratios with a significance threshold alpha of 0.05. Therapy targets were selected from the list of significantly differentiated genes. Boxplots and heatmaps were made using R packages. Cumulative Incidence plots for time to progression were constructed using XLStats and Grays test for significance. Results: QNBC CA have higher expression of PDCD4 (p < .001), CD46 ( p < .001), CD3EAP ( p = .04) and CD84 ( p = .07) compared to QNBC AA. CD47 ( p = .63) and PD1 (p = .96) express no significant differences in race. QNBC AA show higher expression of NFKB ( p < .001), CCL2 ( p < .001), and IL12 ( p < .001) compared to QNBC CAs. Interestingly, QNBCs with high expressions of CD47 ( p = .04) have poor prognosis. Thus, QNBC patients with low expression of CD46 (p = .025), PDCD4 ( p < .001), and CD3EAP ( p < .001) have poor prognosis and overall survival. Conclusions: Current immune targeted therapies like CD47 and PD1 looks favorable for treatment in some QNBC patients. Race appears to effect other major therapy target gene expressions in the QNBC immune basal signature as well. This may imply that QNBC AA and CA have different immune response which may explain racial progression differences. Assessment of immune markers may contribute to more accurate prognosis.
Effect of BL-8040, high-affinity CXCR4 antagonist, on T-cell infiltration, tumor growth, and synergy with immunomodulatory agents.
Authors: Abraham Michal , Mishalian Inbal , Harel Yaniv , Klein Shiri , Pereg Yaron , Oberkovitz Galia , Wald Hanna , Eizenberg Orly , Bulvik Baruch , Vainstein Haras Abi , Aharon Arnon , Peled Amnon
Published: September 2018

e14544

Background: Cancer cells affect their micro-environment by recruiting immune cells that support tumor growth, metastasis and inhibition of anti-tumor effector T and NK cell recruitment. In this study, we investigated the role of BL-8040, a CXCR4 antagonist in cancer immunotherapy and its ability to modulate the immunosuppressive tumor micro-environment. Methods: The effect of BL8040 on tumor micro-environment was tested in 3 different cancer mouse models: lung cancer, pancreatic cancer and melanoma. The mobilization of immune cells to the periphery in response to BL8040 was tested, as well as the accumulation of immune cells both within and surrounding the tumor in the pancreatic cancer mouse model. Results: BL8040 was found to be a potent and robust mobilizer of immune cells. Immunophenotyping of the mobilized cells revealed that the mobilization of CD4 and CD8 T lymphocytes, as well as of dendritic cells (DC), was significantly increased in the cancer-bearing mice compared to their naïve counterparts. Importantly, a significant mobilization of effector CD8 T cells and activated CD8 T cells in the cancer-bearing mice was also detected following BL8040 treatment. Concomitantly, in the pancreatic cancer mouse model, treatment with BL8040 increased CD8 T cell accumulation within the tumor and inhibited tumor growth. Conclusions: The immune cell population that is mobilized in response to BL8040 treatment is different in cancer mouse models and naïve mice. The ability of BL8040 to induce mobilization of leukocytes, cytotoxic and activated CD8 T cells and DCs is affected by the presence of a tumor. In our models of pancreatic cancer, mobilization of immune cells from the bone marrow into the circulation and their accumulation within the tumor and tumor microenvironment resulted in inhibition of tumor growth. These results indicate that BL8040 may affect the tumor microenvironment and therefore can potentially synergize with immunomodulatory agents. In vivo pre-clinical studies as well as clinical studies are currently ongoing for testing the combination of BL8040 with immunomodulatory agents in different cancer models.
Efficacy of CD19-targeted chimeric antigen receptor T cells in the treatment of relapsed extramedullary B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL).
Authors: Hu Yongxian , Wu Zhao , Yu Jian , Wang Jiasheng , Wei Guoqing , Wu Wenjun , Luo Yi , Shi Jimin , Xiao Lei , Huang He
Published: September 2018

e14549

Background: Chimeric antigen receptor T cells directed at CD19 (CART19) have shown promising results in the treatment of refractory/relapsed acute lymphoblastic leukemia and chronic lymphocytic leukemia. Evidence of efficacy on mass lesions such as extramedullary ALL and non-Hodgkin’s lymphoma is still emerging. Methods: Patient-derived T cells were transfected ex vivo with lentiviral vector encoding anti-CD19 scFv, human 4-1BB, and CD3ζ signaling domains. 2 patients with relapsed extramedullary ALL and 2 patients with relapsed DLBCL were enrolled (median age 25.5, range 17~35). Lymphodepletion regimens were fludarabine 50mg/m2 infused over 3 days, and cyclophosphamide 750mg/m2 infused over 3 days in DLBCL patients or over 2 days in ALL patients. CART19 were infused one time or fractionated over 3 days with dose from 1×106/kg to 1×107/kg. Results: The 2 ALL patients received prior allogenic HSCT; one relapsed with isolated testicular ALL, the other with mammary/axillary lymph node ALL with 15% blast cells in the bone marrow. The other two patients relapsed with DLBCL. After CART19 therapy, all patients achieved complete remission (CR) within a median of 30d (range 29~52d). With a median follow up of 53.5d (range 52~153d), the 2 DLBCL patients remained in CR; the testicular B-LBL patient relapsed with isolated testicular involvement on +153d and received a second CART19; the other B-LBL patient relapsed with isolated bilateral mammary glands involvement on +52d and remained in stable disease. Grade 2 cytokine release syndrome (CRS) were observed in the 2 DLBCL patients (50%). CRS self-resolved within 10d without treatment. Conclusions: CART19 was effective and safe against mass lesions such as relapsed extramedullary ALL and DLBCL with high CR rate. CART19 can induce rapid remission in lymphoma patients around one month.
Evaluation of safety and efficacy of ipilimumab and nivolumab (ipi+nivo) combination in patients (pts) previously treated with anti-PD-1 antibodies (PD1): A single-center experience.
Authors: Park Soo , Daniels Gregory A.
Published: September 2018

e14556

Background: All clinical trials studying ipi+nivo have involved treatment-naive pts. Knowledge about the safety and efficacy of ipi+nivo is limited for pts previously treated with PD1. Methods: Nine pts were retrospectively evaluated and treated with ipi (3 mg/kg) and nivo (1 mg/kg) q3wk for 4 doses followed by maintenance nivo q2wk after progression on PD1 from 10/2014 to 11/2016. Data regarding clinical history, treatment response, and toxicity were collected. Results: Six pts had advanced melanoma, 2 pts had metastatic HNSCC (mHNSCC), and 1 pt had recurrent parotid myoepithelial carcinoma. Age ranged from 44 to 86. Eight pts had ECOG PS 0-1; 1 pt had ECOG PS 2. Three melanoma pts were BRAF+; 1 was BRAF WT and 2 were NRAS+. Both mHNSCC pts were p16+. Pts received a median of 3 prior lines of treatment including chemotherapy and immune treatments encompassing ipi, PD1, 4-1BB agonist, autologous TILs, high-dose IL2, IFN, T-VEC, and TLR8 agonist. All 9 pts received pembro prior to ipi+nivo; 1 pt received both pembro and nivo separately. Median number of PD1 doses prior to ipi+nivo was 10 (range 3-13). All 9 pts received all 4 doses of ipi+nivo without delay. Seven pts received nivo maintenance for median number of 11 cycles (range 1-22). Two pts were unable to receive nivo maintenance due to progressive disease (PD) and instead were treated with ipi+T-VEC and BRAF/MEK inhibition. Objective responses were seen in 6/9 pts (67%) with 2 radiological CRs and 4 radiological PRs. PD was seen in 3/9 pts (33%) including in the 1 pt with ECOG PS 2; all 3 pts died from clinical deterioration unrelated to ipi+nivo treatment. CRs were observed in 1 BRAF+ and 1 NRAS+. 7/9 pts (78%) had ≥1 clinically significant irAE and 3 of these pts required systemic steroids. Five pts are still receiving maintenance nivo with clinical benefit. One pt with CR was taken off nivo maintenance, remains disease-free, and is now on surveillance. Conclusions: Ipi+nivo demonstrated significant anti-tumor activity in pts previously treated with PD1. The toxicity profile is consistent with known irAEs. While this is a small series, these data support the use of ipi+nivo after PD1 failure.