bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glioblastoma-derived cells exhibit differential responses to glycolysis inhibition under hypoxia
Authors: Pistollato F. , Abbadi S. , Rampazzo E. , Viola G. , Della Puppa A. , Cavallini L. , Panchision D. M. , te Kronnie G. , Basso G. 
Published: August 2020

e13031 It has been suggested that oxygen tension is a crucial component of the brain tumor niche, as hypoxia positively correlates with tumor aggressiveness and over-activity of hypoxia inducible factor-1α (HIF-1α) reinforces tumor progression. Furthermore, hypoxia has been implicated in the regulation of several signaling pathways (Notch, BMP), angiogenesis and importantly, glucose metabolism. Here we investigate the effects mediated by in vitro glycolysis inhibition by using 2-deoxyglucose (2-DG) in glioblastoma (GBM) derived cells maintained under two different oxygen tensions, a lowered oxygen tension (2%) versus a higher non-physiological (20%). GBM account for 50% of all gliomas and arise after age 50 in most patients and it has been seen that younger patients tend to have a better prognosis than the elderly. Our results show that adult GBM displaying a highly immature phenotype manifested the highest resistance to glucose deprivation. Furthermore, increase of multi-drug resistant cell fraction, described as side population, occurred following 2-DG treatment, but only under hypoxia. Neuronal committed precursors were selected by 2-DG, but these effects were mitigated by hypoxia. Also, hypoxia inhibits the mitochondria-controlled apoptosis induced by 2-DG, by conferring cell resistance through progressive activation of pro-survival NF-kB and induction of tumor cell autophagy. Importantly, HIF-1α level reduction and proline hydroxylase 2 (PHD2) upregulation occurred following 2-DG treatment even under hypoxia, and this may depend on reactive oxygen species reduction. These results indicate differences in tumor cells behavior that may be predictive of cell response to therapy aiming to limit glucose uptake or glucose metabolism. No significant financial relationships to disclose.
Preliminary results of an open-label phase I pharmacokinetic/pharmacodynamic study of JNJ26481585: Early evidence of antitumor activity
Authors: Postel-Vinay S. , Kristeleit R. , Fong P. , Venugopal B. , Crawford D. , Van Beÿsterveldt L. , Fourneau N. , Hellemans P. , Evans J. , De-Bono J. 
Published: August 2020

e13504 Background: JNJ26481585 is a novel orally active pan-histone deacetylase inhibitor (HDACI) which showed potent antitumor efficacy in a wide range of animal tumor models. Methods: A 2-stage accelerated titration design Phase I trial was conducted to characterize safety, establish the maximum tolerated dose (MTD) and determine pharmacokinetics in patients (pts) with refractory solid tumors, of performance status <2 and with adequate hematologic, renal, hepatic and cardiac function. The drug was administered orally, once daily in 3 weekly cycles. Results: To date, 9 pts (median age 59; range 32–74) have been treated at 4 dose levels (DL): 2 (2 pts), 4 (2 pts), 8 (3 pts), and 12 (2 pts) mg. The median number of cycles administered was 2 (range 1–9). Dose-limiting toxicity was seen at 12mg (CTCAE Grade [G] 3 non-sustained ventricular tachycardia [VT] [1 pt] and G3 fatigue [1 pt]) and the 8mg cohort is being expanded. Other toxicity observed at 12mg comprised G2 palpitations with QT prolongation (1 pt), G2 anorexia (1 pt), G2 vomiting (1 pt) and G2 dysgeusia (1 pt). At 8mg, 1 pt on warfarin developed a G2 INR increase. Non-specific ECG changes were observed from the 2mg DL onwards. The drug was generally well tolerated up to 8mg. Exposure to JNJ26481585 increased proportionally over the 2 to 12mg dose range, with a constant metabolite/parent ratio (3.5 for Cmax; 7 for AUC). Two partial responses (PR) and one stable disease (SD) have been observed. PR occurred in 2 pts with metastatic melanoma treated at 12mg : one pt had a PR in visceral and complete response in subcutaneous melanoma metastases after 22 days of drug and has ongoing response 5 months after stopping treatment; the second pt had PR in lymph nodes and reduction of cutaneous lesions of melanoma. One non small cell lung cancer pt treated at 4mg showed SD for 9 cycles. Assessment of histone acetylation as a pharmacodynamic biomarker in peripheral blood lymphocytes and hair follicles is ongoing. Conclusions: JNJ26481585 is generally well tolerated at doses up to 8mg daily. Evidence of promising antitumor activity has been observed with 2 PR to date in patients with metastatic melanoma. The 8mg cohort is being expanded with increased cardiac monitoring. Other schedules may be explored in the future. [Table: see text]
Integrated safety findings with tesetaxel, an orally administered taxane, in patients (pts) with gastric, colon, breast, and nonsmall cell lung cancer: Phase II results
Authors: Novick S. C. , Wu J. , Ilson D. 
Published: August 2020

e13516 Background: The orally active taxane tesetaxel has potent cytotoxic activity against various human and murine cancer cell lines in vitro and in xenograft tumor models, including those that express P-glycoprotein (pgp). In a Phase 1 study, 48 pts with advanced solid tumors were treated at doses of 1.5 mg/m2 to 40 mg/m2. AUC and Cmax increased in a dose-proportional manner. There was no dose-limiting toxicity (DLT) at doses ≤18 mg/m2. Above 18 mg/m2, Grade 4 neutropenia > 5 days in duration was the most common DLT. The MTD was 27 mg/m2 for heavily pretreated pts and 35 mg/m2 for minimally pretreated pts. These doses were further evaluated in a Phase 2 program in 4 studies, and activity was demonstrated in gastric, colorectal, breast, and non-small cell lung cancers. To assess safety across all indications prior to beginning randomized trials, we conducted an integrated analysis of the safety of the 27 mg/m2 dose as initial therapy in Phase 2. Methods: All pts had been previously treated with a nontaxane regimen. Tesetaxel was given on Day 1 of a 21-day cycle; the dose was rounded to the nearest 10 mg. Prophylactic treatment with such drugs as antiemetics and colony- stimulating factors (CSFs) was permitted only after Cycle 1. Results: A total of 142 subjects received tesetaxel 27 mg/m2 as initial therapy. The most common Grade 3–4 adverse events were neutropenia (33%), leukopenia (22%), and anemia (11%). Grade 3–4 neuropathy was distinctly uncommon (3%). Conclusions: Taxanes are highly active in solid tumors, but most are associated with neurotoxicity and infusion reactions. Oral tesetaxel eliminates infusion reactions and consequent requirements for extended observation and premedication, is associated with a low incidence of Grade 3–4 neurotoxicity, and may be useful in diseases associated with high pgp expression. Like other taxanes, the most common adverse event is neutropenia, which can be ameliorated with appropriate monitoring and use of CSFs. These and other safety considerations will be incorporated into planned registration trials. [Table: see text]
Cardiovascular safety profile of IPI-504 (retaspimycin hydrochloride), a novel Hsp90 inhibitor: Results from two independent phase I trials in patients with advanced cancer
Authors: MacRae C. , Richardson P. G. , Walker J. , Grayzel D. S. , Demetri G. D. 
Published: August 2020

e14539 Background: Heat shock protein 90 (Hsp90) is a protein chaperone that regulates the proper folding, stability, and function of multiple mutated and wild type signaling proteins that promote malignant phenotypes. Numerous clinical trials are investigating the activity of the Hsp90 inhibitor IPI-504. Since Hsp90 is a novel cancer target that is ubiquitously expressed in normal cells, a comprehensive evaluation of potential cardiac effects, including the risk of ventricular arrhythmia, was performed in two Phase I trials. Methods: ECG data were pooled and analyzed from 60 pts in two-open label Phase I trials of patients with advanced cancers. Pts received 90 to 400 mg/m2 of IPI-504 IV twice weekly for 2 out of 3 weeks. Subset analyses for 35 pts who received the MTD of 400 mg/m2 were performed. ECGs were obtained in triplicate at 5, 60, and 360 minutes after IPI-504 infusion. Interpretation was conducted at a central, independent laboratory. Results: Over 6,500 ECGs were obtained from 60 pts. At the MTD 3,000 ECGs were obtained from 35 patients. No ventricular arrhythmias or changes in QTcF of ≥60 msec were noted, and no statistically significant relationship between the concentration or dose of IPI-504 and QTcF was observed. At the MTD 5 minutes post infusion, changes from baseline were observed in QTcF (5.4 ms increase), heart rate (15.2 bpm decrease), and PR interval (27.9 ms increase). All of these changes reversed by 6 hours post-infusion and no clinical hemodynamic disturbances were observed. Conclusions: In phase I studies, IPI-504 was not associated with any significant ventricular arrhythmia and no clinically significant QTcF interval changes were noted. These studies did show however that IPI-504 administration was associated with transient, dose-related bradycardia and PR interval lengthening, suggestive of autonomic effects associated with the drug infusion. No clinically significant and IPI-504 related cardiac safety events were observed at the MTD dose of 400 mg/m2. Given these findings, appropriate monitoring of heart rate immediately post-infusion is recommended during further studies with IPI-504. [Table: see text]
Results from a phase I safety lead-in study investigating the combination of erlotinib and the histone deacetylase inhibitor entinostat in patients with advanced NSCLC
Authors: Konduri K. , Spira A. I. , Jotte R. M. , Boyd T. , Boyd T. , Gaffar Y. A. , Reynolds C. , Witta S. E. 
Published: August 2020

e14545 Background: Preclinical studies showed the synergistic effect of entinostat with epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) in NSCLC cell lines. Entinostat (SNDX-275, Syndax Pharmaceuticals) is an oral, class 1 isoform selective HDACi that restores the expression of e-cadherin and sensitivity to EGFR-TKI in NSCLC cell lines. The aim of this study was to determine the safety and feasibility of combining entinostat with erlotinib in advanced NSCLC patients in order to determine the recommended Phase 2 dose. Methods: Patients with recurrent or metastatic NSCLC whose tumors progressed on prior chemotherapy were treated with either 5 or 10mg orally of entinostat once every two weeks and erlotinib 150mg daily. Results: A total of 9 patients were enrolled (3 at entinostat 5mg; 6 at 10mg). Characteristics: Sex: M/F: 6/3; Age range: 46–84 yrs; ECOG PS: 0–1; Smoking status: 1/8 (never/current or prior smokers); Number of prior treatments: 1–2. There was one DLT of grade 3 asthenia. This occurred in one of the six patients in the 10mg dose cohort. The most common adverse events were anorexia, and asthenia. This was more often noted in elderly patients. Of the 9 evaluable patients, one patient had a confirmed partial response and remains on study (>5 cycles) and another patient had stable disease for 8 months. Pharmacokinetic analysis has been completed with both drugs exhibiting levels comparable to historical data. No drug:drug interaction was observed. EGFR FISH, EGFR mutation, and epithelial-to-mesenchymal marker analysis is in progress. Conclusions: This study has established the safety and a recommended phase 2 dose of 10 mg of entinostat once every other week in combination with 150 mg daily of erlotinib in a 28-day cycle in advanced NSCLC patients. A randomized, double blinded phase 2 study has been initiated with 43 patients enrolled to date. [Table: see text]
Combination of bortezomib with a FLT3 inhibitor potentiates inhibition of proliferation and apoptosis of AML in vitro
Authors: Cheng P. C. , Crane J. , Hunter T. 
Published: August 2020

e14551 Background: FLT3 receptor tyrosine kinase activating mutations contribute to leukemogenesis and poor prognosis in approximately 30% of acute myeloid leukemia (AML). An internal tandem duplication (ITD) mutation in the juxtamembrane domain of FLT3 results in loss of autoinhibition that leads to constitutive, ligand-independent activation of the receptor, with subsequent activation of multiple downstream signaling pathways, including RAS/MAPK and STAT5. Early phase clinical trials of FLT3 inhibitors show a lack of durability of responses, suggesting combination therapy may work better. Methods: In the course of conducting a synthetic lethality screen with a FLT3 inhibitor on the Ba/F3 murine cell line stably expressing human FLT3 or FLT3-ITD, we identified bortezomib, a proteasome inhibitor, as having potent activity against FLT3-ITD cells. The effects of drugs on proliferation, apoptosis, and phosphosignaling were quantified in Ba/F3 cells and in the HL60 (WT FLT3) and MV4–11 (FLT3-ITD) human cell lines, using an MTS- based colorimetric assay, caspase 3 and 7 activity assays, and immunoblotting, respectively. Results: A highly potent and specific FLT3 inhibitor was shown to have an IC50 of 1.9 nM, inhibiting proliferation, inducing apoptosis, and abrogating downstream STAT5 and ERK phosphorylation in FLT3-ITD cells. The IC50 of bortezomib for FLT3-ITD cells was 10 nM as compared to an IC50 of 40 nM for WT FLT3 cells. Surprisingly, bortezomib abrogated tyrosine phosphorylation of FLT3, STAT5, and ERK within 60 min of adding drug. When the FLT3 inhibitor and bortezomib were used at IC25 concentrations, a more pronounced inhibition of cell proliferation was observed when they were used in combination than with either alone. Conclusions: Bortezomib preferentially kills FLT3- ITD cells, showing a four-fold more potent inhibition of cell proliferation, induces apoptosis, and abrogates activation of FLT3 and its downstream effector pathways. The combination of proteasome inhibition with FLT3 inhibition results in enhanced cytotoxicity. The mechanism by which bortezomib affects the FLT3-ITD signaling axis and the possible synergy with FLT3 inhibitors remains to be elucidated. No significant financial relationships to disclose.
Effect of a mouth rinse formulation with human trefoil factor 1-secreting Lactococcus lactis in experimental oral mucositis in hamsters
Authors: Rottiers P. , Caluwaerts S. , Steidler L. , Vandenbroucke K. , Watkins B. , Sonis S. , Coulie B. 
Published: August 2020

e14570 Background: Oral mucositis (OM) is a painful and dose-limiting toxicity of cancer chemotherapy and irradiation, characterized by breakdown of the oral mucosa. Trefoil factors (TFFs) are involved in protecting and healing mucosal tissue, and might thus represent a pharmacological tool for treatment of OM. Local delivery of recombinant TFFs at the oral mucosa by living, genetically modified Lactococcus (L.) lactis bacteria (ActoBiotics) seems a promising, safe and cost-effective clinical approach for the prevention and attenuation of oral mucositis. Methods: An environmentally contained Lactococcus lactis strain (AG013), engineered to express human (h)TFF1, was formulated for topical administration in the form of a mouth rinse. Efficacy of AG013 was assessed in a clinically relevant hamster model of acute, radiation-induced OM. The dosing regimen was 1.3 x 109 CFU/dose, once (qd) or three rinses (tid) daily, from day 0 (=day of radiation) to day 18. OM was scored from day 6 to day 28 using the WHO grading scale, and compared to the score of placebo-treated hamsters. The viability and survival of live L. lactis and the pharmacokinetics of the hTFF1 secreted were studied in healthy and OM hamsters. Results: Topical application of AG013 to the oral mucosa significantly reduced the severity and course of radiation-induced OM. In the AG013-treated groups, the number of animals days with ulcerative mucositis (grade 3 or higher) was significantly reduced to 27.5% and 30.8% (qd and tid respectively; P < 0.001), compared to 45.8 % in the placebo-treated group. Based on the observed survival and weight changes, AG013 appeared to be well-tolerated. Pharmacokinetic studies demonstrated that both living L. lactis and the hTFF1 secreted could be recovered from the administration site, for maximum 24 hours post-dosing, without systemic exposure. Conclusions: Oral administration of AG013 is safe and effective in reducing the severity and the course of OM in the hamster model, and therefore supports proof-of-concept for a mouth rinse formulation of AG013 to treat OM patients. [Table: see text]
Phase I dose-escalation study of thoracic radiotherapy in combination with gefitinib in patients with IIIB/IV non-small cell lung cancer (NCT00497250)
Authors: Fan M. , Xie L. , Xu X. , Zhang G. , Chen J. , Fu X. , Zhou X. , Li W. , Jiang G. 
Published: August 2020

e14581 Background: Cinical studies have confirmed that gefitinib, an EGFR-TKI, is effective for some advanced NSCLC patients. Patients with Asian ethnicity are reported to have a higher response rate with gefitinib monotherapy. However, a higher incidence of interstitial lung disease, sometimes lethal, is also found. The combination of gefitinib and radiotherapy has been observed to have a synergistic, anti-proliferative effect against NSCLC in vitro. This phase I study assessed the safety, clinical feasibility and optimally tolerated regimen (OTR) of this combination in patients with pretreated locally advanced or metastatic (IIIB/IV) NSCLC. Methods: Patients with stage IIIB or selected stage IV, failure of platinum-based chemotherapy regimen NSCLC were eligible. Four Cohorts of eight patients each were planned to be treated with escalating doses from 54 to 60 Gy of conformal or intensity- modulated radiotherapy (2Gy/Fx) administered in combination with gefitinib 250mg daily during RT and 60 days after the completion of RT to determine the OTR. Results: Since June 2007, 2 cohorts, a total of 16 patients, were enrolled and treated: 8 stage IIIB and 8 stage IV; 2 squamous-cell carcinoma and 14 adenocarcinoma; 8 smokers and 8 nonsmokers. Prior-chemotherapy regimen was consisted of NP, GP and TP for a median of 3.5 cycles (range, 1–5). Median follow-up time was seven months. Mean progression-free survival time was 5.2 months (median, 3.9; range, 1.7–12.3). Overall, adverse events were mild to moderate in severity. The most frequent grade 2 events included pneumonitis (31%) and dysphagia (19%). There were one treatment-related grade 3 event, which was nausea, and no grade 4 events. Most of the failure patterns were out-of-field (11/13) and the most common distant metastasis organ was the lungs. Three patients are progression-free to date. Conclusions: Thoracic radiotherapy up to 56 Gy concurrent with gefitinib 250 mg daily was well tolerated and clinically active in this group of pretreated Chinese NSCLC patients, including nonsmokers with adenocarcinoma. Accrual is continuing. Sponsorship: This work was partly supported by Program for New Century Excellent Talents in University (NCET), Ministry of Education. No significant financial relationships to disclose.
Plasma levels of 4-OHT with topical tamoxifen gel (afimoxifene) and therapeutic local antiestrogenic effect in premenopausal women with cyclical mastalgia
Authors: Goyal A. , Baruah B. , Le Nestour E. , Masini-Etévé V. , Mansel R. 
Published: August 2020

e14598 Background: 4-hydroxytamoxifen(4-OHT) is a potent anti-estrogenic metabolite of tamoxifen with a much higher affinity for estrogen receptors than tamoxifen. Methods: Plasma levels of 4-OHT in 19 premenopausal women taking 20 mg/d oral tamoxifen for at least 2 months were compared with those of 16 premenopausal women assigned to apply 4mg 4-OHT in a 0.228% Afimoxifene gel daily for 21 days in a pharmacokinetic(PK) study. To evaluate the clinical effectiveness of the gel, premenopausal women experiencing moderate-to-severe mastalgia were randomized to receive placebo, 2mg or 4 mg of Afimoxifene daily delivered as a transdermal hydroalcoholic gel for 4 menstrual cycles. The primary efficacy parameter was change in mean pain intensity, as measured by the VAS for the 7 worst pain score days within a cycle, from baseline to the 4th cycle. Results: In the PK studies, the 4-OHT plasma levels following oral tamoxifen were 16–18 times higher than 4-OHT levels following 4mg 4-OHT administration by topical gel. At steady state, mean Cmax levels in the Afimoxifene group and oral tamoxifen group were 149+99 pg/mL and 2398+901 pg/mL respectively. The Cave concentrations, derived from AUC0–24h/24, were 117+77 pg/mL (Afimoxifene) and 2078+811 pg/mL (oral tamoxifen). After 4 cycles of gel treatment, significant improvements relative to placebo were seen in mean VAS score in the 4-mg Afimoxifene group (-12.71 mm [95% confidence interval, -0.96 to -24.47; P = 0.034]). Patient global assessment of pain, physician assessment of pain, tenderness on palpation and nodularity following 4 cycles of treatment were significantly improved in the 4-mg group, compared with placebo (P = 0.010 [pain]; P = 0.012 [tenderness]; P = 0.017 [nodularity]). There were no changes in menstrual pattern or plasma hormone levels and no breakthrough vaginal bleeding in patients treated with Afimoxifene. Conclusion: Topical application avoids high systemic exposure to 4-OHT compared with oral tamoxifen, a 16–18-fold difference, thus reducing the risk of systemic side-effects. Afimoxifene is an effective treatment for moderate-to-severe mastalgia and potentially may be used for breast cancer chemoprevention and gynecomastia. No significant financial relationships to disclose.
Effect of (-)-gossypol (AT-101) on transcriptional regulation of Noxa and Puma and on Mcl-1-mediated cancer cell resistance to apoptosis
Authors: Wang S. , Jiang F. , Bai L. , Long J. Jianting , Qiu S. , Chen J. , McEachern D. 
Published: August 2020

e14611 Background: AT-101 is being evaluated in Phase II clinical trials for the treatment of human cancers and demonstrates anticancer activity as a single agent and in combination with docetaxel. Despite extensive investigations, the mechanism of action for its antitumor activity is not completely understood. In this study, we have performed detailed investigations using a panel of human cancer cell lines on the mechanism of action for AT-101. Methods: A series of human breast and prostate cancer cell lines were utilized to evaluate the antitumor activity of AT-101. Cell growth inhibition, cell viability and apoptosis were determined by WST assay, trypan blue assay and flow cytometry, respectively. Gene specific siRNAs were used to knockdown target gene expression. Quantitative RT- PCR was performed to detect the mRNA levels of Puma and Noxa. Co-immunoprecipitation was carried out to detect the association between Mcl-1 and Noxa or Puma. Results: AT-101 induced apoptosis in both Bax/Bak-dependent and -independent manners in a variety of human cancer cell lines concomitant with increased expression of Noxa and Puma in a p53-independent manner. The up-regulation of Noxa was not observed in normal primary breast epithelial cells or normal-like human breast epithelial MCF-12F cells. Transcription inhibitor actinomycin D blocked AT-101-induced up-regulation of Puma and Noxa. Knockdown of Noxa or Puma attenuated AT-101-induced apoptosis. Furthermore, AT-101 effectively overcame Mcl-1-mediated cancer cell resistance to apoptosis. Co-immunoprecipitation studies demonstrated that Mcl-1 specifically associated with Noxa but not Puma. Conclusions: Our findings suggest that transcriptional up-regulation of pro-apoptotic Noxa and Puma contributes to the antitumor activity of AT-101, which plays a dominant role in antagonizing Mcl-1 and overcoming Mcl-1-mediated resistance to apoptosis of cancer cells. AT-101 functions as an antagonist of Bcl-2, Bcl-xL and Mcl-1 through direct binding to these proteins, as well as through upregulation of Noxa and Puma. [Table: see text]