bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting of human cancers by miRNAs delivered by mesenchymal stem cell derived microparticles.
Authors: Epenetos Agamemnon A. , Prokopi Marianna , Pitsillides Costas 
Published: September 2018

e14062 Background: Recent data has shown that several oncogenic and tumor suppressor kinases that are deregulated in human cancers can be targeted via specific miRNA sequences. miRNAs can inhibit oncogenic kinase activity as well as upregulate tumor suppressor kinases in cancer cells, leading to inhibition of tumor processes such as invasion, migration and resistance to apoptosis. Examples include the inhibition of PLK1 activity that is overexpressed in breast, ovarian, pancreatic and colorectal cancers by the ectopic expression of miR-10b, miR-100 or miR-593, and the targeting of the increased FAK expression in breast cancer cells by miR-7. Methods: In this study, we have employed preclinical models of cancer disease and have utilized advanced genomics technologies in combination with innovative in vivo imaging techniques to conduct pharmacokinetics and pharmacodynamics studies as well as safety and efficacy studies in order to establish a mechanism of action and demonstrate that miRNA-loaded microparticles can interfere with tumor promoting kinase activity in vivo Results: Our results demonstrate that delivering specific miRNAs targeted against aberrant protein kinase activity may potentially be a novel approach to selectively inhibit cancer cell processes. Conclusions: We report the development of a new microRNA-based approach to target cancer cells by potentially interfering in multiple signaling pathways that are mediated by kinase-dependent mechanisms. We propose that therapeutic miRNA sequences can be delivered to cancer cells via microparticles (MPs) derived from umbilical cord mesenchymal stem cells (MSCs). The engineered MPs home selectively to tumor sites via specific chemokine receptors, fuse with the cell membrane and incorporate miRNA directly into the target cancer cells.
A phase I safety study of topical calcitriol (BPM 31543) for the prevention of chemotherapy-induced alopecia (CIA).
Authors: Lacouture Mario E. , Konner Jason A. , Belum Viswanath Reddy , Stevens Janice , Dion Hedy , Ciccolini Kathryn , Kitts Sarah , Ye Ran , Ravipaty Shobha , Akmaev Viacheslav R , Sarangarajan Rangaprasad , Jimenez Joaquin Juan , Narain Niven R. , Berman Brian , Goldfarb Shari Beth 
Published: September 2018

e14064 Background: Chemotherapy-induced alopecia (CIA) may lead to significant psychosocial and quality of life issues. Currently there are no FDA approved oral or topical agents available to prevent CIA. In murine studies, topical calcitriol reduced CIA, likely due to arrest of cell cycle in healthy hair follicles, and reduction in the sensitivity of follicular epithelium to chemotherapy. Methods: A prospective dose escalation study is being performed in up to 31 women with breast cancer, gynecologic cancer and sarcomas. Each patient is applying 1mL of BPM 31543 to her scalp BID, ≥ 5 days prior to initiation of taxane-based chemotherapy for at least 3 months or until the completion of chemotherapy. The study cohorts are: 5/10/20/40/60/80 μg/mL. All 6 cohorts have been completely enrolled. Each patient undergoes PK analysis, adverse event (AE) monitoring, patient self-assessment diaries (1-10 scale), and blinded photographic assessments. Results: Twenty-eight patients have been enrolled (evaluable, n = 21). PK data (n = 21; 5-80 μg/mL) showed inter-individual variability, with increases in serum vitamin D in the 10/20/40/60/80 μg/mL cohorts (range, < 21.3-110 pg/mL). Treatment-related AEs (probably/possibly) were mild/moderate in nature and included scalp pain (n = 1; 5 μg/mL), elevated vitamin D levels in 3 patients (20/40/60 μg/mL) and passage of renal calculus in another (n = 1; 40 μg/mL). A clinical response was observed at each dose level. The study will be complete and final study data will be available and presented at ASCO. Conclusions: Data have shown that the twice daily application of BPM 31543 in patients receiving taxane-based chemotherapy was safe and well-tolerated. The Maximum Tolerated Dose (MTD) was not detected. No Dose Limiting Toxicities (DLTs) or severe treatment-related adverse events occurred in any of the dose cohort. A signal of efficacy was detected at each dose level. Clinical trial information: NCT01588522.
A drug-drug interaction study of capecitabine and celecoxib in patients with advanced solid malignancies.
Authors: Ramirez Jacqueline , House Larry , Karrison Theodore G. , Janisch Linda A. , Turcich Michelle , Salgia Ravi , Ratain Mark J. , Sharma Manish 
Published: September 2018

e14066 Background: Warfarin is an anticoagulant and CYP2C9 substrate commonly used in oncology patients. Several studies suggest a drug-drug interaction between capecitabine and warfarin that may be mediated by CYP2C9. Celecoxib is a CYP2C9 substrate that may also have anticancer activity. We aimed to characterize the magnitude and the time course of the capecitabine-celecoxib interaction in cancer patients in order to better understand the effect of capecitabine on CYP2C9. Methods: Patients received 200 mg celecoxib PO twice daily continuously, with capecitabine (1,000 mg/m2 PO twice daily for 14 days every 21 days) starting 7 days later. Celecoxib and celecoxib-OH pharmacokinetics (PK) were collected on days 7, 14 and 21. Thirteen patients were evaluable for PK analysis. Results: Comparison of steady state PK parameters showed an average 31%, 17% and 34% increase in celecoxib’s Cmax (p = 0.036; paired t-test), Cmin (p = 0.043) and AUC (p = 0.006) between day 7 (celecoxib only) and day 14 (celecoxib + capecitabine), respectively. PK comparison of day 7 vs. day 21 (after one week washout of capecitabine) showed a further increase in Cmax (46%, p = 0.011), Cmin (92%, p = 0.002) and AUC (49%, p = 0.006). Conclusions: Coadministration of capecitabine results in higher exposure to celecoxib, and the interaction persists for at least 7 days after discontinuation of capecitabine. Clinical trial information: NCT01705106.
Plasma and cerebrospinal fluid pharmacokinetics of doxil after intravenous administration in adults with primary CNS lymphoma.
Authors: Higham Christine , Murphy Robert F. , Bhaumik Sucharita , Dunleavy Kieron , Wilson Wyndham Hopkins , Widemann Brigitte C. 
Published: September 2018

e14067 Background: Doxil, a pegylated liposomal doxorubicin (PLD) has excellent CNS penetration in rodent brain tumor models and is active in patients with lymphoma. The CNS penetration of doxil in humans is unknown. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of doxil in adults primary CNS lymphoma (PCNSL) as a surrogate for CNS penetration. Methods: Adults with PCNSL enrolled on a NCI phase I study of ibrutinib and multi-agent immune-chemotherapy (NCT02203526) received doxil 50 mg/m2 IV over 1 hour on day 2 of 21-day cycles of chemotherapy. In 4 patients with indwelling Ommaya reservoirs serial blood and CSF samples were obtained prior to infusion and until a median of 345 hours, (range 72-477 hours) after doxil administration. Total doxorubicin concentration (liposome bound + protein bound + free) was quantified with a validated liquid chromatography/tandem mass spectrometry assay (lower limit of quantification plasma=0.29 ng/mL, and CSF=0.06 ng/mL). PK parameters were estimated using non-compartmental methods. CSF penetration was calculated from the AUCCSF:AUCplasma. Results:Total doxorubicin plasma concentration time curves were characterized by sustained drug exposure and a median terminal half-life of 64.5 hours. (range, 61.9-65.1 hours). Doxorubicin was measurable in CSF in all patients, but CSF penetration was low. The terminal half-life of doxorubicin in CSF could not be calculated due to persistently measurable concentrations throughout the sampling times. Conclusions: In patients with PCNSL doxorubicin was measurable in CSF for prolonged time periods after doxil administration, but CSF penetration is low. Clinical trial information: NCT02203526. [Table: see text]
Plasma and cerebrospinal fluid pharmacokinetics of selumetinib in non-human primates (NHP).
Authors: Gross Andrea M. , McCully Cynthia M. , Warren Katherine E. , Widemann Brigitte C. 
Published: September 2018

e14070 Background: Selumetinib (AZD6244 hyd sulfate) is an orally bioavailable agent targeting mitogen-activated protein kinase (MEK) 1/2. Selumetinib has shown activity in children with NF1 plexiform neurofibromas and refractory low-grade gliomas. The central nervous system (CNS) penetration of selumetinib in humans is unknown. Methods: We analyzed selumetinib in the cerebrospinal fluid (CSF) of NHP as a surrogate for CNS penetration. Four adult male rhesus macaques were each given a single dose of selumetinib capsules 2.5 mg/kg (human equivalent dose 50 mg/m2) by mouth on an empty stomach. Selumetinib was quantified in serial paired plasma and CSF samples from 0 to 48 hours after administration by Covance Bioanalytical Services (lower limit of quantification 0.5 ng/mL). Free selumetinib was estimated at 2.3% of total based on reported plasma protein binding of 97.7% in NHP. Pharmacokinetic parameters including area under the concentration x time curve (AUC) of selumetinib were calculated using non-compartmental methods and CSF penetration was calculated from the ratio of AUC (CSF): AUC (plasma). Results: Selumetinib was detected in plasma in all four NHPs, but in the CSF of only one NHP (ZH60). The mean (± SD) AUC0-∞ and half-life (t1/2) in plasma were 3350 ± 489 ng•h/mL and 10.8 ± 2.5 hours, respectively. In ZH60, the CSF AUC0-48 hr was 10.6 ng•h/mL. The CSF penetration of total and free selumetinib in this animal was 0.4%, and 14%, respectively. The mean plasma AUC and t1/2 were comparable to that of children (2842 ng•h/mL and 6.9 hours, respectively) at a similar dose in a phase I trial. However, the average peak concentration in children occurred at approximately 1 hour with a Cmax of 841 ng/mL, while the Cmax in NHP plasma ranged from 1 – 4 hours and averaged 198.8 ng/mL. Conclusions: The CSF penetration of oral selumetinib is limited; in one NHP it was 0.4% and 14% when corrected for plasma protein binding of selumetinib. The fact that plasma AUC0-∞ and half-lives in NHP were similar to previously reported human plasma PK indicates that this model may accurately reflect human CSF penetration as well.
Pharmacokinetics (PK) and safety of enzalutamide in healthy Chinese males.
Authors: Chen Qian , Liu Yan-Mei , Zhang Xiaopeng , Fukushi Risa , Asahina Seitaro 
Published: September 2018

e14073 Background: Enzalutamide (ENZ), an androgen receptor inhibitor, is approved in over 60 countries except China for use in metastatic castration-resistant prostate cancer. The PK of ENZ have been assessed in healthy Caucasian males (Gibbons 2015). This open-label, single-dose study evaluated the PK of ENZ and its major metabolites, and safety of ENZ, in healthy Chinese male volunteers. Methods: Non-elderly healthy Chinese male volunteers received a single oral dose of ENZ (160 mg) under fasting conditions on day 1 and were followed for 50 days. Full PK profiles were obtained for ENZ and its major metabolites, carboxylic acid metabolite (M1; inactive metabolite) and N-desmethyl enzalutamide (M2; active metabolite), on day 1 up to 1176 hours (49 days). Safety data were collected from screening until the end of study visit. Results: 14 healthy Chinese male volunteers were enrolled and received a single ENZ dose (mean age, 29.0 years; mean BMI, 21.7 kg/m2). All volunteers receiving study drug were included in the PK and safety analyses; two subjects withdrew from the study during the study period. ENZ plasma concentration rapidly increased (median tmax of 1.5 hours) followed by a slow decrease (mean t1/2 of 90.7 hours). Plasma concentrations of M1 and M2 increased gradually with a median tmax of 72.0 and 121 hours, respectively. M1 and M2 mean metabolite to parent ratio was 0.206 and 1.32, respectively. Mean AUC0-inf of the sum of ENZ and M2 was 828 μg·h/mL compared to 368 μg·h/mL for ENZ. Cmax and tmax of the sum of ENZ and M2 were comparable to ENZ. Mean t1/2 of the sum of ENZ and M2 was 155 hours, which was similar to that of M2 (162 hours). Treatment-emergent adverse events (TEAEs) were reported in seven out of 14 males (50.0%). Possible/probable drug-related TEAEs were reported in four males (28.6%); one each of upper respiratory tract infection, chest discomfort, increased bilirubin, and decreased white blood cell count. No deaths, serious TEAEs, or TEAEs of grade ≥3 were observed. Conclusions: The PK profiles of ENZ, M1, M2, and the sum of ENZ and M2 in healthy Chinese males were generally consistent with Caucasian males. No clinically relevant safety concerns were reported. Safety and PK profiles indicate that ENZ 160 mg/day is appropriate in a Chinese population.
Cancer associated thrombosis in patients taking direct oral anticoagulants (DOACs): Retrospective review of a single institutional series.
Authors: Angelov Sophia , Dean Andrew Peter 
Published: September 2018

e14080 Background: Venous thromboembolism (VTE) is a common and often serious complication for patients with malignancy. Even though low molecular weight heparin (LMWH) is recommended as first line therapy for initial and long term anticoagulation, patient choice may demand oral anticoagulants. This retrospective review illustrates the repeated observation of recurrent thromboembolic disease in patients taking the new class of oral anticoagulant, DOAC. Methods: The pharmacy database at our institution was searched to identify oncology patients who had received a prescription for a DOAC (rivaroxaban or apixiban). Sixtyfive patients were identified and case records were then examined for evidence of venous thromboembolism. Results: Five seperate episodes of recurrent venous thromboembolism were identified in four patients in our cohort., one patient having two seperate episodes of pulmonary embolus. All were on recommended therapeutic doses of DOAC at the time of thromboembolic event. Two patients experienced proven pulmonary embolus on CT pulmonary angiography (1 twice), one lower limb deep vein thrombosis and one upper limb deep vein thrombosis. Conclusions: This retrosepctive review reinforces the clinical guidelines stated by the Cochrane review and ASCO that LMWH should always be first line for the initial and continuation treatment of a VTE. The guidelines did not focus on the suboptimal anticoagulation aspect of the newer oral anticoagulants but more on the safety issues. Research has been mainly focused on comparing LMWH with unfractionated heparin (UFH) or oral warfarin. Comparisons between DOAC versus Warfarin as an oral form of therapy have also been made. In the available published literature, there is a paucity of research comparing DOACs to LMWH. We have identified four patients out of sixtyfive treated with therapeutic doses of DOAC who developed subsequent thromboembolism. This is additional supportive evidence that newer oral anticoagulant agents may not be efficacious in malignancy driven VTE and that LMWH should remain the standard of care. Patients specifically requesting DOAC for cancer associated VTE should be made aware of this data.
IRX4204 in combination with erlotinib to target distinct pathways in lung cancer cells.
Authors: Liu Xi , Roszik Jason , Karakami Masanori , Sanders Martin , Chandraratna Rosh , Dmitrovsky Ethan , Dragnev Konstantin H. 
Published: September 2018

e14095 Background: IRX4204 is a Retinoid X Receptor (RXR) specific agonist (rexinoid). IRX4204 has high potency as a RXR agonist with low binding affinity to Retinoic Acid Receptors (RARs), PPAR, FXR or LXR. Our prior work with the less specific rexinoid bexarotene and erlotinib showed clinical activity in patients with lung cancer cases that harbored KRAS mutations. IRX4204 inhibits lung cancer cell proliferation and can chemoprevent carcinogen-induced lung cancers in mice. We sought to explore the underlying mechanisms engaged by the combination of IRX4204 and erlotinib. Materials and Methods: Human (H1703 and HOP62) and murine (ED1 and LKR13) lung cancer cell lines were treated with IRX4204, erlotinib, IRX4204 plus erlotinib, or vehicle. Reverse phase protein array (RPPA) and mRNA microarray analyses were performed to analyze comprehensively for differentially expressed growth regulatory proteins. Results: Combination of IRX4204 and erlotinib suppressed proliferation of both KRAS mutant (HOP62 and LKR13) and wild-type (H1703 and ED1) lung cancer cell lines. Additive effect was observed as compared to IRX4204 or erlotinib treatment alone. Combining IRX4204 with erlotinib markedly increased inhibition of specific therapeutic targets including Src, phosphorylated Akt and ribosomal S6 proteins. At the mRNA level, Ingenuity Pathway Analysis of species significantly increased or decreased by the combination treatment revealed multiple pathways related to oncogenic signaling. Specifically, we found in H1703 cell line regulation of Granzyme A and AMPK signaling and in HOP62 cell line inhibition of angiogenesis was implicated by altering TSP1 expression. Notably, in ED1 cell line PPARα/RXRα activation, PTEN signaling, PI3K/AKT signaling, TGF-β signaling, and AMPK signaling were each associated with effects of IRX4204 combined with erlotinib. Conclusions: Taken together, these data highlight specific mechanisms and candidate pharmacodynamic biomarkers of response to the combination of this rexinoid and EGFR-TKI in lung cancer. Based on these findings, a clinical trial (NCT02991651) with IRX4204 in combination with erlotinib is underway to treat patients with chemotherapy-refractory non-small cell lung cancer.
Targeting anti-PD1-resistant tumors via indoleamine 2,3-dioxygenase 1 (IDO1) inhibition.
Authors: Li Ailin , Schoenhals Jonathan E. , Barsoumian Hampartsoum B. , Wang Xiaohong , Valdecanas David R. , Niknam Sharareh , Klopp Ann , Younes Ahmed I. A. , Gomez Daniel Richard , Chang Joe Y. , Komaki Ritsuko , Li Guang , Cortez Maria Angelica , Welsh James William 
Published: September 2018

e14103 Background: Anti-PD1 inhibitors are effective in only a subset of lung cancers, and many that respond later develop resistance. We recently found in a mouse model of anti-PD1 resistance that tumor-infiltrating lymphocytes (TILs) overexpressed indoleamine 2,3-dioxygenase 1 (IDO1), a rate-limiting step in the catabolism of tryptophan (Trp) to kynurenine (Kyn) often implicated in immunosuppression. We tested whether inhibiting IDO would affect anti-PD1 mediated resistance. Methods: We used our anti-PD1-resistant lung cancer model (344SQ_R), which involved treating the parental 344SQ cells (344SQ_P) with anti-PD1 antibody followed by passage in 129SV/ev mice. We treated 344SQ_P and 344SQ_R mice with or without a selective IDO1 inhibitor (INCB023843) and measured tumor growth and lung metastasis. Plasma Trp and Kyn levels were tested by liquid chromatography–tandem mass spectrometry. TILs from blood and tumor-draining lymph nodes were isolated, analyzed by flow cytometry, and RNA was extracted for qPCR. Plasma C-C motif chemokine 22 (CCL22) levels were tested by ELISA. Data were analyzed with Prism 5.0 (GraphPad Software) and Flowjo V-10. Results: In untreated mice, IDO1 expression was 12 times higher in TILs from 344SQ_R mice than 344SQ_P mice, and mean plasma Kyn and Kyn/Trp levels were 3 times higher in 344SQ_R than in 344SQ_P. IDO inhibition was effective only in the PD1-resistant mice, reducing both tumor growth and lung metastasis. A subpopulation of myeloid-derived suppressor cells (Gr1int/lo CD11b+F4/80+) showed the greatest increase in IDO1 expression when comparing 344SQ_R to 344SQ_P and decreased after INCB023843 treatment only in 344SQ_R. INCB023843 also increased infiltrating CD8+ T cells, decreased CCL22 and regulatory T cells only in 344SQ_R tumors. Conclusions: Our results suggest that IDO1 is overexpressed in TILs from tumors resistant to anti-PD1 therapy; that a high plasma Kyn/Try ratio may be a marker of anti-PD1 resistance; and that IDO1 inhibition could be a promising approach for treating lung cancer that does not respond to anti-PD1 therapy.
Assessment of heterogeneity of PD-L1 expression in NSCLC, HNSCC, and UC with Ventana SP263 assay.
Authors: Scott Marietta L. , Scorer Paul , Lawson Nicola , Ratcliffe Marianne J , Barker Craig , Rebelatto Marlon , Walker Jill 
Published: September 2018

e14502 Background: Clinical assessment of PD-L1 status relies on the result of testing 1 FFPE section per patient (pt). Heterogeneity of PD-L1 expression within a single tissue block and between paired blocks from the same pt could impact pt classification. This study characterizes the intra-block and intra-case heterogeneity using the VENTANA PD-L1 (SP263) Assay in non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC) and urothelial carcinoma (UC) for tumor cell (TC) and immune cell (IC) staining. Methods: Two blocks from the same tumor for 5 cases of each of 3 indications (30 unique blocks) representing a range of PD-L1 staining were commercially acquired and sectioned serially at 4 μm. Tumor continuity throughout the blocks was confirmed by staining sections 1 and 51 with H&E. Sections 2, 25 and 50 were stained with VENTANA SP263 and scored by a single trained pathologist, using the SP263 scoring algorithm and interpretation guide. Total percentages of PD-L1+ TCs and ICs were determined. Multiple diagnostic cutoffs were applied to TC and IC scores from multiple sections within each block and pair of blocks to establish overall percentage agreement (OPA) within and between blocks at each cutoff. Additional data were available in NSCLC for 200 cases with repeat SP263 staining (minimum separation 70 μm). Results: TC PD-L1 status at all cutoffs showed no intra-block (sections ~100 μm apart) or intra-case heterogeneity (Table). IC PD-L1 status showed limited intra-block and intra-case heterogeneity, with IC % staining in discordant sections varying by no more than 5%. Results are supported by the 200 NSCLC cases, with a minimum TC OPA across cutoffs of 91% (78.5% for ICs). Conclusions: Intra-block and intra-case concordance of TC PD-L1 status is high, and IC PD-L1 agreement is good across cutoffs. This supports the reproducibility of pt PD-L1 status in NSCLC, HNSCC and UC, within and between blocks. [Table: see text]