bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 977: Characterizing the regulation and function of miR-155 in hypoxia biology
Authors: Czochor Jennifer , Glazer Peter M. 
Published: May 2015

Abstract
Aberrant expression of microRNAs has been correlated with the initiation and progression of many diseases. One such microRNA, miR-155, is an oncogenic microRNA that has been associated with several different types of cancer, including lung, breast, and lymphoma. We are studying the role of miR-155 in promoting hypoxia-driven tumor phenotypes such as therapy resistance and genomic instability. Previously, we have shown that miR-155 expression is induced under hypoxic conditions and that over-expression of miR-155 under normal oxygen conditions confers resistance to ionizing radiation therapy. Additionally, we have shown that by knocking down expression of miR-155 under hypoxic conditions, we were able to sensitize these cells to ionizing radiation. Here, we demonstrate that miR-155 expression is tightly linked to genomic instability, another characteristic of hypoxia. We have found that over-expression of miR-155 drives increased mutation frequency as measured by a mutation reporter assay screen both in vitro and in vivo. These results are consistent with a recent finding that miR-155 over-expression targets mismatch repair proteins, MLH1, MSH2, and MSH6. An increase in mutation frequency could be due to a decrease in mismatch repair function. Surprisingly, we have also found that loss of miR-155 increases the baseline level of double strand breaks observed in a fibroblast cell line. Taken together, this data suggests that a finite regulation of miR-155 is necessary to maintain cellular homeostasis. Our goal is to gain a better understanding of the role of miR-155 in promoting hypoxic cancer cell survival.
Citation Format: Jennifer Czochor, Peter M. Glazer. Characterizing the regulation and function of miR-155 in hypoxia biology. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 977. doi:10.1158/1538-7445.AM2014-977
Abstract 979: microRNA-mediated leukemia-initiating cell activity
Authors: Velu Chinavenmeni S. , Chaubey Aditya , Phelan James D. , Meyer Sara , Horman Shane R. , Wunderlich Mark , Guzman Monica L. , Jegga Anil G. , Zeleznik-Le Nancy J. , Chen Jianjun , Mulloy James C. , Cancelas Jose A. , Jordan Craig T. , Aronow Bruce J. , Marcucci Guido , Bhat Balkrishen , Gebelein Brian , Grimes H. Leighton 
Published: May 2015

Abstract
The HoxA9 transcription activator and the Gfi1 transcriptional repressor compete for the regulation of common target genes. We exploited HoxA9 versus Gfi1 antagonism to identify the genes encoding microRNA-21 and microRNA-196b as transcriptional targets of Hox-based leukemia oncoproteins. Therapeutic inhibition of microRNA-21 and microRNA-196b significantly inhibits in vitro colony forming activity, and quantitatively depletes in vivo leukemia-initiating-cell activity of Hox-based leukemias leading to leukemia-free survival of murine AML and significant delay in disease onset in xenograft models. A novel microRNA target identification platform both validates therapeutic intervention and reveals biological impact of disrupting microRNA function. These data establish microRNA as functional effectors of endogenous HoxA9 and Hox-based leukemia oncoproteins, provide a concise in vivo platform to test RNA therapeutics, and suggest therapeutic value for microRNA antagonists in AML.
Citation Format: Chinavenmeni S. Velu, Aditya Chaubey, James D. Phelan, Sara Meyer, Shane R. Horman, Mark Wunderlich, Monica L. Guzman, Anil G. Jegga, Nancy J. Zeleznik-Le, Jianjun Chen, James C. Mulloy, Jose A. Cancelas, Craig T. Jordan, Bruce J. Aronow, Guido Marcucci, Balkrishen Bhat, Brian Gebelein, H. Leighton Grimes. microRNA-mediated leukemia-initiating cell activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 979. doi:10.1158/1538-7445.AM2014-979
Abstract 98: A novel mouse model for intestinal serrated polyposis
Authors: Cotton Jennifer , Huang He , Rajurkar Mihir , Mao Junhao 
Published: May 2015

Abstract
Serrated polyps have recently been proposed to comprise at least 30% of the origins of human colorectal cancer (CRC). Unlike adenomatous polyps, which are initiated by APC/β-catenin mutations, the genetic and molecular mechanisms underlying the serrated pathway that leads to serrated polyp initiation and progression remain poorly understood.
Here we describe a novel genetically modified mouse model of serrated polyposis via conditional activation of SMAD7, an inhibitory SMAD protein, in the intestinal epithelia. We show that SMAD7 activation is sufficient to drive serrated polyp initiation and progression to aggressive adenocarcinoma in both mouse intestine and colon. Mechanistically, we find that SMAD7-induced foci formation in non-transformed intestinal epithelial cells in vitro and serrated polyposis in vivo are Wnt/β-catenin independent. Furthermore, we find that, in addition to its regulation of TGFβ/BMP pathway, SMAD7 interacts with BRAF/MAPK signaling to regulate serrated polyposis. Taken together, our studies implicate for the first time the involvement of SMAD7 in serrated polyposis and reveal a potential novel molecular mechanism underlying the serrated polyp pathway.
Citation Format: Jennifer Cotton, He Huang, Mihir Rajurkar, Junhao Mao. A novel mouse model for intestinal serrated polyposis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 98. doi:10.1158/1538-7445.AM2014-98
Abstract CT208: Absolute bioavailability of dacomitinib (PF-00299804): Comparison of oral and intravenous administration in healthy volunteers
Authors: Giri Nagdeep , LaBadie Robert R. , Liang Yali , Boutros Tanya , Goldberg Zelanna , Bello Carlo L. 
Published: May 2015

Abstract
Background: Dacomitinib (D) is a highly selective, irreversible small molecule inhibitor of the human epidermal growth factor receptor family of tyrosine kinases in clinical development for the treatment of non-small cell lung cancer (NSCLC). A 45-mg once daily oral dose is currently being evaluated in Phase 3 for NSCLC therapy in multiple settings. D has not previously been administered clinically as an intravenous dose. The absolute bioavailability (F%) of D in rats, dogs and monkeys was found to range from 56% to 100% at doses between 20 and 50 mg/kg. The current study was conducted to estimate the absolute bioavailability of D after oral administration (Test) relative to intravenous (IV, Reference) administration.
Methods: A total of 14 healthy volunteers (HV) were enrolled in this Phase 1, open-label, 2-period, 2-treatment, fixed sequence study. Each HV received 2 treatments of D: Reference (20 mg IV infusion over 1 hour) and Test (45 mg oral), with a washout period of at least 16 days between each. Plasma samples to determine concentrations of D and its metabolite, PF-05199265, were collected at intervals up to 216 hours post-dose after IV or oral dose, and safety was assessed. F% was estimated as the ratio of dose-normalized adjusted geometric means of AUCinf for oral D and IV D using a mixed-effect model with treatment as a fixed effect and subject as a random effect. Corresponding 90% confidence intervals (CIs) were to be obtained from the same model.
Results: The mean AUCinf, Cmax and CL/F for D after a single 45-mg oral dose were 1487 ng*hr/mL, 19.84 ng/mL and 30.27 L/hr, respectively. The mean AUCinf, Cmax and CL for D after a single 20-mg IV dose were 847 ng*hr/mL, 52 ng/mL and 23.61 L/hr, respectively. Mean pharmacokinetic parameters following a single oral dose in this study were similar to those observed in other single oral dose studies in HV.
Conclusions: Assuming that clearance of D is similar via oral or IV administration at the administered doses, the absolute bioavailability of D was estimated to be 80.01% (90% CI: 74.90%, 85.47%). Single oral doses of D in both treatments were generally safe and well tolerated in the HV evaluated in this study.
Citation Format: Nagdeep Giri, Robert R. LaBadie, Yali Liang, Tanya Boutros, Zelanna Goldberg, Carlo L. Bello. Absolute bioavailability of dacomitinib (PF-00299804): Comparison of oral and intravenous administration in healthy volunteers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT208. doi:10.1158/1538-7445.AM2014-CT208
Abstract CT234: Dabrafenib stimulates radioiodine uptake in BRAF V600E mutant advanced papillary thyroid cancer
Authors: Rothenberg Stephen M. , McFadden David G. , Palmer Edwin L. , Daniels Gilbert H. , Wirth Lori J. 
Published: May 2015

Abstract
Purpose: To determine whether the selective BRAF inhibitor dabrafenib can stimulate radioactive iodine uptake in BRAF V600E mutated advanced papillary thyroid cancer (PTC) that is unable take up iodine.
Patients and Methods: Ten patients with unresectable or metastatic PTC were enrolled. All had tumors with a BRAF V600E mutation and complete absence of radioiodine uptake on iodine-131 whole body scan obtained within 14 months of study entry. Each patient received dabrafenib (150 mg twice daily) for 3 weeks followed by thyrotropin alfa-stimulated iodine-131 whole body scan. If new iodine uptake occurred, dabrafenib was continued for an additional two weeks, followed by the administration of a therapeutic dose of iodine-131.
Results: All ten patients completed the study. Dabrafenib resulted in new iodine-131 uptake in six of the ten patients. All six were treated with radioioactive iodine, leading to a complete response in one patient, a partial response in a second patient and stable disease in three patients. Four of six treated patients had decreases in serum thyroglobulin. No toxic effects of grade 2 or higher were attributable to dabrafenib. One patient developed a new squamous cell carcinoma of the skin which was successfully excised with clear margins.
Conclusion: Dabrafenib produces increases in iodine uptake in patients with iodine-refractory advanced BRAF V600E mutant PTC and is well tolerated. Additional studies to determine efficacy are warranted.
Citation Format: Stephen M. Rothenberg, David G. McFadden, Edwin L. Palmer, Gilbert H. Daniels, Lori J. Wirth. Dabrafenib stimulates radioiodine uptake in BRAF V600E mutant advanced papillary thyroid cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT234. doi:10.1158/1538-7445.AM2014-CT234
Abstract CT323: Pemetrexed versus docetaxel in patients with EGFR-mutant lung adenocarcinoma previously treated with epidermal growth factor receptor tyrosine kinase inhibitors
Authors: Kyu-Sik Kim , Lee Bo Ram , Yoon Sung Hoon , Yu Jinyeong , Oh Injae , Kim Young Chul , Song Sangyun , Choi yooduk , Ban Hee Jung 
Published: May 2015

Abstract
Background: Patients with epidermal growth factor receptor (EGFR) mutation positive adenocarcinoma exhibited marked response to EGFR tyrosine kinase inhibitors (TKIs). In most cases, the patients showed disease progression after EGFR TKI treatment. We evaluated the efficacy and safety of pemetrexed versus docetaxel after the failure of EGFR TKI in patients with adenocarcinoma with EGFR mutation.
Methods: Patients harboring EGFR mutant adenocarcinoma who received weekly docetaxel (35-40 mg/m2 on days 1 and 8 every 3 weeks) or pemetrexed (500 mg/m2 every 3 weeks) at a single university-affiliated hospital following failure of first line EGFR TKI treatment were retrospectively reviewed.
Results: 44 patients were included between 2012 and 2013. Patients who had previously treated with EGFR TKI as first line treatment were received docetaxel (n=11) or pemetrexed (n=33) in second- or later-line treatment. The efficacy of docetaxel was superior to that of pemetrexed (ORR: 36.4% vs. 6.1%, p = 0.011, DCR: 72.7% vs. 39.4%, p = 0.055). Progression-free survival of docetaxel was 6.2 months versus 1.9 months with pemetrexed. (HR 0.55; 95% CI 0.25-1.22; p = 0.140). There were no significant differences in either the grade 3-4 hematologic or nonhematologic toxicities between the 2 regimens.
Conclusion: Pemetrexed shows unfavorable result compared to docetaxel in patients with acquired drug resistance after EGFR TKI treatment. We will have to study the efficacy of pemetrexed versus docetaxel after EGFR TKI treatment prospectively.
Citation Format: Kim Kyu-Sik, Bo Ram Lee, Sung Hoon Yoon, Jinyeong Yu, Injae Oh, Young Chul Kim, Sangyun Song, yooduk Choi, Hee Jung Ban. Pemetrexed versus docetaxel in patients with EGFR-mutant lung adenocarcinoma previously treated with epidermal growth factor receptor tyrosine kinase inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT323. doi:10.1158/1538-7445.AM2014-CT323
Abstract CT337: Phase I/Ib study of the PARP inhibitor (PARPi) olaparib (O) with carboplatin (C) in triple negative breast cancer (TNBC) at low genetic risk (NCT00647062)
Authors: Chiou Victoria L. , Kohn Elise C. , Annunziata Christina M. , Minasian Lori , Zujewski JoAnne , Yu Minshu , Ji Jay , Doroshow James , Gordon Nicolas , Houston Nicole , Lee Jung-Min 
Published: May 2015

Abstract
Background: PARPi O demonstrates single agent activity in breast and ovarian cancer (Br/OvCa) pts with germline BRCA1/2 mutation (gBRCAm), and with BRCA-like phenotype. Subsets of TNBC are known to respond to therapies targeting DNA repair mechanisms. We hypothesize that O and C combination can be safely tolerated in TNBC pts and may result in benefit.
Methods: Pts with recurrent or unresectable TNBC, BRCAPro score &lt;10% or absent gBRCAm, and normal end-organ function were eligible. An open-label 3x3 dose escalation included daily oral O capsule formulation (200mg then 400 mg q12h, d1-7) with C/AUC3-5 on d2 q21d (dose level [DL]1-3). No more than 8 O/C cycles were given, followed by daily O until progression. Pts were evaluated for toxicity every 3 weeks by CTCAEv3.0, and every two cycles for response using RECISTv1.0.
Results: 25 women (median age 52 [39-76]) were treated. All pts except one received prior therapy (median 5 [0-12]; prior platinum in 3pts). DLT was thrombocytopenia (DL 2: O 400mg/C AUC4 [1/6pts] and DL3: O 400mg/C AUC 5 [2/3pts]). MTD was reached at DL3 (C/AUC 5 with O 400mg capsule q12h d1-7 q21d). The expansion dose was O 400mg q12h d1-7, C/AUC 4. Gr 3/4 AEs included neutropenia (36%), thrombocytopenia (12%), and anemia (12%). 2 pts required C dose reduction and early discontinuation due to delayed marrow recovery. 13 pts (52%) needed peg-filgrastim, 6 (24%) blood transfusion, and 3 (12%) erythropoietin on at least one cycle. Responses (N=22 evaluable) included 1 CR (46+ mo), 2 PR (3, 5 mo), and 8 with SD ≥4 mo (36%; median 5 [4-7]), for a disease control rate of 50%. The pt who achieved CR had a strong family history of Br/OvCa. Peripheral blood mononuclear cells preC1, d3 or d7, and prior to C2 were collected for PAR incorporation ELISA. Paired tumor biopsies (pre/post-cycle1) were obtained from expansion cohort patients for biomarker proteomics and apoptosis endpoints; results will be presented.
Conclusions: RP2D O capsule formulation 400 mg q12h d1-7 with C AUC4 q21d is tolerable in heavily pretreated TNBC pts. Interactive marrow suppression was observed.
Citation Format: Victoria L. Chiou, Elise C. Kohn, Christina M. Annunziata, Lori Minasian, JoAnne Zujewski, Minshu Yu, Jay Ji, James Doroshow, Nicolas Gordon, Nicole Houston, Jung-Min Lee. Phase I/Ib study of the PARP inhibitor (PARPi) olaparib (O) with carboplatin (C) in triple negative breast cancer (TNBC) at low genetic risk (NCT00647062). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT337. doi:10.1158/1538-7445.AM2014-CT337
Abstract CT343: Phase II study of low-dose rate thoracic radiotherapy for treatment of intrathoracic relapsed or progressive small cell lung cancer
Authors: Jones Guy C. , Mitchell James B. , Johnson Bruce E. , Camphausen Kevin , Glatstein Eli , Simone Charles B. 
Published: May 2015

Abstract
Purpose: Standard therapy for limited-stage (LS) small cell lung cancer (SCLC) and extensive-stage (ES) SCLC with thoracic-only disease is a combination of chemotherapy with radiotherapy, which is associated with high rates of grade ≥3 esophagitis. Low dose rate (LDR) radiotherapy may reduce normal tissues toxicity, without sacrificing tumor response. This phase II trial was conducted to assess the toxicity, local control, and survival using LDR radiotherapy to treat thoracic relapsed or progressive ES-SCLC.
Methods: Eligible patients had ECOG performance status 0-2 with histologically confirmed ES-SCLC with relapse or progression predominantly in the chest after chemotherapy. Radiotherapy was delivered twice daily in 150cGy fractions to 4500cGy to an involved field. Dose rate was 5cGy per minute.
Results: Seventeen ES-SCLC patients were enrolled at the National Cancer Institute. Fifteen evaluable patients were a median of 59 years at enrollment with relapsed or progressive thoracic disease following a median of 2 prior courses of chemotherapy (range 1-3). Four were treated concomitantly with radiotherapy to other sites of extrathoracic metastases. Radiotherapy was well tolerated with acute grade 1 esophagitis in 60% but no acute or late grade ≥2 toxicity. No clinical pneumonitis was reported. Evaluable patients had responsive thoracic disease (50% complete, 50% partial responses) with no local failures on post-radiotherapy imaging at 3 and 6 months. All patients survived a median of 13.9 months and mean of 30.4 months following ES-SCLC diagnosis and 3.3 months and 19.8 months following radiotherapy completion, with 1-year and 2-year survivals after radiotherapy of 27% and 20%, respectively.
Conclusion: LDR radiotherapy for ES-SCLC was a well-tolerated salvage therapy for treatment failure after chemotherapy. Toxicity was significantly less than historical controls, and thoracic tumor response was not compromised with LDR techniques. This trial serves as the basis of a planned multi-center, prospective trial of consolidative or salvage LDR radiotherapy for ES-SCLC.
Citation Format: Guy C. Jones, James B. Mitchell, Bruce E. Johnson, Kevin Camphausen, Eli Glatstein, Charles B. Simone. Phase II study of low-dose rate thoracic radiotherapy for treatment of intrathoracic relapsed or progressive small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT343. doi:10.1158/1538-7445.AM2014-CT343
Abstract CT416: Intratumoral administration of an Oncolytic Polio/Rhinovirus Recombinant (PVSRIPO) in recurrent glioblastoma (GBM): Preliminary results of the Phase I clinical trial
Authors: Desjardins Annick , Sampson J H. , Peters K B. , Ranjan T , Vlahovic G , Threatt S , Herndon J E. , Boulton S , Lally-Goss D , McSherry F , Friedman A , Friedman H S. , Bigner D D. , Gromeier M 
Published: May 2015

Abstract
Background: PVSRIPO is the live attenuated, oral (SABIN) serotype 1 poliovirus vaccine containing a heterologous internal ribosomal entry site stemming from human rhinovirus type 2. An oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy, nectin-like molecule-5, is recognized by PVSRIPO. We report the preliminary results of a phase I clinical trial evaluating the intratumoral administration via convection-enhanced delivery (CED) of PVSRIPO.
Methods: Eligibility criteria for adult patients included: recurrent supratentorial GBM; 1-5 cm in diameter; ≥1cm away from the ventricles; ≥4 weeks after chemotherapy, bevacizumab (BEV) or study drug; adequate organ function; KPS &gt;70%; and positive anti-poliovirus titer. Dose was rapidly escalated using a two-step continual reassessment method with anticipated accrual of 1 patient each on dose levels 1-4, and up to 21 patients at dose level 5.
Results: Thus far, ten patients have been treated (1 each at levels 1 and 3, 2 at level 2, 2 at level 4, 4 at level 5). One dose limiting toxicity (patient #8) was observed at level 5, a grade 4 intracranial hemorrhage at the time of catheter removal, which required de-escalation to level 4. Grade 3 adverse events possibly related to study include hemiparesis (n=1) and lymphopenia (n=1). No grade 5 study related adverse events were observed. Eight patients remain alive, with two patients now 20 and 19 months post PVSRIPO, respectively. Two patients having previously failed BEV died six months post-infusion after initiating hospice care due to persistence of baseline neurologic deficits. After observing prolonged steroid use in 5 of 7 patients treated on dose levels 3 to 5 and after results of new immunogenic analysis became available, it was agreed upon that dose level 2 is probably the optimal dose level. The study has been amended to treat a total of 6 patients at dose level 2.
Conclusion: Infusion of PVSRIPO via CED in the clinical setting is safe thus far and observed efficacy outcomes are intriguing. Dose expansion at dose level 2 is ongoing.
Citation Format: Annick Desjardins, J H. Sampson, K B. Peters, T Ranjan, G Vlahovic, S Threatt, J E. Herndon, S Boulton, D Lally-Goss, F McSherry, A Friedman, H S. Friedman, D D. Bigner, M Gromeier. Intratumoral administration of an Oncolytic Polio/Rhinovirus Recombinant (PVSRIPO) in recurrent glioblastoma (GBM): Preliminary results of the Phase I clinical trial. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT416. doi:10.1158/1538-7445.AM2014-CT416