tbuckley/cabot-search huggingface dataset:
Abstract 5257: Upregulation of glutathione S-transferase P1 by green tea polyphenols: A novel transcriptional target of p53 tumor suppressor gene
Authors: Vijay S. Thakur, Gauri Deb, Mark W. Jackson, Sanjay Gupta
Journal: Cancer Research (2016)

Abstract Green tea polyphenols (GTPs) and its major constituent (-)-epigallocatechin-3-gallate (EGCG) reactivate epigenetically silenced genes in cancer cells. Glutathione S-transferase P1 (GSTP1), an enzyme involved in detoxification process, is frequently inactivated in prostate cancer due to epigenetic modifications. The mechanisms underlying the re-expression of GSTP1 expression by GTP/EGCG in prostate cancer is currently not well understood. Earlier we demonstrated the ability of GTP/EGCG to increase p53 transcriptional activity through suppression of class I histone deacetylases (Carcinogenesis 33(2):377-84, 2012). Here we report that the GSTP1 gene is an unrecognized downstream transcriptional target of the tumor suppressor p53, and that GTP/EGCG has ability to increase GSTP1 expression mediated through p53. Treatment of human prostate cancer LNCaP cells with 5μg/ml GTP and 20μM EGCG, activate p53 through acetylation at the Lys373 and Lys382 residues along with consequent increase in GSTP1 protein expression in time-dependent manner. To study the possible interaction between GSTP1 and p53, LNCaP cells stably-transfected with short hairpin-RNA against p53 (LNCaPshp53) and control vector (LNCaPshV) for generation of p53 knockout cells. GTP/EGCG treatment induced p53 activation and acetylation at p53 Lys373 and Lys382 specifically in LNCaPshV cells in time-dependent manner, but not in LNCaPshp53. This increase in p53 acetylation led to activation of GSTP1 in LNCaPshV cells both at protein and message levels. GTP/EGCG-mediated increase in GSTP1 expression is caused by increase binding of p53 to its consensus binding site on the intron 4 of GSTP1 gene as analyzed by electrophoretic mobility shift binding assay. Furthermore, this association was validated by ChIP assay where GTP/EGCG treatment led to an increase in the amount of acetylated p53-Lys373 associated within the intron site of GSTP1, compared to untreated controls. Taken together, our findings indicate the ability of p53 to transcriptionally activate the human GSTP1 gene, which defines a novel mechanism of protection of the genome by green tea polyphenols. Citation Format: Vijay S. Thakur, Gauri Deb, Mark W. Jackson, Sanjay Gupta. Upregulation of glutathione S-transferase P1 by green tea polyphenols: A novel transcriptional target of p53 tumor suppressor gene. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5257.
Response to ‘PET after response to R-CHOP in primary mediastinal large B-cell lymphoma’
Authors: TP Vassilakopoulos, S Papageorgiou, GA Pangalis, S Chatziioannou, MK Angelopoulou, P Panayiotidis, K Konstantopoulos, P Rondogianni
Journal: Leukemia (2016)
Safety and efficacy of durvalumab (MEDI4736), a PD-L1 antibody, in urothelial bladder cancer.
Authors: Christophe Massard, Michael S. Gordon, Sunil Sharma, Saeed Rafii, Zev A. Wainberg, Jason John Luke, Tyler J. Curiel, Gerardo Colon-Otero, Omid Hamid, Rachel E. Sanborn, Peter H. O'Donnell, Alexandra Drakaki, John Kurland, Marlon C. Rebelatto, Xiaoping Jin, John A. Blake-Haskins, Ashok Kumar Gupta, Neil Howard Segal
Journal: Journal of Clinical Oncology (2016)

4502 Background: A Phase 1/2 dose escalation and dose expansion study is evaluating the safety and efficacy of durvalumab, a modified human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80, in solid tumors including urothelial bladder cancer (UBC). Methods: Eligible patients (pts) have inoperable or metastatic UBC, ECOG PS 0-1, with no prior anti-PD-1/PD-L1 exposure. Durvalumab 10 mg/kg is administered IV q2w for up to 12 mos. PD-L1 expression on tumor cells (TC) and tumor-associated immune cells (IC) is assessed with the Ventana SP263 assay (PD-L1+ defined as ≥ 25% of TC or IC staining for PD-L1). Response is investigator assessed per RECIST v1.1. Results: As of 20 Nov 2015, 61 pts (40 PD-L1+, 21 PD-L1‒; mean age 65 yrs [range 34-81]; 69% male; ECOG 0/1: 28%/72%; 51% with ≥ 2 prior systemic treatments) received a median of 4 doses (range 1-26). Drug-related AEs occurred in 64%; most frequent were fatigue (13%) and diarrhea (10%). Three pts had drug-related Grade ≥ 3 AEs: infusion-related reaction, tumor flare, and acute kidney injury (biopsy-proven nephritis). No drug-related AEs led to death. Forty-two pts were response evaluable with treatment initiated ≥ 12 wks before data cutoff (median follow-up 6.5 mos [range 0.8-14.8]; Table). PD-L1 expression in TC or IC both appeared to independently enrich for treatment response; 15/16 responders were PD-L1+ in TC or IC. ORR was 25% (3/12) in pts with liver metastases and 50% (4/8) in pts with lymph node‒only disease. Responses are ongoing in 15/16 pts; longest duration of response is ongoing at 11.3+ mos (median not reached). Conclusions: Durvalumab has an acceptable safety profile with evidence of clinical activity in heavily pretreated UBC pts. Defining PD-L1 status based on TC and IC expression effectively separates the pt population into 2 subgroups with distinct response rates. Nearly all responses occurred in the PD-L1+group. Studies of durvalumab in UBC are ongoing. Clinical trial information: NCT01693562.ORR (confirmed/unconfirmed) by PD-L1 expression and localization. PD-L1 Expression by Location PD-L1 Status ORR n/N (%) 95% CI All evaluable Any 16/42 (38.1) 23.6‒54.4 TC + 8/15 (53.3) 26.6‒78.7 ‒ 8/27 (29.6) 13.8‒50.2 IC + 11/18 (61.1) 35.7‒82.7 ‒ 5/24 (20.8) 7.1‒42.2 TC or IC + 15/28 (53.6) 33.9‒72.5 ‒ 1/14 (7.1) 0.2‒33.9
Veliparib (ABT-888) or placebo combined with carboplatin and paclitaxel in patients with previously untreated advanced/metastatic squamous (Sq) non-small cell lung cancer (NSCLC): A randomized phase 3 trial.
Authors: Mark D. McKee, Igor Bondarenko, Salih Zeki Guclu, Vera Gorbunova, Laszlo Urban, Philip Clingan, Krzysztof Leśniewski-Kmak, Julien Mazières, Suresh S. Ramalingam, Michelle Pedersen, Angela DeLuca, Caroline Nickner, Qin Qin, Vincent L. Giranda
Journal: Journal of Clinical Oncology (2015)

TPS8107 Background: NSCLC is often diagnosed at an advanced stage, conferring a poor prognosis. The current standard of care for first-line treatment comprises platinum-based regimens. Veliparib is a potent, orally bioavailable PARP1/2 inhibitor that can delay DNA repair following damage induced by chemotherapeutic agents. In preclinical tumor models, veliparib has been shown to enhance antitumor activity of carboplatin, and phase 1 data show that it can be safely combined with carboplatin and paclitaxel. A phase 2 study indicated favorable efficacy for veliparib plus carboplatin and paclitaxel vs placebo plus carboplatin and paclitaxel in the subgroup of patients with Sq NSCLC (Ramalingam et al. Ann Oncol 2014;25(Suppl 4):1234P). Based on these results, this phase 3 pivotal trial has been initiated. Methods: This is a randomized, double blind, multicenter, phase 3 trial (NCT02106546). Patients ( ≥ 18 years) who have received no prior chemotherapy or chemoradiotherapy for advanced/metastatic Sq NSCLC are randomized 1:1 to oral veliparib (120 mg) or placebo, twice daily on Days −2 through 5 (7 consecutive days) of 21-day cycles. Randomization is stratified by tumor extent, smoking history, ECOG performance status, and geographic region. All patients receive carboplatin (AUC 6 mg/mL/min i.v.) and paclitaxel (200 mg/m2 i.v.) on Day 1 of each 21-day cycle. Treatment continues for a maximum of 6 cycles, or until radiographic progression or unacceptable toxicity. The primary study objective is to determine if the addition of veliparib to carboplatin and paclitaxel improves overall survival, compared with placebo plus carboplatin and paclitaxel. Secondary objectives are to assess progression-free survival and objective response rate. Duration of overall response, safety, tolerability, ECOG performance status, and quality of life are also evaluated. Sites from 37 countries are planned for trial participation. Recruitment began in Apr 2014 and 900 patients are planned for enrollment. Clinical trial information: NCT02106546.
Abstract 205: Analysis of resistance to RTK inhibitors using a novel RTK multiplex assay
Authors: Lu Chen, Anthony J. Saporita, Wen-Rong Lie, Reeti Maheshwari, Melissa Schluter, Jehangir Mistry, Joseph Hwang
Journal: Cancer Research (2016)

Abstract A novel multiplex immunoassay was developed for examining acquired resistance to Receptor Tyrosine Kinase (RTK) inhibitors. RTKs are transmembrane proteins which act as receptors for growth factors, neurotrophic factors and other extracellular signaling molecules. These cell-surface kinases are activated by extracellular ligands leading to receptor dimerization and tyrosine phosphorylation at specific residues in the cytoplasmic tails to initiate RTK-mediated signal transduction. Of the &amp;gt;500 known protein kinases in the human genome there are approximately 60 RTKs. They are central components of cell signaling networks and play crucial roles in normal physiological processes and disease processes ranging from diabetes to cancer. Many RTKs, such as EGFR, HER2, c-Kit, PDGFR and VEGFR, have been used as targets for drug development and RTK-targeted therapies have illustrated the utility of these treatments for selected cancers. However, in many cases, compensatory RTK signaling enables cancer cells to acquire resistance to RTK inhibitors that selectively target a single RTK. For example, some EGFR and HER2 inhibitors have led to resistance and are associated with increased expression of IGF1R. In order to understand the mechanisms of resistance to RTK inhibitors, we have developed a bead-based multiplex immunoassay capable of simultaneously detecting phosphorylation of 18 different RTKs. First we demonstrate detection of RTK phosphorylation in response to growth factor stimulation using various cell lines. Next we examined the specificity of two inhibitors targeting EGFR and HER2. These inhibitors specifically reduced growth factor-stimulated phosphorylation of EGFR and HER2, without inhibiting the activation of other RTKs. Although we did not observe compensatory activation of other RTKs in response to the two EGFR and HER2 inhibitors we tested, this study demonstrates the feasibility of using this novel 18-plex RTK panel for examining the mechanism of resistance to single RTK inhibitors. In summary, the RTK multiplex panel allowed for simultaneous detection of multiple tyrosine phosphorylated RTKs in a specific, sensitive, and reproducible manner. Citation Format: Lu Chen, Anthony J. Saporita, Wen-Rong Lie, Reeti Maheshwari, Melissa Schluter, Jehangir Mistry, Joseph Hwang. Analysis of resistance to RTK inhibitors using a novel RTK multiplex assay. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 205.
Reevaluating the Need for Electrocardiograms Prior to Initiation of Treatment With Propranolol for Infantile Hemangiomas
Authors: Jenna L. Streicher, E. Brooks Riley, Leslie A. Castelo-Soccio
Journal: JAMA Pediatrics (2016)

This study evaluates the cost of routine pretreatment electrocardiogram screening and determines whether testing led to significant management changes for 198 patients evaluated for initiation of treatment with propranolol over a 2-year period.
Validation of the MIBG SIOPEN scoring method in two independent high-risk neuroblastoma trials.
Authors: Ariane Boubaker, Ulrike Poetschger, Bieke Lambert, Maria Rita Castellani, Zvi Bar-Sever, Aurore Oudoux, Anna Kaminska, Katarina Taborska, Lorenzo Biassoni, Susan G. Kreissman, Gregory A Yanik, Arlene Naranjo, Marguerite T Parisi, Barry L. Shulkin, Katherine K. Matthay, Julie R. Park, Dominique Valteau-Couanet, Ruth L Ladenstein
Journal: Journal of Clinical Oncology (2014)

10029 Background: Harmonised evaluation standards of MIBG scintigraphy for (re)staging of neuroblastoma (NB) are an international aim. In the HR-NBL1/SIOPEN trial population a SIOPEN score (SISCO) >3 was associated with a significantly poorer event free survival (EFS) on pre and post induction mIBG. This analysis validates the SISCO prognostic value in the independent dataset (DS) of the Children's Oncology Group (COG) protocol A3973. Methods: SIOPEN scoring evaluates mIBG uptake over 12 skeletal regions (scored 0-6/region, maximum of 72), not considering extra-osseous disease nor the primary site. MIBG scans from mIBG-avid stage 4 NB pts in 2 collaborative trials were reviewed and judged evaluable by the SIOPEN Nuclear Medicine review committee: the COG-A3973 (DSA; n=216) and SIOPEN HR-NBL1 trial (DSB; n=343). Predefined categories from DSB were used with a SISCO of 0, 1-3, 4-17 and ≥18. In addition, the YOUDEN index was used to identify single cut points (CPY). The median follow-up time was 7.1 and 5.5y, respectively. Results: Both DS showed a significantly superior EFS with a SISCO ≤3 at diagnosis [5-yr EFS in DSA: 51%±7% vs 34%±4%, p= 0.047 and in DSB 47%±7% vs 26%±3%, p=0.007]. However, the YOUDEN index yielded different results at diagnosis with a CPY of 40 in DSA and 10 in DSB and failed to identify a consistent poor prognosis group. A post induction SISCO of ≤3 also revealed a significant superior outcome [5-yr EFS in DSA: 43%±5% vs 16%±6%, p=0.004 and in DSB 36%±4% vs 14%±4%, p< 0.001]. The post induction CPY was 3 in DSB (in line with the DSB stratification criterion of ≤3 mIBG positive spots to proceed to high dose chemotherapy) and 0 in DSA. Pts with a SISCO of 0 post induction have the best outcome in both DS. In MYCN amplified pts, the pre and post-induction SISCO of ≤3 showed a significant impact in both groups, whilst in MYCN non-amplified pts this effect is only seen post induction. A SISCO ≤3 has independent statistical significance in Cox models including age and MYCN. Conclusions: A SIOPEN score ≥ 3 of mIBG scans carries relevant prognostic significance for the management of patients with high-risk NB at diagnosis and at the end of induction chemotherapy in the HRNBl1/SIOPEN trial and was confirmed in the independent COG A3973 data set. Clinical trial information: NCT01704716.
Abstract 1912: Combinatorial targeting of PI3K and MAPK signaling pathways using microRNAs to inhibit tumor growth and metastasis in breast cancer
Authors: Merve Mutlu, Ozge Saatci, Erol Eyupoglu, Umar Raza, Ozgur Sahin
Journal: Cancer Research (2016)

Abstract PI3K/Akt and MAPK signaling pathways, regulating cancer cell proliferation, apoptosis and metastasis, are among the top most deregulated pathways in cancer. Current kinase inhibitors used in clinics have limited success since one of these pathways gets activated when the other is suppressed. Alternatively, simultaneous silencing of both pathways results in high toxicity. Here, we aimed to establish a microRNA-based, non-toxic approach to inhibit these pathways simultaneously in breast cancer. By analyzing our previously published Reverse Phase Protein Array (RPPA) data showing differential expression of 26 proteins upon overexpression of 733 different miRNAs, we selected top miRNAs significantly deregulating PI3K and MAPK pathways as well as cell cycle. We narrowed down the list by selecting miRNAs whose predicted targets were among the PI3K and MAPK pathway elements. We came up with a tumor suppressor miRNA affecting both in vitro viability and migration/invasion of breast cancer cells. We identified the set of differentially expressed genes in breast cancer patients under low and high expression of the miRNA. A significant association was observed between the expression of the miRNA or its identified gene signature and clinico-pathological properties of breast cancer patients. Combinatorial knockdown of targets of the miRNA that are in PI3K and MAPK pathways as a cocktail phenocopied the tumor suppressive effects of the miRNA in breast cancer cell lines. Notably, low expression of the target cocktail predicts a better outcome in breast cancer patients. Overall, we identified a tumor suppressor miRNA to be used an alternative to current kinase inhibitor-based therapies for major subtypes of breast cancer by suppressing both PI3K and MAPK pathways and as a result inhibiting proliferation and migration/invasion in breast cancer. Citation Format: Merve Mutlu, Ozge Saatci, Erol Eyupoglu, Umar Raza, Ozgur Sahin. Combinatorial targeting of PI3K and MAPK signaling pathways using microRNAs to inhibit tumor growth and metastasis in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1912.
Impact of Lenalidomide On Immune Functions in the Setting of Maintenance Therapy for Multiple Myeloma
Authors: Eolia Brissot, Aline Clavert, Nicolas Blin, Virginie Roland, Thierry Guillaume, Viviane Dubruille, Beatrice Mahe, Thomas Gastinne, Steven Le Gouill, Béatrice Gaugler, Philippe Moreau, Mohamad Mohty
Journal: Blood (2012)
Mutational analysis of biomarker samples from the CORRECT study: Correlating mutation status with clinical response to regorafenib.
Authors: Michael Jeffers, Eric Van Cutsem, Alberto F. Sobrero, Salvatore Siena, Alfredo Falcone, Marc Ychou, Yves Humblet, Olivier Bouche, Laurent Mineur, Carlo Barone, Antoine Adenis, Josep Tabernero, Takayuki Yoshino, Heinz-Josef Lenz, Richard M. Goldberg, Daniel J. Sargent, Frank Cihon, Andrea Wagner, Dirk Laurent, Axel Grothey
Journal: Journal of Clinical Oncology (2013)

381 Background: In the CORRECT Ph3 trial, regorafenib demonstrated significant improvement in OS and PFS vs. placebo in subjects with metastatic colorectal cancer (mCRC) who had progressed on standard therapies. An exploratory biomarker substudy was conducted on samples collected from subjects enrolled in CORRECT. Methods: DNA was isolated from archival tumor tissue and fresh baseline plasma samples that were available from 239 (31%) and 503 (66%) subjects enrolled in CORRECT, respectively. Mutations in KRAS, PIK3CA and BRAF were evaluated via BEAMing technology. Results: Mutations were readily detected in DNA isolated from both tumor and plasma samples: KRAS: 59/69%; PIK3CA: 12/17% and BRAF: 1.5/3.4%. The frequency of KRAS mutation detected in tumor samples via BEAMing (59%) was identical to the frequency determined from pre-existing “historical” KRAS mutation data that was available from 96% of the subjects enrolled in the study. Concordance among the mutations detected via BEAMing in tumor vs. plasma was 76% (KRAS), 88% (PIK3CA), and 97% (BRAF). A subset of CRC which was found to be KRAS-wildtype in DNA from archival tumor, but KRAS-mutant in DNA from fresh plasma was identified and may represent subjects whose KRAS mutational status had changed during prior therapy. Correlative subgroup analyses demonstrated that regorafenib mediated a trend for clinical benefit vs. placebo in both KRAS wildtype and mutant subgroups identified by plasma BEAMing (OS: KRAS WT, HR: 0.67, 95% CI: 0.41–1.08; KRAS mutant, HR: 0.81, 95% CI: 0.61–1.09; interaction p=0.561). Similar results were noted for PIK3CA WT/mutant subgroups (OS: WT, HR: 0.75, 95% CI: 0.57–0.99; mutant, HR: 0.84, 95% CI: 0.47–1.50; interaction p=0.723). BRAF was not analysed due to the small number of BRAF-mutant samples. Conclusions: The mutational analysis of DNA isolated from fresh plasma is feasible and robust using the BEAMing platform and may better represent the mutational status of the tumor(s) that a mCRC patient harbors at the time of enrollment than does the mutational analysis of archival primary tumor tissue. Regorafenib was associated with clinical benefit (vs. placebo) in all mutational subgroups evaluated. Clinical trial information: NCT01103323.
Interleukin-1α: a key player for epithelial-to-mesenchymal signalling in COPD?
Authors: Antoine Froidure, Maha Zohra Ladjemi, Charles Pilette
Journal: European Respiratory Journal (2016)

The lungs are continuously exposed to inhaled particles and irritants. Tobacco smoking is the leading cause of several airway diseases, including lung cancer, idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease (COPD). In COPD, repeated exposure to cigarette smoke induces chronic inflammation and structural remodelling of the airways, with peribronchial fibrosis and epithelial-to-mesenchymal transition [1], resulting in (mostly irreversible) airway obstruction. Thus, abnormal airway responses to noxious gases probably results from aberrant signalling and crosstalk between epithelial, mesenchymal and immune cells. Interleukin-1 alpha released by airway epithelial cells may instruct fibroblasts to become pro-inflammatory in COPD <http://ow.ly/CLYK301tyOj>
Interferon‐inducible T‐cell alpha chemoattractant (ITAC) induces the melanocytic migration and hypopigmentation through destabilizing p53 via histone deacetylase 5: a possible role of ITAC in pigment‐related disorders
Authors: E. Lee, S.‐Y. Choi, B.‐H. Bin, N.‐H. Kim, K.H. Kim, D.‐H. Choi, J. Han, H. Choi, A.‐Y. Lee, T.R. Lee, E.‐G. Cho
Journal: British Journal of Dermatology (2016)

Cell migration plays a major role in the immune response and in tumorigenesis. Interferon-inducible T-cell alpha chemoattractant (ITAC) elicits a strong chemotactic response from immune cells.To examine the effect of ITAC on melanocyte migration and pigmentation and its involvement in related disorders, and to investigate potential key players in these processes.Human melanocytes or melanoma cells were treated with ITAC and a migration assay was carried out. Global gene expression analysis was performed to find genes regulated by ITAC treatment. The function of key players involved in ITAC-induced cellular processes was addressed using knockdown or overexpression experiments in combination with ITAC treatment. ITAC expression in the inflammation-associated hypopigmentary disorder, vitiligo, was examined.Among CXCR3 ligands, only ITAC induced melanocyte migration. ITAC treatment upregulated the expression of histone deacetylase 5 (HDAC5) and downregulated that of p53, a known target of HDAC5. Through knockdown or overexpression of HDAC5 and p53, we confirmed that HDAC5 mediates ITAC-induced migration by decreasing levels of p53 via deacetylation. In addition, ITAC treatment could decrease pigmentation in a p53- and HDAC5-dependent manner. Finally, the increased migration of human melanoma cells by ITAC treatment and the increased ITAC expression in the epidermis of vitiligo skin were verified.This study provides in vitro evidence for the migratory and hypopigmentation effects of ITAC on melanocytic cells, gives translational insights into the roles of ITAC in pathological conditions, and suggests that HDAC5 and its substrate p53 are potent targets for regulating ITAC-induced cellular processes.