tbuckley/cabot-search huggingface dataset:
Abstract 2931: Integrated genomic approaches identify upregulation of SCRN1 as a novel mechanism associated with acquired resistance to erlotinib in non small cell lung cancer cells with oncogenic EGFR mutation
Authors: Nayoung Kim, Ahye Cho, Hideo Watanabe, Yoon-La Choi, Meraj Aziz, Michelle Kassner, Je-Gun Joung, Angela KJ Park, Joshua Francis, Joon Seol Bae, Soo-min Ahn, Kyoung-Mee Kim, Joon-Oh Park, Woong-Yang Park, Myung-Ju Ahn, Keunchil Park, Hongwei Holly Yin, Jeonghee Cho
Journal: Cancer Research (2016)

Abstract Therapies targeting the tyrosine kinase activity of Epidermal Growth Factor Receptor (EGFR) have been proven to be effective in treating a subset of non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations. Inevitably these patients develop resistance to the EGFR-targeted tyrosine kinase inhibitors (TKIs). Here, we performed integrated genomic analyses using an in vitro system to uncover alternative genomic alterations responsible for acquired resistance to EGFR-TKIs. Specifically, we identified 80 genes whose expression is significantly increased in the resistant clones and RNAi-based systematic synthetic lethal screening revealed that suppression of one upregulated transcript, SCRN1, a secernin family member, restores sensitivity to erlotinib by enhancing inhibition of PI3K/AKT signaling pathway. Furthermore, we detected increased levels of SCRN1 in 5 of 11 lung tumor specimens from EGFR-TKIs refractory patients by immunohistochemistry. Taken together, we propose that upregulation of SCRN1 is an additional mechanism associated with acquired resistance to EGFR-TKIs in a subset of lung cancer patients and that its suppression serves as a novel therapeutic strategy to overcome drug resistance in these patients. Citation Format: Nayoung Kim, Ahye Cho, Hideo Watanabe, Yoon-La Choi, Meraj Aziz, Michelle Kassner, Je-Gun Joung, Angela KJ Park, Joshua Francis, Joon Seol Bae, Soo-min Ahn, Kyoung-Mee Kim, Joon-Oh Park, Woong-Yang Park, Myung-Ju Ahn, Keunchil Park, Hongwei Holly Yin, Jeonghee Cho. Integrated genomic approaches identify upregulation of SCRN1 as a novel mechanism associated with acquired resistance to erlotinib in non small cell lung cancer cells with oncogenic EGFR mutation. [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 2931.
Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with second-line nilotinib (NIL): First results from the ENESTop study.
Authors: Timothy P Hughes, Carla Boquimpani, Dong-Wook Kim, Noam Benyamini, Nelma Cristina D. Clementino, Vasily Shuvaev, Sikander Ailawadhi, Jeffrey Howard Lipton, Anna G. Turkina, Raquel De Paz Arias, Beatriz Moiraghi, Franck E. Nicolini, Jolanta Dengler, Tomasz Sacha, Naoto Takahashi, Rafik Fellague-Chebra, Sandip Acharya, Stephane Wong, Yu Jin, Francois-Xavier Mahon
Journal: Journal of Clinical Oncology (2016)

7054 Background: The ENESTop (NCT01698905) study explores the discontinuation of NIL therapy in pts who achieved sustained MR4.5 (BCR-ABL1IS≤ 0.0032%) after switching from imatinib (IM) to NIL. Methods: The single-arm phase 2 study enrolled pts with CML-CP treated with tyrosine kinase inhibitor (TKI) for ≥ 3 y (including IM for > 4 wk followed by NIL for ≥ 2 y) and achieved MR4.5 on NIL. On study, pts continued NIL for 1 y (consolidation phase [CONS]). After 1 y, pts without confirmed loss of MR4.5 (consecutive BCR-ABL1IS > 0.0032%), were eligible to stop NIL (TFR). RQ-PCR was monitored every 12 wk in CONS and every 4 wk during first 48 wk of TFR. Upon confirmed loss of MR4 (consecutive BCR-ABL1IS > 0.01%) or loss of MMR (BCR-ABL1IS> 0.1%), NIL was re-initiated (ReRx). Primary endpoint was the proportion of pts with successful TFR (neither loss of MMR nor confirmed loss of MR4 by 48 wk of TFR) after a ≥ 48 wk follow up (data cutoff, 26 Nov 2015). Results: Of the 163 pts in CONS, 126 entered TFR (median duration of TKI prior to TFR, 87.7 mo; median duration of NIL, 53 mo). At data cut-off, of the 126 pts, 57.9% (95% CI: 48.8-66.7) remained in TFR at 48 wks. Median follow up in TFR was 49.8 wk. During TFR, 18 pts had confirmed loss of MR4 (1 pt did not enter ReRx due to investigator decision), 34 lost MMR and one pt came off study for atypical transcript. Of the 51 pts who re-initiated NIL, 50 (98%) regained at least MMR by data cut-off, and 48 (94.1%) and 47 (92.2%) regained MR4 and MR4.5, respectively; 1 pt switched to another TKI, 22 wk after restart (BCR-ABL1IS: 62% at restart, 3% at study exit). Median time to regain MR4 was 12 wk and 13.1 wk for MR4.5. No new safety findings were observed on treatment. In CONS vs TFR, the rates of all grade (grade 3/4) musculoskeletal pain were 14.3% (0%) vs 42.1% (1.6%), cardiovascular events were 4.8% (2.4%) vs 0% (0%), and fluid retention were 1.6% (0%) vs 10.3% (0%). Conclusions: To date this is the largest prospective TFR data set in a population of pts who achieved a sustained deep molecular response after switching from IM to NIL. The study showed that TFR attempts are safe and that TFR is likely to be achievable in the majority of pts in this setting. Clinical trial information: NCT01698905.
Abstract 1238: A novel Ras inhibitor potently and selectively suppresses lung tumor cell growth by blocking Ras-Raf binding
Authors: Bing Zhu, Xi Chen, Veronica Ramirez-Alcantara, Kevin Lee, Jacob Valiyaveettil, Joshua Canzoneri, Sara Sigler, Kristy Berry, Ashley Lindsey, Adam Keeton, Michael R. Boyd, Gary A. Piazza
Journal: Cancer Research (2016)

Abstract Mutations in ras genes that result in constitutive activation of Ras proteins are key drivers of oncogenesis, but no effective drugs have been developed that target these aberrant gene products. Screening using a phenotypic assay designed to select for Ras inhibitors and iterative chemical synthesis, identified a preclinical drug development candidate with attractive drug-like properties designated as DC070-547. Here we evaluated the sensitivity of non-small cell lung cancer (NSCLC) cell lines to DC070-547. The compound potently suppresses the growth of human A549, H460, HOP62, H1299, H1975 lung tumor cells having high levels of activated Ras with low nanomolar IC50 values. By contrast, normal human airway epithelial cells (NHAECs) and H322 lung tumor cells with low levels of activated Ras displayed IC50 values in the mid micromolar range. The Ras selectivity of DC070-547 was confirmed by ectopic expression of mutant H-Ras-G12V (H-Rasm) in H322 cells using a retroviral construct, in which the IC50 value of DC070-547 for growth inhibition was reduced approximately 2,500 fold compared with vector control cells. To study the mechanism of action, Ras activation status was measured by Ras-Raf pull-down assays using GTP-bound Ras from cell lysates with GST-Raf1-RBD/GSH sepharose and followed by western blotting with Ras antibodies. Direct binding to Ras was apparent by the ability of DC070-547 to inhibit Ras-Raf binding at concentrations that inhibit Ras-dependent tumor cell growth. Pull-down assays also showed a dose-dependent inhibition of Ras-GTP levels in intact H-Rasm-H322 cells treated with DC070-547 at the same concentration range. Western blot analysis of Ras-immunoprecipitated proteins revealed that DC070-547 also attenuated high levels of EGFR phosphorylation at Y1068 in H-Rasm-H322 cells but not in control cells. These results demonstrate novel Ras inhibitory activities of DC070-547 in NSCLC cell lines. DC070-547 and its pipeline analogs are being evaluated for antitumor efficacy in preclinical mouse models of lung cancers. Citation Format: Bing Zhu, Xi Chen, Veronica Ramirez-Alcantara, Kevin Lee, Jacob Valiyaveettil, Joshua Canzoneri, Sara Sigler, Kristy Berry, Ashley Lindsey, Adam Keeton, Michael R. Boyd, Gary A. Piazza. A novel Ras inhibitor potently and selectively suppresses lung tumor cell growth by blocking Ras-Raf binding. [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 1238.
In-depth tissue profiling using multiplexed immunohistochemical consecutive staining on single slide
Authors: Romain Remark, Taha Merghoub, Niels Grabe, Geert Litjens, Diane Damotte, Jedd D. Wolchok, Miriam Merad, Sacha Gnjatic
Journal: Science Immunology (2016)

Despite remarkable recent achievements of immunotherapy strategies in cancer treatment, clinical responses remain limited to subsets of patients. Predictive markers of disease course and response to immunotherapy are urgently needed. Recent results have revealed the potential predictive value of immune cell phenotype and spatial distribution at the tumor site, prompting the need for multidimensional immunohistochemical analyses of tumor tissues. To address this need, we developed a sample-sparing, highly multiplexed immunohistochemistry technique based on iterative cycles of tagging, image scanning, and destaining of chromogenic substrate on a single slide. This assay, in combination with a newly developed automated digital landscaping solution, democratizes access to high-dimensional immunohistochemical analyses by capturing the complexity of the immunome using routine pathology standards. Applications of the method extend beyond cancer to screen and validate comprehensive panels of tissue-based prognostic and predictive markers, perform in-depth in situ monitoring of therapies, and identify targets of disease.
Elective stenting of unprotected left main coronary artery stenosis
Authors: Seung-Jung Park, Myeong-Ki Hong, Cheol Whan Lee, Jae-Joong Kim, Jae-Kwan Song, Duk-Hyun Kang, Seong-Wook Park, Gary S Mintz
Journal: Journal of the American College of Cardiology (2001)
Next generation sequencing (NGS) in resectable non-small cell lung cancer (NSCLC): Therapeutic implications.
Authors: Valerie W. Rusch, Kay See Tan, Amanda Ghanie, Maria E. Arcila, William D. Travis, David Randolph Jones, Bernard J. Park, James Huang, Charles M. Rudin, David Michael Hyman, David B. Solit, Michael F. Berger, Jose Baselga, Marc Ladanyi, Gregory J. Riely
Journal: Journal of Clinical Oncology (2016)

8541 Background: Tumor molecular profiling to direct therapy is standard for patients with advanced lung adenocarcinoma (AC) but is not routine in early stage NSCLC. Clinical trials are only beginning to test this approach for postoperative adjuvant therapy. After systematic preoperative consent and tumor/blood acquisition, we analyzed molecular profiling data in resectable NSCLC to enhance clinical trial participation and design. Methods: Prospective genomic analysis of resectable NSCLC was initiated in 2015 using MSK-IMPACT, a multiplexed NGS assay that detects base substitutions, short indels, copy number alterations and select gene rearrangements involving 341 (v1) or 410 (v2) cancer associated genes. Frequencies of mutations are summarized by histology (AC or squamous cell). AC further classified by histologic predominance as good (lepidic, MIA), intermediate (acinar, papillary), poor (micropapillary, solid) prognosis. Results: 123 tumors from 119 consecutive patients (4 synchronous 10); median age 67.8; 80(67%) females; 96(81%) Caucasian, 5(4.2%) Asian; 15 (13%) never smokers, median 26 pk/yrs smoking; 98 (80%); pStage I/II 103(84%). 60 AC (59%) had multiple mutations, predominantly EGFR+TP53 and KRAS+STK11. Conclusions: Initial experience shows a high frequency of multiple targetable mutations in resectable NSCLC that can be used to direct patients to appropriate adjuvant therapy trials. Mutations All AC * (N=102; 83%) AC Good (N=14; 14%) AC Intermediate (N=59; 58%) AC Poor (N=26; 26%) Squamous (SCC) (N=12; 10%) EGFR 28 (28%) 3 (21%) 22 (37%) 3 (12%) 1** KRAS 45 (44%) 6 (43%) 25 (42%) 13 (50%) 1 ALK 3 0 0 2 0 ROS1 3 1 1 0 0 BRAF 8 3 3 2 0 RET 5 1 1 3 0 MET ex14 3 1 0 2 0 MET other 6 0 3 3 0 ERBB2 0 0 0 0 0 TP53 42 (41%) 3 (21%) 25 (42%) 13 (50%) 10 STK11 22 (22%) 1 (7.1%) 14 (24%) 6 (23%) 1 Rb1 5 1 2 1 1 PTEN 1 1 0 0 1 P1K3CA 8 1 5 2 1 Data shown exclude carcinoid, SCLC, pleomorphic tumors (n=9); *histologic predominance unavailable (n=3); **amplification.
Comparable Efficacy and Safety with Voriconazole or Posaconazole as Primary Antifungal Prophylaxis in Acute Myeloid Leukemia (AML) Patients Receiving Induction Chemotherapy.
Authors: Gene A Wetzstein, Timothy J. George, Mahsa Sharifi, Van D Hoang, Viet Q Ho, Rod E Quilitz, Dana A Spears, Rami S. Komrokji, Alan F List, Jeffrey E Lancet, John N Greene
Journal: Blood (2009)
Abstract 2899: Selinexor inhibits NF-κB activity by sequestering IkB-a in the nucleus and blocking IkB-a degradation
Authors: Trinayan Kashyap, Christian Argueta, Boris Klebanov, TJ Unger, Benjamin Link, Maxwell Werman, Margaret Lee, Sharon Shacham, Yosef Landesman
Journal: Cancer Research (2016)

Abstract Background: Selinexor is a small-molecule therapeutic that inhibits XPO1 mediated nuclear export, resulting in nuclear accumulation of tumor suppressor proteins (TSPs) and subsequently cancer cell death while sparing normal cells. It has been previously demonstrated that the inhibitor of NFκB, IκB-, is localized to the cytoplasm by XPO1 in several cancer cell lines and that treatment of cancer cells with selinexor reduces NF-κB transcriptional activity. The mechanism of NF-κB inhibition by selinexor, however, is not fully understood. We hypothesized that nuclear retention of IκB- and down-regulation of IκB- kinase (IKK) in response to selinexor treatment would inhibit NF-κB transcriptional activity. Methods: U2OS (Osteosarcoma) cells were treated with selinexor in the presence or absence of TNF stimulation and whole protein lysates were analyzed by Western blotting. IκB- localization was evaluated by immunofluorescence microscopy and NF-κB transcriptional activity by ELISA (Thermo Scientific). Results: TNFα induced the phosphorylation of NF-κB p65 subunit on serine 536 and IκB- on serine 32/36 through IKK. This resulted in the dissociation of IκB-α from NF-κB and led to IκB-α degradation via the 26S proteasome. Free NF-κB could now migrate into the nucleus and initiate transcriptional activation supporting tumorigenicity and inflammation. The IKK kinase is a complex made of two kinases (IKKα and IKKβ) and one regulatory subunit, NEMO/IKKγ. We found that selinexor treatment blocked IKK activity through the down regulation of the IKK (IKKγ) gamma subunit protein levels. This inhibition was dose dependent and prevented IκB- phosphorylation, thereby protecting IκB- from degradation. The protection of intact IκB- from degradation and its forced nuclear accumulation through XPO1 inhibition enabled inhibition of NF-κB transcriptional activity even in the presence of TNFα. Selinexor did not alter the protein levels of IKK or IKK. Conclusions: Selinexor blocks TNFα induced degradation of IκB- by reducing the levels of IKK. In addition, selinexor increased nuclear IκB- levels through the inhibition of nuclear export. This blocked NF-κB activity and enhanced cancer cell death. We are currently investigating the beneficial effects of combining selinexor with proteasome inhibitors, which are known to prevent IκB- degradation. Citation Format: Trinayan Kashyap, Christian Argueta, Boris Klebanov, TJ Unger, Benjamin Link, Maxwell Werman, Margaret Lee, Sharon Shacham, Yosef Landesman. Selinexor inhibits NF-κB activity by sequestering IkB-a in the nucleus and blocking IkB-a degradation. [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 2899.
Abstract 472: A digital sorting-based detection and isolation assay for single disseminated cancer cells from lymph nodes of melanoma patients
Authors: Sebastian Scheitler, Kathrin Weidele, Barbara Alberter, Christian Werno, Christoph A. Klein, Bernhard Polzer
Journal: Cancer Research (2016)

Abstract We recently showed that sentinel lymph node (SLN) disaggregation followed by immunocytology enables precise quantification of disseminated cancer cells (DCC). We demonstrated that this approach has a 20-fold higher sensitivity to detect melanoma DCCs than routine histopathology and that the DCC density (DCCD, defined as the number of DCCs per million lymph node cells) together with ulceration state and tumor thickness enables individual risk prediction superior to current AJCC guidelines (Ulmer et al., PLoS Medicine, 2014). Here, we present the adaptation of this method to a semi-automated workflow, including automated single cell detection and isolation by DEPArrayTM technology for subsequent molecular analysis of DCCs from SLN of melanoma patients. The developed workflow includes a mechanical disaggregation of lymph node tissue and collection of the mononuclear cells after Percoll density centrifugation. Several tumor cell enrichment methods were tested (CellSearch® and size-based enrichment technologies), however, failed to process cell suspensions generated from lymph nodes due to clumping of cells during the enrichment procedure. Tumor cell enrichment using MACS depletion of CD45+ cells delivered approx. 50% of spiked-in cell line cells with a mean depletion rate of lymphocytes and erythrocytes &amp;gt; 98%. To prevent limitations in DCC detection caused by phenotypic heterogeneity of tumor cells, we established a double staining against two melanoma-associated markers gp100 and MCSP. Individual melanoma cells are then detected and isolated by DEPArrayTM technology enabling single cell whole genome amplification (Ampli1TM) for subsequent molecular analysis as assessment of copy number alterations (e.g. by arrayCGH) or sequence analysis for melanoma specific point mutations (e.g. BRAF or NRAS). We successfully applied the workflow to first SLN samples from melanoma patients. The established workflow enables a standardized detection of single DCCs from lymph nodes of melanoma patients applicable in clinical diagnostic labs. Automated single cell isolation and subsequent molecular analysis of DCCs is feasible within short time after SLN biopsy. In the future, this approach could help to select individualized therapies for melanoma patients. Citation Format: Sebastian Scheitler, Kathrin Weidele, Barbara Alberter, Christian Werno, Christoph A. Klein, Bernhard Polzer. A digital sorting-based detection and isolation assay for single disseminated cancer cells from lymph nodes of melanoma patients. [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 472.
Mutation JAK2 V617F in Patients with Myeloproliferative Disorders and Technical Aspects of Its Detection.
Authors: Sona Pekova, Rudolf Hoffmann, Pavel Jindra, Ludmila Novakova, Tomas Kozak, Vera Vozobulova, Miroslava Schutzova, Jozef Balasz, Lucie Tomsikova, Miroslav Prucha
Journal: Blood (2006)
Abstract 1968: Systematic validation of microRNA based prognostic biomarkers for stage II, III and IV colorectal cancer
Authors: Dongling Ma, Yaqi Xue, Andrew Fesler, Haiyan Zhai, Jie Yang, Apisri Ieamniramit, Wenzhe Li, Jingfang Ju
Journal: Cancer Research (2016)

Abstract microRNA (miRNA) based biomarkers have great potential due to their critical regulatory functions, superior stability, and relative small number compared to mRNAs. We have previously discovered a number of miRNAs that play key roles in colon cancer stem cell resistance and demonstrated their clinical potential as prognostic biomarkers. In this study, we have validated the prognostic potential of a panel of miRNAs in 204 stage II, III, and IV colorectal cancer specimens by qRT-PCR analysis. Many of the miRNAs have been functionally validated to be important in contributing to chemoresistance to 5-FU based chemotherapy. We also determined that miR-16 is the most consistent miRNA for expression normalization. We have validated several miRNAs that are significantly associated with disease free survival (DFS) and overall survival (OS) of stage II, III and IV colorectal cancer patients. This study, together with some of the previous studies, establishes a solid foundation for miRNA based precision management of colorectal cancer. Citation Format: Dongling Ma, Yaqi Xue, Andrew Fesler, Haiyan Zhai, Jie Yang, Apisri Ieamniramit, Wenzhe Li, Jingfang Ju. Systematic validation of microRNA based prognostic biomarkers for stage II, III and IV colorectal 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 1968.
Abstract 3720: Tissue-specific blockage of DNA damage responses sensitizes breast cancer chemotherapy
Authors: Rong Xu, Haifa Shen
Journal: Cancer Research (2016)

Abstract Systemic chemotherapy is not effective at eradicating metastatic breast cancer, and approaches to improve the outcomes for these patients are urgently needed. The ideal method to enhance chemotherapy would involve targeting a protein that is differentially or exclusively expressed in cancer compared to normal tissue; however, such targets are rare. We sought to target the actively dividing breast cancer cells in the distant metastatic organs with tumor tissue-specific delivery of therapeutic siRNA that suppresses the expression of key DNA damage response (DDR) genes such as CHK1 and RAD51 in order to sensitize chemotherapy. Knockdown of CHK1 and RAD51 expression by the gene-specific siRNA oligos was confirmed in vitro in MDA-MB-231 human breast cancer cells. Treatment of nude mice bearing lung metastatic MDA-MB-231 tumors with tumor-enriched nanoparticle-packaged CHK1 or RAD5 siRNA did not significantly suppress tumor growth. Single agent treatment with biweekly 6 mg/kg doxorubicin treatment did not slow down growth of the metastatic tumors either. In contrast, combination treatment with 6 mg/kg doxorubicin and 15 μg CHK1 or RAD51 siRNA in nanoparticles dramatically inhibited tumor growth and extended animal survival. Our result supports the development of tumor tissue-enriched siRNA therapeutics targeting the DDR pathways to sensitize breast cancer therapy. Citation Format: Rong Xu, Haifa Shen. Tissue-specific blockage of DNA damage responses sensitizes breast cancer chemotherapy. [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 3720.
Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma
Authors: Sarit E. Assouline, Torsten Holm Nielsen, Stephen Yu, Miguel Alcaide, Lauren Chong, David MacDonald, Axel Tosikyan, Vishal Kukreti, Abbas Kezouh, Tina Petrogiannis-Haliotis, Marco Albuquerque, Daniel Fornika, Sepideh Alamouti, Remi Froment, Celia M. T. Greenwood, Kathleen Klein Oros, Errol Camglioglu, Ayushi Sharma, Rosa Christodoulopoulos, Caroline Rousseau, Nathalie Johnson, Michael Crump, Ryan D. Morin, Koren K. Mann
Journal: Blood (2016)
Concomitant Administration Of Activated Prothrombin Complex Concentrate and Recombinant Activated Factor VII At Low Doses Are Efficacious and Safe In Hemophilic Mice
Authors: Michael Dockal, Sabine Knappe, Peter Leidenmuehler, Christina Piskernik, Sylvia Tippl, Marlene Resch, Dagmar Verdino, Alexander Bauer, Werner Hoellriegl, Friedrich Scheiflinger
Journal: Blood (2013)