tbuckley/cabot-search huggingface dataset:
Abstract CT081: Poziotinib activity and durability of responses in previously treated EGFR exon 20 NSCLC patients - a Phase 2 study
Authors: Xiuning Le, Jonathan Goldman, Jeffrey Clarke, Nishan Techekmedyian, Zofia Piotrowska, David Chu, Gajanan Bhat, Francois Lebel, Mark Socinski
Journal: Cancer Research (2020)

Abstract Introduction and Purpose of Study: Effective and approved therapy for treating non-small cell lung cancer (NSCLC) with EGFR exon 20 mutations is an unmet medical need. Poziotinib is a potent tyrosine kinase inhibitor (TKI) of EGFR and HER2 exon 20 insertion mutants. We evaluated the efficacy and safety of poziotinib in previously treated NSCLC patients with EGFR exon 20 insertion mutations (ZENITH20-1) in an independent cohort of a multi-cohort, multi-center Phase 2 study. Methods: Poziotinib (16 mg) was administered orally QD, allowing dose reductions for AEs, with follow up for 24 months. The primary endpoint was objective response rate (ORR), evaluated by central radiographic review using RECIST v1.1. The ORR endpoint was to be met if the lower bound of 95% CI&amp;gt;17% in the As-Treated Population. The secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and safety. Safety monitoring was conducted throughout the study. Results: A total of 115 patients with a median age of 61 years (33-83) were enrolled. Patients had received and failed prior therapy (median of 2 [1-9]) with majority receiving both chemo and immunotherapy. The median relative dose intensity was 72% (7-100%) with 65% having dose reductions. 10% of patients discontinued due to related AEs. The ORR was 14.8% (95% CI 8.9%-22.6%), and the DCR was 68.7% (95% CI 59.4%-77.0%). Seventeen patients had a confirmed partial response (PR), 5 patients had unconfirmed PR and 62 (53.9%) patients had stable disease (SD). Overall, 75 (65%) patients had tumor size reductions. The median DoR was 7.4 months (95% CI 3.7-9.7) and the median PFS was 4.2 months (95% CI 3.7-6.6). Safety profile was mechanism related and similar to other 2nd generation tyrosine kinase inhibitors with the most common treatment-related Grade ≥3 AEs (preferred term) being rash (28%), diarrhea (26%), stomatitis (9%) and paronychia (6%). The incidence of treatment-related pneumonitis, an important AE associated with TKIs, was 4%. Conclusion: Although the ORR primary endpoint was not met, poziotinib induced tumor size reduction in the majority (65%) of patients. The tumor size reduction combined with long duration of response demonstrated the clinical activity of poziotinib in treating this patient population. We are further optimizing dosing and AE management. Citation Format: Xiuning Le, Jonathan Goldman, Jeffrey Clarke, Nishan Techekmedyian, Zofia Piotrowska, David Chu, Gajanan Bhat, Francois Lebel, Mark Socinski. Poziotinib activity and durability of responses in previously treated EGFR exon 20 NSCLC patients - a Phase 2 study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT081.
Phase I and Biomarker Study of the Wnt Pathway Modulator DKN-01 in Combination with Gemcitabine/Cisplatin in Advanced Biliary Tract Cancer
Authors: Lipika Goyal, Cynthia Sirard, Michael Schrag, Michael H. Kagey, Jennifer R. Eads, Stacey Stein, Anthony B. El-Khoueiry, Gulam A. Manji, Thomas A. Abrams, Alok A. Khorana, Rebecca Miksad, Devalingam Mahalingam, Andrew X. Zhu, Dan G. Duda
Journal: Clinical Cancer Research (2020)

Dickkopf-1 (DKK1) modulates Wnt signaling, promoting tumor growth, metastasis, and immunosuppression. High DKK1 expression has been detected in various tumor types-including biliary tract cancer (BTC)-and is associated with poor prognosis. DKN-01-a humanized mAb targeting DKK1-was evaluated in a phase I multicenter study in combination with gemcitabine and cisplatin in patients with unresectable or metastatic BTC with no prior systemic therapy for advanced disease.This study included a dose-escalation phase assessing DKN-01 at two dose levels (150 mg and 300 mg) combined with gemcitabine (1,000 mg/m2) and cisplatin (25 mg/m2) followed by dose expansion. Primary endpoints evaluated safety and tolerability; secondary endpoints evaluated efficacy, pharmacokinetics, and circulating biomarkers.Fifty-one patients with intrahepatic cholangiocarcinoma (63%), extrahepatic cholangiocarcinoma (8%), and gallbladder cancer (29%) were enrolled. No dose-limiting toxicities were seen, and the expansion phase proceeded with DKN-01 300 mg (N = 47). The most frequent grade 3/4 treatment-emergent adverse events included neutropenia (60%), thrombocytopenia (34%), and anemia (23%). The objective response rate was 21.3% and median progression-free survival was 8.7 months (95% confidence interval, 5.4-10.3 months). Better outcomes were associated with biomarkers of angiogenesis inhibition (increased sVEGFR1 and lower VEGF-C) and reduced inflammation (lower IL6 and decreased TNFα).DKN-01 300 mg was well tolerated in this combination but did not appear to have additional activity beyond historically reported efficacy with gemcitabine/cisplatin alone. Exploratory pharmacokinetic and biomarker data indicate potential antiangiogenic and immunomodulatory activity of DKN-01/chemotherapy and the need for increased dose/intensity. A study with DKN-01 600 mg in combination with a PD-1 inhibitor in BTC is ongoing.
Abstract A73: BCL-XL dependency in a subset of ovarian clear-cell carcinoma cell lines
Authors: Elizabeth H. Stover, Maya K. Gelbard, Ursula A. Matulonis, Matthew Meyerson
Journal: Clinical Cancer Research (2020)

Abstract Clear-cell ovarian carcinoma is a rare histologic subtype of epithelial ovarian cancers. Clear-cell ovarian cancers tend to be less responsive to platinum-based chemotherapy compared to high-grade serous ovarian cancers. In a dataset of large-scale CRISPR knockout and RNAi screens of cancer cell lines (depmap.org), a subset of ovarian clear-cell carcinoma cell lines were sensitive to knockout or knockdown of BCL2L1, encoding antiapoptotic protein BCL-XL. Most clear-cell ovarian cancer cell lines also express BCL2L1 mRNA and protein. We therefore tested a panel of ovarian cancer cell lines for response to BH3 mimetic drugs, which inhibit different members of the BCL-2 family of antiapoptotic proteins. Initial data showed that a subset of ovarian clear-cell carcinoma cell lines was sensitive to single-agent BCL-XL inhibition with A1331852 and dual BCL-2/BCL-XL inhibition with ABT-263. In contrast, these cell lines were relatively insensitive to single-agent BCL-2 inhibition or MCL1 inhibition. We are currently applying BH3 profiling, a functional assay for apoptotic priming, to test the response of ovarian clear-cell carcinoma cell lines to BCL-XL inhibition using a BCL-XL specific peptide, HRK. Collectively, these studies suggest that ovarian clear-cell carcinomas may be sensitive to BCL-XL inhibition, either alone or in combination with chemotherapy. Citation Format: Elizabeth H. Stover, Maya K. Gelbard, Ursula A. Matulonis, Matthew Meyerson. BCL-XL dependency in a subset of ovarian clear-cell carcinoma cell lines [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A73.
Multichannel Electrocardiograms Obtained by a Smartwatch for the Diagnosis of ST-Segment Changes
Authors: Carmen Anna Maria Spaccarotella, Alberto Polimeni, Serena Migliarino, Elisa Principe, Antonio Curcio, Annalisa Mongiardo, Sabato Sorrentino, Salvatore De Rosa, Ciro Indolfi
Journal: JAMA Cardiology (2020)

Acute coronary syndromes are the leading cause of death worldwide and the leading cause of disease burden in high-income countries. Quick and accurate diagnosis of acute coronary syndromes is essential to avoid fatal events, for timely intervention, and to improve the prognosis.To prospectively investigate the feasibility and accuracy of a smartwatch in recording multiple electrocardiographic (ECG) leads and detecting ST-segment changes associated with acute coronary syndromes compared with a standard 12-lead ECG.A commercially available smartwatch was used in 100 participants to obtain multiple-channel ECGs. The study was conducted from April 19, 2019, to January 23, 2020. Fifty-four patients with ST elevation myocardial infarction, 27 patients with non-ST elevation myocardial infarction, and 19 healthy individuals were included in the study. The watch was placed in different body positions to obtain 9 bipolar ECG tracings (corresponding to Einthoven leads I, II, and III and precordial leads V1-V6) that were compared with a simultaneous standard 12-lead ECG.The concordance among the results of the smartwatch and standard ECG recordings was assessed using the Cohen κ coefficient and Bland-Altman analysis.Of the 100 participants in the study, 67 were men (67%); mean (SD) age was 61 (16) years. Agreement was found between the smartwatch and standard ECG for the identification of a normal ECG (Cohen κ coefficient, 0.90; 95% CI, 0.78-1.00), ST-segment elevation changes (Cohen κ coefficient, 0.88; 95% CI, 0.78-0.97), and non-ST-segment elevation changes (Cohen κ coefficient, 0.85; 95% CI, 0.74-0.96). In addition, the Bland-Altman analysis demonstrated agreement between the smartwatch and standard ECG to detect the amplitude of ST-segment changes (bias, -0.003; SD, 0.18; lower limit, -0.36; and upper limit, 0.36). Use of the smartwatch ECG for the diagnosis of normal ECG showed a sensitivity of 84% (95% CI, 60%-97%) and specificity of 100% (95% CI, 95%-100%); for ST elevation, sensitivity was 93% (95% CI, 82%-99%) and specificity was 95% (95% CI, 85%-99%); and for NSTE ECG alterations, sensitivity was 94% (95% CI, 81%-99%) and specificity was 92% (95% CI, 83%-97%).The findings of this study suggest agreement between the multichannel smartwatch ECG and standard ECG for the identification of ST-segment changes in patients with acute coronary syndromes.
APOBEC3A catalyzes mutation and drives carcinogenesis in vivo
Authors: Emily K. Law, Rena Levin-Klein, Matthew C. Jarvis, Hyoung Kim, Prokopios P. Argyris, Michael A. Carpenter, Gabriel J. Starrett, Nuri A. Temiz, Lindsay K. Larson, Cameron Durfee, Michael B. Burns, Rachel I. Vogel, Spyridon Stavrou, Alexya N. Aguilera, Sandra Wagner, David A. Largaespada, Timothy K. Starr, Susan R. Ross, Reuben S. Harris
Journal: The Journal of Experimental Medicine (2020)

The APOBEC3 family of antiviral DNA cytosine deaminases is implicated as the second largest source of mutation in cancer. This mutational process may be a causal driver or inconsequential passenger to the overall tumor phenotype. We show that human APOBEC3A expression in murine colon and liver tissues increases tumorigenesis. All other APOBEC3 family members, including APOBEC3B, fail to promote liver tumor formation. Tumor DNA sequences from APOBEC3A-expressing animals display hallmark APOBEC signature mutations in TCA/T motifs. Bioinformatic comparisons of the observed APOBEC3A mutation signature in murine tumors, previously reported APOBEC3A and APOBEC3B mutation signatures in yeast, and reanalyzed APOBEC mutation signatures in human tumor datasets support cause-and-effect relationships for APOBEC3A-catalyzed deamination and mutagenesis in driving multiple human cancers.
Abstract 447: Integrated omics modeling of transcriptional regulation in medulloblastoma subtypes
Authors: Owen S. Chapman, Tobias Ehrenberger, Tenley C. Archer, Maxwell P. Gold, Filip Mundt, Miriam Adam, Clarence K. Mah, Karsten Krug, Sahaana Chandran, Jesse R. Dixon, Scot L. Pomeroy, Ernest Fraenkel, Jill P. Mesirov, Lukas Chavez
Journal: Cancer Research (2020)

Abstract Medulloblastoma (MB) is one of the most common pediatric brain tumors. Current treatment options carry substantial risk for lifelong cognitive and neurological impairment. Consequently, there is a pressing need to elucidate molecular mechanisms with the ultimate goal of developing targeted tumor-specific therapies. In a recent study on proteomes and phospho-proteomes of primary MB tumors, we identified proteomic MB subtypes that were not apparent from transcriptional or methylation data. To identify gene regulatory circuitries that drive these MB subtypes, we have now mapped accessible chromatin and 3D chromosome conformation in 23 and 13 MB tumors from the same cohort, using ATAC-seq and Hi-C respectively. We identify subtype-specific accessible regulatory chromatin regions, including a subset of regions not identifiable by the enhancer mark H3K27ac. We associate regulatory regions to their target gene promoters by correlating transcription with ATAC-seq signal strength, and confirm these relationships using the newly generated Hi-C data. Using an unpublished adaptation of the GSEA algorithm, which we tailored for an enrichment analysis of non-coding regulatory elements instead of genes, we identify transcription factors and master regulators with binding sites specific to an MB subtype. By associating these master regulators with their transcriptional targets, we have derived models of regulatory circuitry in MB which implicate central mechanisms of MB pathogenesis and may inform future therapeutic targeting. Citation Format: Owen S. Chapman, Tobias Ehrenberger, Tenley C. Archer, Maxwell P. Gold, Filip Mundt, Miriam Adam, Clarence K. Mah, Karsten Krug, Sahaana Chandran, Jesse R. Dixon, Scot L. Pomeroy, Ernest Fraenkel, Jill P. Mesirov, Lukas Chavez. Integrated omics modeling of transcriptional regulation in medulloblastoma subtypes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 447.
Abstract 92: Increasing TTFields treatment efficacy by targeting G2 cell cycle checkpoint
Authors: Paul Slangen, Mariska van Geldorp, Mark de Gooijer, Olaf van Tellingen, Gerben Borst
Journal: Cancer Research (2020)

Abstract Introduction; Tumor Treating Fields (TTFields) is a novel non-invasive anticancer treatment modality utilizing alternating electric fields. TTFields is FDA approved for glioblastoma patients after demonstrating a 5 months increase in overall survival, and for unresectable mesothelioma patients after the STELLAR trial showed an overall survival of 18 months without increasing the toxicity. While the effectiveness of TTFields is initially attributed to the effects of TTFields during cell division, studies are ongoing analysing its interphase effects and impact on the tumor (micro)environment. Our aim is to further exploit the working mechanism of TTFields by analysing its effect on the cell cycle and identify targets to increase its efficacy. Material and Methods; To analyse the effect of TTFields on the cell cycle, A172 glioblastoma cells were synchronized in S-phase by double thymidine block. Six hours post-release, cells were subjected to TTFields treatment (200kHz; 4,5V/cm). Cell cycle analysis was performed by flow cytometry (PI, α-phospho-histone H3Ser10). Efficacy of combination strategies were tested in 3 different glioblastoma cells lines (A172, U251 and SNB-19). Efficacy was quantified by colony formation assay (CFA) testing the cell reproductive death after treatment (i.e. only viable cells after treatment are replated to analyse the colony forming capacity). Results: TTFields treatment of synchronized A172 cells showed that TTFields causes an accumulation of cells in G2 phase and delayed entry into mitosis with less than 1% of the cells in mitosis 4 hours after TTFields exposure (versus 5% of mitotic cells in the control arm, p&amp;lt;0.001). This arrest can be abrogated by Wee1 inhibition (AZD1775) increasing the mitotic population to more than 35% at 4 hours after TTFields exposure (p&amp;lt;0.001). To test the efficacy of targeting the G2 checkpoint during TTFields treatment, cells were treated with TTFields and a Wee1 (AZD1775, PD0166285) or Chk1 (AZD7762) inhibitor for 72 hours and then replated for CFA. We observed an impressive synergistic effect between TTFields and any of these G2 cell cycle interfering drugs in all three cell lines (p&amp;lt;0.001). Conclusion: The underlying mechanism of the G2 checkpoint activation and the synergistic effect of TTFields plus G2 checkpoint targeting agents is subject of ongoing research. By any means, the combination of TTFields and G2 checkpoint targeting agents causes a synergistic treatment effect and is a very promising strategy. Citation Format: Paul Slangen, Mariska van Geldorp, Mark de Gooijer, Olaf van Tellingen, Gerben Borst. Increasing TTFields treatment efficacy by targeting G2 cell cycle checkpoint [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 92.
Abstract 3584: CENPA, MYBL2, and FOXM1 are identified as key transcriptional regulators in lung adenocarcinoma using TENET 2.0
Authors: Daniel J. Mullen, Chunli Yan, Diane S. Kang, Beiyun Zhou, Zea Borok, Crystal N. Marconett, Peggy J. Farnham, Ite A. Offringa, Suhn K. Rhie
Journal: Cancer Research (2020)

Abstract Lung cancer is the leading cause of cancer-related death in the United States, with lung adenocarcinoma being the most common subtype. Although a number of genetic alterations have been identified as potential drivers in lung adenocarcinoma, there is still a large gap in our understanding of tumor development. Epigenetic alterations have been implicated in the pathogenesis of tumors. To identify epigenetic alterations that drive lung adenocarcinoma, we used an improved version of the Tracing Enhancer Networks using Epigenetic Traits method (TENET 2.0) in primary normal lung and lung adenocarcinoma cells. We identified over 17,000 enhancers that appear activated in lung adenocarcinoma but not in normal lung and linked the activity of these enhancers to transcriptional regulators. We identified that CENPA, MYBL2, and FOXM1 are key transcriptional regulators activated in a subgroup of lung adenocarcinomas and they are linked to numerous cancer-specific enhancers. High expression of these regulators is associated with poor patient survival. In addition, we identified individual enhancers that are linked to these regulators and whose increased activities are strongly associated with poor patient survival. Knockdown experiments of MYBL2 and FOXM1 suggested that they regulate genes involved in controlling cell cycle progression and cell division. We also showed that high expression of TK1, a presumed target gene of a MYBL2-linked enhancer, is strongly associated with poor patient survival. Identification and characterization of key transcriptional regulators and associated cancer-specific enhancers in lung adenocarcinoma provides important insights into the deregulation of lung adenocarcinoma transcriptomes and novel potential targets for clinical intervention. Citation Format: Daniel J. Mullen, Chunli Yan, Diane S. Kang, Beiyun Zhou, Zea Borok, Crystal N. Marconett, Peggy J. Farnham, Ite A. Offringa, Suhn K. Rhie. CENPA, MYBL2, and FOXM1 are identified as key transcriptional regulators in lung adenocarcinoma using TENET 2.0 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3584.
Response to: ‘Comment on: ‘EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2019 update’ by Gossec<i>et al</i>’ by Wei<i>et al</i>
Authors: Laure Gossec, Xenofon Baraliakos, Iain McInnes, Andreas Kerschbaumer, Maarten de Wit, Maxime Dougados, Jette Primdahl, Désirée van der Heijde, Josef S Smolen
Journal: Annals of the Rheumatic Diseases (2020)

We thank Wei et al 1 for their correspondence on the recently published European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis (PsA). 2 The authors of this correspondence raise some interesting points.The first point relates to the role of cyclosporine A (CsA) in the treatment of patients with psoriatic disease.The authors mention that this drug is often used in Asia, in particular in skin psoriasis.They suggest that CsA could be proposed for PsA.While CsA is recommended for the management of skin psoriasis, 3 EULAR's systematic literature searches did not reveal a convincing efficacy in PsA based on two small randomised controlled trials 4 5 ; indeed, even a randomised trial on the addition of CsA in patients who had an insufficient response to methotrexate failed to meet its primary endpoint. 6Therefore, CsA is not put forward in the EULAR recommendations for the management of PsA, 2 and these recommendations do not deal with patients who only have psoriasis.The second point of the authors' comments relates to the definition of oligoarticular disease and, more specifically, the necessity for a full 66/68 joint count.We fully support using the 66/68 joint counts in PsA, as studies have shown that more limited joint counts may miss significant proportions of inflammation. 7he authors mentioned the Disease Activity in Psoriatic Arthritis (DAPSA) score, which is also recommended in the updated EULAR recommendations and, indeed, uses the 66/68 counts. 8ei et al support the new recommendation for tapering of biological DMARDs in patients reaching sustained remission, but suggest that an algorithm or a tapering guidance would be useful. 1 2Currently, given the lack of data on this subject, it is difficult to propose formal tapering strategies. 4In the absence of any data for PsA, Wei et al may be referred to the EULAR RA management recommendations 9 for a potential orientation, given that in RA tapering schedules have been studied. 10Tapering should be further investigated in PsA.The last point regards elderly patients and we agree with the authors that research is warranted on the management of elderly patients with PsA.
101HEMB01 Is a Phase 1/2 Open-Label, Single Ascending Dose-Finding Trial of DTX101 (AAVrh10FIX) in Patients with Moderate/Severe Hemophilia B That Demonstrated Meaningful but Transient Expression of Human Factor IX (hFIX)
Authors: Steven Pipe, Kimo Stine, Anita Rajasekhar, Tamara Everington, Allen Poma, Eric Crombez, Charles Rm Hay
Journal: Blood (2017)