tbuckley/cabot-search huggingface dataset:
Abstract 3784: Role of HPV-human fusion transcripts in oropharyngeal cancer development
Authors: Lisa Pinatti, Heather Walline, Thomas Carey
Journal: Cancer Research (2019)

Abstract Human papillomavirus (HPV) genomic integration is frequently seen in oropharyngeal squamous cell carcinoma (OPSCC). Integration into cellular genes can cause the generation of HPV-host fusion transcripts, which have been associated with worse survival in OPSCC patients, but their functional consequences are unknown, as HPV alone is capable of transformation. The forced expression of fusion transcripts versus HPV transcripts in spontaneously immortalized human oral keratinocytes (NOKSI) could demonstrate their effects on cell behavior. Our research focuses on characterizing HPV integration sites and fusion transcripts in cell lines and tumors, followed by in vitro analysis of fusion transcript function. By Detection of Integrated Papillomavirus Sequences (DIPS-PCR) and RT-PCR, we have identified integration events and fusion transcripts in a subset of samples in both intergenic and genic regions of the genome. We began our analysis with a fusion transcript reading from HPV16 E6-E7-E1 into the tumor suppressor gene TP63 from UM-SCC-47. The full fusion transcript and the HPV portion only were cloned into lentiviral vectors, and stable NOKSI populations expressing these transcripts were selected. These cultures, as well as control cultures, were subjected to proliferation, migration and invasion assays. Subsequent in-depth molecular characterization and in vivo studies will help clarify their effects on cancer formation and metastasis. These studies will advance our understanding of how fusion transcripts lead to worse patient survival and help develop new therapies for these patients. Citation Format: Lisa Pinatti, Heather Walline, Thomas Carey. Role of HPV-human fusion transcripts in oropharyngeal cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3784.
Abstract 2290: Expression pattern of androgen receptor (AR), splice variant 7 (AR-V7) and splice variant 567 (AR-567) in circulating tumor cells and paired plasma-derived exosomes in metastatic castration resistant prostate cancer
Authors: Areti D. Strati, Martha Zavridou, Evangelos Bournakis, Sophia Mastoraki, Evi S. Lianidou
Journal: Cancer Research (2019)

Abstract INTRODUCTION: Androgen-receptor splice variant 7 (AR-V7)is a highly promising liquid biopsy predictive biomarker indicating primary or acquired resistance to novel androgen receptor signaling inhibitors in metastatic castration resistant prostate cancer (mCRPC). We present for the first time the expression pattern of AR-FL, AR-V7, and AR-567es at a quantitative level in circulating tumor cells (CTCs) and paired plasma-derived exosomes in mCRPC. METHODS: We first developed and analytically validated a novel multiplex RT-qPCR assay for AR full length (AR-FL), AR-V7, AR-567es and AR-total. We then quantified the expression levels of AR-splice variants, CK-19 (epithelial marker) and B2M (reference gene) in EpCAM+ CTCs and paired plasma-derived exosomes isolated from peripheral blood (20mL) of 62 mCRPC patients and 10 healthy donors. RESULTS: In CTCs AR-FL was detected in 57/62(92%),AR-V7 in 32/62(52.0%),AR-567es in15/62(24.2%) and AR-total in 56/62(90.0%). In paired plasma-derived exosomes, AR-FL was detected in 45/62(72.5%), AR-V7 in 4/62(6.5%), AR-567 in 2/62(3.2%) and AR total in 47/62(75.8%).CK-19 expression was detected in 18/62(29.0%) of CTCs and in 28/62(45.2%) of exosomes. In all cases AR splice variants were expressed at higher levels in CTCs than in paired exosomes, while AR-V7 was detected at higher percentages than AR-567es. CONCLUSIONS: Our results reveal for the first time a remarkable heterogeneity on the expression levels of AR-FL, AR-V7 and AR-567es in EpCAM+ CTCs and paired exosomes between individual mCRPC patients. The clinical significance of this finding will be further investigated in large patient cohorts in respect to therapy response. Citation Format: Areti D. Strati, Martha Zavridou, Evangelos Bournakis, Sophia Mastoraki, Evi S. Lianidou. Expression pattern of androgen receptor (AR), splice variant 7 (AR-V7) and splice variant 567 (AR-567) in circulating tumor cells and paired plasma-derived exosomes in metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2290.
CLI24-001: First-in-human study of SEL24/MEN1703, an oral dual PIM/FLT3 kinase inhibitor, in patients with acute myeloid leukemia.
Authors: Farhad Ravandi, Stephen Anthony Strickland, Scott R. Solomon, Aziz Nazha, Roland B. Walter, Ilaria Valimberti, Alessia Tagliavini, Caterina Fiesoli, Monica Binaschi, Krzysztof Brzozka, Simone Baldini, Steffen Heeger, Andrea Ugo Pellacani
Journal: Journal of Clinical Oncology (2019)

TPS7062 Background: FLT3-ITD is one of the most common genetic lesions in acute myeloid leukemia (AML). PIM kinases are oncogenic FLT3-ITD targets expressed in AML cells and increased PIM kinase expression is found in relapse samples from AML patients treated with FLT3 inhibitors. In addition, inhibition of PIM kinases restores sensitivity to FLT3 inhibitors and dual FLT3/PIM inhibition eradicates FLT3-ITD+ cells including primary AML cells. SEL24/MEN1703, a potent PIM/FLT3 dual inhibitor, demonstrates a significantly broader spectrum of activity in AML cell lines and primary AML blasts, irrespective of FLT3 status, compared to monotherapy with either FLT3 or PIM inhibitors such as quizartinib or AZD1208. Methods: CLI24-001 is a First in Human, open label, non-randomized, multi-center, Phase I/II dose-escalation and cohort expansion study of SEL24/MEN1703 in AML patients (excluding APL) not suitable for chemotherapy. SEL24/MEN1703 is given orally, QD, for 14 days in a 21-day cycle with cycles repeated until disease progression or unacceptable toxicity. Dose escalation follows a 3+3 design to identify the recommended phase 2 dose (RP2D). In the phase 2 part/cohort expansion, subjects will receive SEL24/MEN1703 at the RP2D, to further investigate the safety profile and signs of antileukemic activity. In both study parts, patients are eligible regardless of mutational status and/or prior exposure to FLT3 inhibitors; prior treatment with PIM inhibitors is not allowed. Main inclusion criteria comprise a white blood count (WBC) of ≤30 x 10 9 /L (hydroxyurea/leukoapheresis permitted to lower WBC). Key secondary objectives include pharmacokinetics (PK) and single agent efficacy. The study is enrolling at 5 US sites and will be extended, both in US and EU, in the cohort expansion part. This is the first trial testing a dual PIM/FLT3 inhibitor with the potential to be active in AML regardless of FLT3 status andwith a potential to overcome FLT3 inhibitor resistance. (Sci Adv. 2015;1:e1500221; Oncotarget. 2018 Mar 30;9(24):16917-16931) Clinical trial information: NCT03008187.
Abstract 4081: Efficacy of MERTK inhibitor in combination with pembrolizumab in lung cancer
Authors: Kyoung-Ho Pyo, Ha-Ni Cho, Chun-Feng Xin, Jae Seok Cho, Han Na Kang, Jiyeon Yun, Hye Ryun Kim, Byoung Chul Cho
Journal: Cancer Research (2019)

Abstract Introduction: MERTK is thought to play a role in cancer immune evasion mechanism based on M2 type macrophage-driven immunosuppression in tumor microenvironment (TME). Thus, MERTK is a highly promising target for anti-cancer therapy under high tumor associated macrophages (TAMs) condition. We evaluated the anti-tumor effects and immune reaction of combination or single MERTK inhibitor in two lung squamous patients derived xenograft (PDX) tumor engrafted Hu-CD34-NSG models. Methods: The aPD-1 sensitive (YHIM2004) and aPD-1 non-sensitive (YHIM2009) squamous cell carcinoma PDX models were selected from pre-test with pembrolizumab. The selected two models were composed four groups; control, pembrolizumab, MERTK inhibitor, and combination. We applied pembrolizumab as aPD-1 blockade (10 mpk, q2w, i.p. inj.). The dose of MERTK inhibitor was 50 mpk, q1d by orally. The treatment was started when tumor size reached 100 mm3. Whole exome sequencing (WES), microarray (mRNA), flow cytometry, and multispectral image analysis were performed on the tumors. To elucidate the involvement of MERTK inhibitor in tumor, the tumor mutation burden, tumor microenvironment and immune cell phenotype were deconvoluted. Results: The TMB of YHIM2004 and YHIM2009 was 3.23 and 2.64 (mutations/Mb) respectively. The PD-L1 and TIL level of YHIM2004 were relatively higher than YHIM2009. Both two models were observed high macrophage in tumor. The two PDX-models, YHIM2004 (aPD-1 sensitive), YHIM2009 (aPD-1 non-sensitive) were observed anti-tumor effects in MERTK inhibitor single treatment groups (TGI = 44.23%, 67.40% respectively, p &amp;lt; 0.05, t-test). Especially, YHIM2004 tumor was reduced after combination therapy more than single treatment. Of note, the NOG-PDX model demonstrated no anti-tumor effect in MERTK inhibitor monotherapy, suggesting that this drug involves anti-cancer immune responses. Flow cytometry data showed increased PD-1+ and granzyme B+ T cells (p &amp;lt;0.05, t-test) in the combined group (YHIM2004) and MERTK inhibitor monotherapy group (YHIM2009) as much as the tumor suppressive effect. Conclusion: We concluded that MERTK signaling involves regulation of anti-cancer immune responses. Our results suggest an anti-cancer therapeutics of MERTK selective inhibitor on aPD-1 sensitive or non-sensitive tumors under high TAM tumor microenvironment. Citation Format: Kyoung-Ho Pyo, Ha-Ni Cho, Chun-Feng Xin, Jae Seok Cho, Han Na Kang, Jiyeon Yun, Hye Ryun Kim, Byoung Chul Cho. Efficacy of MERTK inhibitor in combination with pembrolizumab in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4081.
Abstract 824: LKB1 loss in lung adenocarcinoma leads to global hypomethylation and altered FOXA binding
Authors: Michael J. Koenig, Joseph Amann, Bernice Agana, Jacob Kaufman, Vicki Wysocki, Christopher Oakes, David P. Carbone
Journal: Cancer Research (2019)

Abstract LKB1 is functionally lost in 30% of lung adenocarcinoma cases. There are no targeted therapies available for LKB1-loss tumors. Previous studies of LKB1-loss in a mouse model of pancreatic cancer suggested that LKB1 loss drives DNA hypermethylation and serine biogenesis. DNA methyltransferases (DNMTs) maintain CpG methylation, which suppresses gene transcription. The primary substrate for DNMTs is S-adenosyl Methionine (SAMe), and the maintenance of CpG methylation has been shown to be dependent on continued regeneration of SAMe. KRAS status is associated both with LKB1 loss and with a CpG island hypermethylation phenotype (CIMP). Using a previously published 16-gene signature for LKB1 loss, we set out to confirm whether the changes that occur in the mouse model of pancreatic cancer also occur in lung cancer. We applied our signature to samples in The Cancer Genome Atlas (TCGA) lung adenocarcinoma dataset (signature-positive samples are described as “LKB1-loss”), which allowed us to compare both gene expression data as well as methylation data from Illumina 450k microarrays. We then developed a cell-line model for LKB1-loss in order to study the mechanism by which LKB1 regulates DNA methylation. We observed that LKB1-loss is associated with widespread demethylation of the genome in TCGA samples. Approximately 14,000 CpG sites were significantly hypomethylated in LKB1-loss tumors, while only 200 were hypermethylated (adjusted p-value cutoff = 0.05). Furthermore, Student’s t-test showed that LKB1-loss samples have significantly lower average methylation (β-values), regardless of KRAS status. Using motif analysis, we found that demethylated CpG sites are significantly enriched for FOXA1/2/3 consensus binding sites. FOXA transcription factors are well known as pioneering transcription factors that mediate demethylation. We discovered in vitro that FOXA1 localization and turnover is dependent on LKB1 expression, specifically the activity of downstream kinase SIK. Rather than showing enhanced serine biogenesis, LKB1-loss tumors express less DNMT1 and LC-MS/MS analysis shows depletion of SAMe. Finally, in vitro models of LKB1-loss show an increased sensitivity to DNMT inhibitors and FOXA1 silencing. Together, these observations suggest that LKB1-loss lung adenocarcinoma patients have a distinct hypomethylation profile. This profile may make them uniquely sensitive to DNMT-inhibition in combination with other therapies, a hypothesis which we will test in future studies. Citation Format: Michael J. Koenig, Joseph Amann, Bernice Agana, Jacob Kaufman, Vicki Wysocki, Christopher Oakes, David P. Carbone. LKB1 loss in lung adenocarcinoma leads to global hypomethylation and altered FOXA binding [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 824.
ATP release drives heightened immune responses associated with hypertension
Authors: Tuantuan V. Zhao, Yu Li, Xiaoli Liu, Shudong Xia, Peng Shi, Li Li, Zexin Chen, Chunyou Yin, Masahiro Eriguchi, Yayu Chen, Ellen A. Bernstein, Jorge F. Giani, Kenneth E. Bernstein, Xiao Z. Shen
Journal: Science Immunology (2019)

Hypertension promotes ATP release from erythrocytes, leading to a P2X7-dependent increase in T cell–mediated immune responses.
Abstract 19637: Superiority of Calcium Sensitizer Over Beta-Adrenoceptor Agonist for Treatment of Myocardial Dysfunction after Deep Hypothermic Circulatory Arrest. Role of Calcium Desensitization
Authors: Alessio Rungatscher, Seth Hallstroem, Alice Giacomazzi, Daniele Linardi, Maddalena Tessari, Tiziano Menon, Alessandro Mazzucco, Giuseppe Faggian
Journal: Circulation (2012)

BACKGROUND: Rewarming from deep hypothermic circutatory arrest (DHCA) produced a calcium desensitization by cTnI phosphorylation that results in myocardial dysfunction. This study was aimed to investigate the acute overall hemodynamic and metabolic effects of epinephrine and levosimendan on myocardial function after rewarming from deep hypothermia. METHODS AND RESULTS Forty male Wistar rats (400-500 g) underwent cardiopulmonary bypass and were cooled to a core temperature of 13°C to 15°C within 30 minutes. After 15 minutes of DHCA, they were randomly assigned to treatment with levosimendan (0.1 μg/kg/min) (n=15) or epinephrine (0.1 μg/kg/min) (n =15) or saline as control (n =10). The rewarming lasted 60 minutes. Systolic and diastolic function was evaluated at different preloads with a conductance catheter. Levosimendan produced a significantly better recovery of the slope of the left ventricular end-systolic pressure volume relationship (Ees) and preload recruitable stroke work (PRSW) than ephinephrine (as percentage of baseline respectively 85+9 vs 51+11, p=0.003 and 78+5 vs 48+8, p=0.005). Levosimendan and not ephinephrine compared to control reduced left ventricular stiffness expressed by end-diastolic pressure volume relationship (EDPVR) and improved ventricular relaxation described by Tau. Levosimendan preserved high-energy phosphates content and energy charge and reduced lactate plasma concentration. Ephinephrine (E) determined a significant cTnI phosphorylation during normothermia (N) and enhanced cTnI phosphorylation after DHCA (H/R). On the contrary levosimendan (L) prevent cTnI phosphorylation that was not different from normothermic control (Fig. 1). CONCLUSIONS: Levosimendan is more effective than epinephrine for treatment of myocardial dysfunction after DHCA. Ephinephrine has a detrimental effect on calcium desensitization that has a key role in myocardial dysfunction after rewarming from DHCA.
The sensitivity and specificity of the routine kidney biopsy immunofluorescence panel are inferior to diagnosing renal immunoglobulin-derived amyloidosis by mass spectrometry
Authors: Maria L. Gonzalez Suarez, Pingchuan Zhang, Samih H. Nasr, Insara Jaffer Sathick, Wonngarm Kittanamongkolchai, Paul J. Kurtin, Mariam P. Alexander, Lynn D. Cornell, Mary E. Fidler, Joseph P. Grande, Loren P. Herrera Hernandez, Samar M. Said, Sanjeev Sethi, Angela Dispenzieri, Morie A. Gertz, Nelson Leung
Journal: Kidney International (2019)
Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ib/II clinical trial NCT02915432
Authors: F. Wang, X.L. Wei, F.H. Wang, N. Xu, L. Shen, G.H. Dai, X.L. Yuan, Y. Chen, S.J. Yang, J.H. Shi, X.C. Hu, X.Y. Lin, Q.Y. Zhang, J.F. Feng, Y. Ba, Y.P. Liu, W. Li, Y.Q. Shu, Y. Jiang, Q. Li, J.W. Wang, H. Wu, H. Feng, S. Yao, R.H. Xu
Journal: Annals of Oncology (2019)

High tumor mutational burden (TMB-H) is correlated with enhanced objective response rate (ORR) and progression-free survival (PFS) for certain cancers receiving immunotherapy. This study aimed to investigate the safety and efficacy of toripalimab, a humanized programmed death-1 (PD-1) antibody, in advanced gastric cancer (AGC), and the predictive survival benefit of TMB and PD-L1.
Prospective Molecular MRD Detection By NGS: A Powerful Independent Predictor for Relapse and Survival in Adults with Newly Diagnosed AML
Authors: Mojca Jongen-Lavrencic, Tim Grob, Francois G. Kavelaars, Adil S.A. Al Hinai, Annelieke Zeilemaker, Claudia A.J. Erpelinck-Verschueren, Yvette Norden, Rosa Meijer, Bart J. Biemond, Carlos Graux, Marinus van Marwijk Kooij, Markus G. Manz, Thomas Pabst, Violaine Havelange, Jakob R. Passweg, Gert J. Ossenkoppele, Gerrit Jan Schuurhuis, Mathijs A. Sanders, Bob Löwenberg, Peter J.M. Valk
Journal: Blood (2017)
Abstract 2693: Targeting the Hippo-YAP pathway with novel small-molecule inhibitors of the YAP-TEAD transcription activity
Authors: Tracy T. Tang, Andrei W. Konradi, Ying Feng, Xiao Peng, Sofie Qiao, Leonard Post
Journal: Cancer Research (2019)

Abstract We have discovered and are developing multiple novel small molecule medicines targeting the Hippo-YAP pathway. Consisting of upstream regulatory components, the Hippo core kinase components (MST1/2, MAP4K1-7, and LATS1/2), and the downstream transcriptional machinery (YAP, TAZ, and TEAD), the mammalian Hippo-YAP pathway is involved in the regulation of cell proliferation, survival, and cell migration. It functions normally to control tissue regeneration and homeostasis and limit organ size/shape. Genetic alterations of pathway components have been reported in a variety of human malignancies. YAP activity is also linked to resistance to targeted therapies and cancer relapse. Through high-throughput phenotypic screens, we have identified novel classes of small molecule compounds that inhibit the YAP-TEAD transcription activity. Medicinal chemistry efforts on lead optimization resulted in highly potent inhibitors that block YAP-TEAD transcription activity at single digit nM. The classes of inhibitors that were demonstrated to interact directly with the TEAD transcription factors by thermal shift assay, co-crystal structures, and inhibition of autopalmitoylation of purified recombinant TEAD proteins will be presented. In cell-based assays, these inhibitors block TEAD palmitoylation in cells and selectively inhibit proliferation of NF2-deficient mesothelioma. In vivo, complete growth inhibition of NF2 mutant xenograft tumors can be achieved at doses that are well tolerated in mice without adverse effect on body weight. With the discovery and development of potent TEAD inhibitors, we bring forth a new generation of cancer therapeutics targeting a thus far undruggable pathway that is dysregulated in many cancers and critically associated with targeted therapy resistance. Citation Format: Tracy T. Tang, Andrei W. Konradi, Ying Feng, Xiao Peng, Sofie Qiao, Leonard Post. Targeting the Hippo-YAP pathway with novel small-molecule inhibitors of the YAP-TEAD transcription activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2693.
Efficacy of retreatment with anti-EGFRs in metastatic colorectal cancer is not predictable by clinical factors related to prior lines of therapy: a multi-institutional analysis
Authors: D. Rossini, F. Pagani, A. Pellino, E. Dell’Aquila, N. Liscia, M. Bensi, M. Germani, G. Masi, R. Moretto, D. Santini, L. Salvatore, M. Scartozzi, S. Lonardi, G. Zucchelli, F. Puglisi, F. Vannini, C. Colombo, A. Falcone, F. Pietrantonio, C. Cremolini
Journal: Annals of Oncology (2019)
Abstract 3052: MGMT inhibition is associated with MAPK pathway inhibition and enhances Raf, MEK, ERK inhibitors and restores meaningful Temozolomide activity in melanoma
Authors: George C. Bobustuc, Amin B. Kassam, Dmitry Bosenko, Deborah L. Donohoe, Richard A. Rovin, Santhi D. Konduri
Journal: Cancer Research (2019)

Abstract Braf and MEK inhibition leads to limited survival gains in melanoma. In this research we show that, in vitro, MGMT controls all MAPK pathway effectors. We show that triple lock - upstream and downstream, along the MAPK pathway - effectively restores durable Braf and MEK inhibitor activity and significantly sensitizes melanoma to Temozolomide. The advantage of a multiple lock approach on the MAPK pathway is substantiated by the lack of signaling cross talk. We briefly discuss how this simple MGMT based regulatory paradigm could be immediately exploited in the care of melanoma patients. We also show how this strategy was exploited in two, surviving, metastatic (to include CNS disease) melanoma patients who had failed Braf and MEK inhibition (2 and 5 years ago) who now show stable or negligible residual disease burden while continuing on an intermittent, low treatment density, combination regimen Citation Format: George C. Bobustuc, Amin B. Kassam, Dmitry Bosenko, Deborah L. Donohoe, Richard A. Rovin, Santhi D. Konduri. MGMT inhibition is associated with MAPK pathway inhibition and enhances Raf, MEK, ERK inhibitors and restores meaningful Temozolomide activity in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3052.
VOYAGER: an open-label, randomised, phase 3 study of avapritinib vs regorafenib in patients with locally advanced metastatic or unresectable gastrointestinal stromal tumour
Authors: S. Bauer, S. George, Y. Kang, R. Jones, O. Mir, W. Tap, A. Doyle, N. Picazio, T. Zhou, M. Roche, M. Heinrich
Journal: Annals of Oncology (2019)