bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-103: Defining oncogenic SWI/SNF complex mediated immune reprogramming in squamous cell carcinoma
Authors: Saladi SrinivasVinod , Morris Robert , Ross Kenneth , Karaayvaz mihriban , Tata Purushothama Rao , mou hongmei , Rajagopal Jayaraj , Lawrence Michael , Ellisen Leif 
Published: August 2019

Abstract
Squamous cell carcinoma (SCC) remains among the most treatment-refractory of human cancers, reflecting in part a limited understanding of the key pathways and mechanisms that drive this disease. The p53-related transcription factor p63 is a central tumor maintenance factor subject to overexpression and/or genomic amplification in a high fraction of SCCs. Loss-of-function mutations in SWI/SNF chromatin remodeling subunit genes are observed in many cancers, but an oncogenic role for SWI/SNF is not well established. We reveal that ACTL6A, encoding a SWI/SNF subunit linked to stem and progenitor cell function, is frequently co-amplified and highly expressed together with p63 in head and neck, and lung squamous cell carcinoma (HNSCC & LUSC). ACTL6A and p63 physically interact and cooperatively control a transcriptional program that promotes proliferation and suppresses differentiation, in part through activation of the Hippo-YAP pathway via regulators including WWC1. Consequently, loss of ACTL6A or p63 in tumor cells induces YAP phosphorylation and inactivation, associated with growth arrest and terminal differentiation, all phenocopied by WWC1 overexpression. In vivo, ectopic ACTLC6A/p63 expression promotes tumorigenesis, while ACTL6A expression and YAP activation are highly correlated in primary HNSCC and predict poor patient survival. More recently, we show the major cell-autonomous pathway repressed by ACTL6A is the interferon response in vitro, while we find ACTL6A amplification in HNSCC is associated with immunologically “cold” tumors despite a high mutation burden in vivo. Collectively, these findings reveal that ACTL6A orchestrates a tumor cell-intrinsic mechanism of immune evasion and define ACTL6A as a potent driver of human SCC.These findings establish a fundamental mechanism for ACTL6A and p63 to alter epigenetic states, and uncover a critical oncogenic function for SWI/SNF, which has been largely viewed as a tumor suppressor in human cancer. Furthermore, by revealing the Hippo-YAP pathway as a major target of ACTL6A/p63 linked to tumor behavior, this work suggests potential therapeutic approaches for refractory HNSCC cases.
Citation Format: SrinivasVinod Saladi, Robert Morris, Kenneth Ross, mihriban Karaayvaz, Purushothama Rao Tata, hongmei mou, Jayaraj Rajagopal, Michael Lawrence, Leif Ellisen. Defining oncogenic SWI/SNF complex mediated immune reprogramming in squamous cell carcinoma [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 LB-103.
Abstract LB-106: Overcoming limitations of current Antibody-Drug Conjugates (ADCs) by a novel linker technology
Authors: Spycher Philipp Rene , Frei Julia Carina , Wehrmüller Jöri Elias , Attinger-toller Isabella , Grabulovski Dragan , Hechler Torsten , Kulke Michael , Pahl Andreas , Behe Martin , Schibli Roger 
Published: August 2019

Abstract
We introduce a novel and versatile ADC-linker technology that is based on site-specific enzymatic payload conjugation to ‘off-the-shelf’ antibodies, i.e., without the need to reduce or engineer the antibody. The functionalization takes place site-specifically and stoichiometrically (drug-to-antibody ratio, DAR = 2.0) at the Fc-part of antibodies. The resulting ADCs show favorable biophysical properties such as high solubility and stability using different payloads. Additionally, initial ELISA findings show that our modification does not interfere with Fc-gamma receptor and FcRn binding. Importantly, our ADCs showed superior efficacy in different tumor animal models as compared to control Thiomab™ ADCs. Using native trastuzumab (non-engineered) as the targeting antibody and amanitin as payload, we generated within 36 hours highly homogeneous and pure ADCs with a well-defined DAR of 2.0 as confirmed by LC-MS. In in-vitro assays our ADCs demonstrated potent cytotoxicity in all tested cell-lines (SKBR-3, BT-474, JIMT-1, and NCI-N87) as compared to the control Thiomab™ ADCs, most strikingly for the JIMT-1 cell-line: EC50 of 0.15nM vs 2.5nM. In the mouse JIMT-1 tumor model, our anti-HER2 ADC was highly potent and resulted in complete tumor remission in all mice (10/10 mice) at a single dose of 2mg/kg. In contrast, the control Thiomab™-functionalized ADC showed tumor regrowth in 4 out of 10 animals, starting on day 50. The same high potency was observed for the NCI-N87 xenograft model at a dose of 3mg/kg in which tumor growth inhibition was significantly delayed versus the reference ADC (8/10 vs 4/10 animals alive on day 110). These encouraging results obtained so far indicate that our linker technology a) allows for fast (&lt; 36 hours) and straightforward manufacturing of ADCs using different payloads without protein engineering efforts, b) results in ADCs with favorable biophysical properties and a clear defined drug-to-antibody ratio, and c) enables the generation of highly potent and stable, thus safer, next-generation ADCs.
Citation Format: Philipp Rene Spycher, Julia Carina Frei, Jöri Elias Wehrmüller, Isabella Attinger-toller, Dragan Grabulovski, Torsten Hechler, Michael Kulke, Andreas Pahl, Martin Behe, Roger Schibli. Overcoming limitations of current Antibody-Drug Conjugates (ADCs) by a novel linker technology [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 LB-106.
Abstract LB-110: Proteasome addiction a new therapeutic opportunity to treat PTEN-deficient brain tumors
Authors: Benitez Jorge A. , Finlay Darren , Rosa-Campos Alexandre , Ma Jianhui , Koga Tomoyuki , Vuori Kristiina , Furnari Frank 
Published: August 2019

Abstract
One of the most common genetic alterations in glioblastoma (30-40%) occurs in the tumor suppressor gene PTEN (phosphatase and tensin homolog), where loss of function has been mechanistically linked to increased tumor cell invasion, and to a lack of radio- and chemo-therapy response. To identify new drug compounds that target PTEN-deficient brain tumors we performed a high throughput drug screening using patient-derived GBM spheres and found that PTEN-deficient samples were highly sensitive to proteasome inhibitors. We confirmed PTEN dependency to proteasome inhibition by genetically overexpressing or deleting PTEN in GBM cells and established that the drug inhibition response relied on PTEN enzymatic activity. Additionally, proteasome inhibition specifically suppressed tumor growth and increased survival of mice orthotopically engrafted with human PTEN-null glioblastoma cancer stem cells. Mechanistically, we determined that PTEN-deficient cells were more sensitive to proteasome inhibition due to an increase in protein synthesis rate and loss of autophagy activity associated with activation of the PI3K/mTOR pathway. Finally, integrated in silico analysis of the Samsung Medical Center dataset corroborated that samples with PTEN/EGFR/PI3K alterations were significantly more sensitive to Carfilzomib, an FDA-approved proteasome inhibitor. This study reveals that PTEN-deficient cells are "proteasome addictive" and opens a new therapeutic opportunity to treat glioblastoma PTEN-deficient patients.
Citation Format: Jorge A. Benitez, Darren Finlay, Alexandre Rosa-Campos, Jianhui Ma, Tomoyuki Koga, Kristiina Vuori, Frank Furnari. Proteasome addiction a new therapeutic opportunity to treat PTEN-deficient brain tumors [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 LB-110.
Abstract LB-113: MAPK pathway suppression unmasks latent DNA repair defects and confers a chemical synthetic vulnerability inBRAF,NRASandNF1-mutant melanomas
Authors: Maertens Ophélia , Kuzmickas Ryan , Manchester Haley , Emerson Chloe , Gavin Alessandra , Guild Caroline , Wong Terence , Raedt Thomas De , Bowman-Colin Christian , Hatchi Elodie , Garraway Levi , Flaherty Keith , Pathania Shailja , Elledge Stephen , Cichowski Karen 
Published: August 2019

Abstract
While the majority of BRAF-mutant melanomas respond to BRAF/MEK inhibitors, these agents are not typically curative. Moreover, they are largely ineffective in NRAS and NF1-mutant tumors. Here we report that genetic and chemical suppression of HDAC3 potently cooperates with MAPK pathway inhibitors in all three Ras pathway-driven tumors. Specifically, we show that entinostat dramatically enhances tumor regression when combined with BRAF/MEK inhibitors, both in models that are sensitive or relatively resistant to these agents. Interestingly, MGMT expression predicts responsiveness and marks tumors with latent defects in DNA repair. BRAF/MEK inhibitors enhance these defects by suppressing homologous recombination genes, inducing a BRCA-like state; however, entinostat addition triggers the concomitant suppression of NHEJ genes, resulting in a chemical synthetic lethality caused by excessive DNA damage. Together these studies identify melanomas with latent DNA repair defects, describe a promising drug combination that capitalizes on these defects, and reveal a tractable therapeutic biomarker.
Citation Format: Ophélia Maertens, Ryan Kuzmickas, Haley Manchester, Chloe Emerson, Alessandra Gavin, Caroline Guild, Terence Wong, Thomas De Raedt, Christian Bowman-Colin, Elodie Hatchi, Levi Garraway, Keith Flaherty, Shailja Pathania, Stephen Elledge, Karen Cichowski. MAPK pathway suppression unmasks latent DNA repair defects and confers a chemical synthetic vulnerability inBRAF,NRASandNF1-mutant melanomas [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 LB-113.
Abstract LB-120: Acetylated Kruppel-like factor 5 and transforming growth factor-β mediated drug resistance in prostate cancer
Authors: Li Yixiang , Zhang Baotong , Dong Jin-Tang 
Published: August 2019

Abstract
Purpose: In this study, we explored the role of Kruppel-like factor 5 (KLF5) and its acetylated form on lysine 369 in transforming growth factor-β (TGFβ) induced drug resistance to promote antitumor synergy and overcome drug resistance in advanced stage prostate cancer. Procedures: Two aggressive prostate cancer cell lines DU 145 and PC-3 were treated with docetaxel to measure cytotoxicity. To assess docetaxel resistance, we used in-vitro cell survival assay, colony survival assay and xenograft mouse model. In addition, TGFβ1 and SB505124 (TGFβ receptor I inhibitor) were used to explore TGFβ induced docetaxel resistance. To measure function of KLF5 and its different acetylation form on lysine 369, stable cell lines were constructed with different KLF5 acetylation status mimics after knocking out endogenous KLF5, utilizing the CRISPR-Cas9 system.
Results: We found that KLF5 alone induced docetaxel resistance in vivo, but not in vitro. Moreover, endogenous knocking out of KLF5 inhibited TGFβ induced docetaxel resistance. In addition to previous findings that TGFβ recruits P300 acetyl-transferase to acetylate KLF5 on lysine 369, we further found that TGFβ induced docetaxel resistance depends on acetylation of KLF5. In addition, Mass Spectrometry analysis revealed that JUNB, a downstream target of non-canonical TGFβ pathway, is a direct binding target of acetylated KLF5 but not de-acetylated KLF5. Knocking down of JUNB in acetylated KLF5 mimic cell line inhibited TGFβ induced docetaxel resistance.
Conclusions: These suggested that acetylated KLF5 is indispensable in TGFβ induced drug resistance through interaction with JUNB. Our study introduced a novel mechanism of acetylated KLF5 and JUNB mediated docetaxel resistance in prostate cancer and contributed to an advanced therapy combination for advanced prostate cancer patients.
Citation Format: Yixiang Li, Baotong Zhang, Jin-Tang Dong. Acetylated Kruppel-like factor 5 and transforming growth factor-β mediated drug resistance in 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 LB-120.
Abstract LB-153: Therapeutic effect of MC-4 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt/pyruvate kinaseM2 and mechanistic target of rapamycin complex 1 pathways
Authors: Kim Hyung Sik , Kim Kyeong Seok 
Published: August 2019

Abstract
Current clinical trials of new anticancer therapies against metastatic renal cell carcinoma (RCC), including molecular-targeted therapies, have not shown promise. The purpose of this study was to preclinically assess the antitumor effects of MC-4, a partially purified material of Artemisia annua L., as a monotherapy or in combination with the known mechanistic target of rapamycin complex 1 (mTORC1) inhibitor, everolimus, against Caki-1 (Von Hippel-Lindau (VHL)+/+) and 786-O (VHL−/−) human RCC cells. MC-4 monotherapy significantly increased tumor growth inhibition and autophagic cell death in RCC cells in vitro and in vivo. Everolimus led to compensatory Akt activation by inhibiting only mTORC1 signaling pathway. In contrast to everolimus, MC-4 enhanced phosphatase and tensin homolog expression and reduced its downstream effector, Akt/pyruvate kinase muscle isozyme M2 (PKM2), leading to decreased expression of glucose transporter 1, which is associated with cancer cell metabolism. The synergistic antitumor and anti-metastatic effects induced by co-administration of MC-4 and everolimus involve cell growth inhibition and autophagic cell death via dual targeting of phosphatidylinositol 3-kinase (PI3K)/Akt/PKM2 and mTORC1. These findings suggest that MC-4 is a novel Akt/PKM2 inhibitor that can overcome the limitation of existing mTOR inhibitors and can be considered a novel strategy to treat patients with rapidly progressing advanced RCC.
Citation Format: Hyung Sik Kim, Kyeong Seok Kim. Therapeutic effect of MC-4 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt/pyruvate kinaseM2 and mechanistic target of rapamycin complex 1 pathways [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 LB-153.
Abstract LB-169: Comprehensive analysis of the expression of eight genes as a prognostic marker in head and neck cancer
Authors: Park Heuijoon , Zhang Yuzheng , Xu Chang , Chen Chu , Wang Pei , Méndez Eduardo 
Published: August 2019

Abstract
Head and neck cancer (HNC) is the 6th most common cancer worldwide, and the survival rate of HNC is about 50%. There has been no significant improvement in survival in HNC for over 50 years. Many HNC cases are not identified until an advanced stage. Thus, prevention, early detection, and better treatment are critical factors to reduce morbidity and mortality in HNC. Genome-wide next generation sequencing techniques allow investigation of patient-specific molecular signatures that may provide insight into the design of customized cancer therapies. Our previous studies have identified critical genetic signatures for HNC initiation and progression, and these signatures are strongly associated with progression-free survival (PFS) of HNC patients. To improve current molecular markers, a survival predictive model was built using ElasticNet Cox regression model with different sets of molecular markers (313 unique genes) from our three published studies and TCGA RNAseq expression data (n = 260). Deregulated expression of eight genes (FADD, PPFIA1, RYK, SMARCA2, SNX10, DCAF13, C18orf21 and THBS1) was identified and showed strong association with PFS. This eight-gene prediction model was validated by an independent oral squamous cell carcinoma (OSCC) specific mortality dataset from MD Anderson Cancer Center (n = 71 OSCC, AUC = 0.857). Next, we analyzed the association between deregulated expression of these eight genes and the top 5% (n = 420) most commonly mutated genes in HNCs (n = 260) via pairwise Pearson correlation coefficient with p value. This analysis revealed that deregulated expression of these eight genes is strongly associated with mutations in TP53 and NOTCH1. This result was confirmed by additional
analysis with a Regularized Multivariate Regression for Identifying Master Predictors (RemMap) model. Finally, to investigate the association of copy number variation (CNV) with expression of the 8-gene panel, pairwise Pearson correlation with p-value calculation was performed between the copy number data and the expression of the eight genes, and the most correlated regions were identified to be in chromosome arms 3p, 5q, and 11q. Further analysis using only HPV-negative OSCC samples revealed an association of eight-gene deregulation with CNV in 11q13.
We conclude that this new eight-gene marker panel is strongly correlated with PFS of HNC patients. Further evaluation using new HNC data sets is thus justified to establish the utility of this new eight-gene panel as a prognostic marker.
Citation Format: Heuijoon Park, Yuzheng Zhang, Chang Xu, Chu Chen, Pei Wang, Eduardo Méndez. Comprehensive analysis of the expression of eight genes as a prognostic marker in head and neck 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 LB-169.
Abstract LB-189: Pharmacological reactivation of MYC-dependent apoptosis cooperates with anti-PD1 immunotherapy
Authors: Haikala Heidi M. , Anttila Johanna M. , Savelius Mariel , Marques Elsa , Raatikainen Tiina , Ilander Mette , Hakanen Henna , Mattson Johanna , Heikkila Paivi , Leidenius Marjut , Joensuu Heikki , Mustjoki Satu , Kovanen Panu , Eilers Martin , Leverson Joel D. , Klefström Juha T. 
Published: August 2019

Abstract
Elevated MYC levels sensitize tumor cells to apoptosis but the therapeutic potential of this mechanism remains unclear. We find, in a model of MYC-driven breast cancer, that pharmacological activation of AMPK dramatically synergizes with BCL-2/BCL-XL inhibitors to activate MYC-dependent apoptosis. We demonstrate the translational potential of an AMPK and BCL- 2/BCL-XL co-targeting strategy in ex vivo and in vivo models of MYC-high breast cancer. Metformin combined with either navitoclax or venetoclax efficiently inhibits tumor growth, confers survival benefits and induces tumor infiltration by immune cells. However, withdrawal of the drugs allowed tumor re- growth with presentation of PD1+/CD8+ T cell infiltrates, suggesting immune escape. A two-step treatment regimen, beginning with neoadjuvant metformin+venetoclax to induce apoptosis and followed by tumor resection and adjuvant metformin+venetoclax+anti-PD1 treatment to overcome immune escape, led to durable antitumor responses even after drug withdrawal. We demonstrate that pharmacological reactivation of MYC-dependent apoptosis is a powerful antitumor strategy involving both tumor cell depletion and immunosurveillance.
Citation Format: Heidi M. Haikala, Johanna M. Anttila, Mariel Savelius, Elsa Marques, Tiina Raatikainen, Mette Ilander, Henna Hakanen, Johanna Mattson, Paivi Heikkila, Marjut Leidenius, Heikki Joensuu, Satu Mustjoki, Panu Kovanen, Martin Eilers, Joel D. Leverson, Juha T. Klefström. Pharmacological reactivation of MYC-dependent apoptosis cooperates with anti-PD1 immunotherapy [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 LB-189.
Abstract LB-202: Immunotherapy with TMV vaccine inhibits metastatic tumor growth in an immune checkpoint resistant murine lung cancer model
Authors: Huang Haley Lei , Bommireddy Ramireddy , Munoz Luis E. , Menon Ashwathi P. , Ramalingam Suresh , Selvaraj Periasamy 
Published: August 2019

Abstract
Lung cancer is the second most common cancer among men and women and the leading cause of cancer deaths in the world. Despite the advancements in diagnostic technologies and the development of novel treatments in the recent years such as immune checkpoint inhibitor (ICI) therapy, the prognosis of lung cancer patients is still poor, and the survival rate is low. The patient-to-patient heterogeneity is the major problem in treating lung cancer, which results in differential responses to ICI therapy. In this study, we investigated the efficacy of a vaccine immunotherapy prepared by modification of tumor membrane vesicles (TMVs) prepared from the tumors to express immunostimulatory molecules in combination with ICI therapy in a partially ICI resistant murine lung cancer model. We demonstrate that prophylactic vaccination of TMV adjuvanted with immunostimulatory molecules prevents the CMT-167 tumor growth in mice and helps the mice develop immunological memory to the tumor cell challenge. In a therapeutic setting, the TMV vaccine inhibited tumor growth and induced primary tumor regression in 40% of mice and significantly reduced the metastatic tumor burden. However, the combination of TMV vaccination with anti-PD-1 mAb doesn’t have a synergistic or additive effect on the primary or metastatic tumor growth. Overall, these studies provide insight into using the TMV vaccine immunotherapy for treating lung cancer.
Funding: Supported by the Lung Cancer seed grant from the Winship Cancer Institute of Emory University
Citation Format: Lei Huang, Dr. Selvaraj's lab. Immunotherapy with TMV vaccine inhibits metastatic tumor growth in an immune checkpoint resistant murine lung cancer model [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 LB-202.