bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 731: A minigene platform to validate novel immunogenic peptides arising from somatic mutations as therapeutic cancer vaccines
Authors: Shi Xiaoshan , Kode Vasumathi , Lee Kayla , Chaudhuri Amit , Chakraborty Papia 
Published: August 2018

Abstract
Cancer vaccines have shown promise in treating late-stage cancers that have failed traditional therapies. Somatic mutations provide a rich source of potential cancer vaccines with minimal T-cell tolerance. We have built a robust screening assay to test somatic mutations for CD8+ T cell activation in a T cell-dendritic cell co-culture assay with synthetic peptides added from outside. Our screening assay revealed that non-mutated wild-type peptides in many instances induced T-cell activation, although their HLA binding affinity was weak. We suspect that addition of high concentration of the peptides from outside may overcome their weak HLA-binding property, allowing them to bind HLA and activate T cells. To reduce the bias of artificial HLA presentation, we have built a minigene platform to screen pairs of wild-type and mutant peptides to assess their immunogenicity. We applied our proprietary cancer vaccine prediction platform to a set of somatic single-nucleotide variants (SNVs) and indels and selected immunogenic peptides by a combination of features that include TCR binding, HLA binding, gene expression and proteasomal processing. Predicted mutant immunogenic peptides and their wild-type counterpart were cloned as minigenes and expressed in HLA restricted antigen-presenting cells (APCs). The minigene-expressing APCs were co-cultured with allogenic CD8+ T cells and activation was monitored by the combined expression of IFN-gamma, TNF-alpha and granzyme-A (CTL phenotype of T cells) by flow cytometry. Our screening assay reveals that a significant number of indels are not presented when they are expressed as a longer peptide because of the stability of the transcripts. However, their presentation and immunogenicity are preserved when they are expressed as short 9-mer peptides with engineered proteasomal cleavage sites. Our study also reveals a range of HLA-binding affinities for peptide presentation. In conclusion, our analysis demonstrates that the two approaches for investigating immunogenicity of peptides—minigene approach and external addition of peptide approach—have differential utilities for testing and validating the immunogenicity of indels and SNVs.
Citation Format: Xiaoshan Shi, Vasumathi Kode, Kayla Lee, Amit Chaudhuri, Papia Chakraborty. A minigene platform to validate novel immunogenic peptides arising from somatic mutations as therapeutic cancer vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 731.
Abstract 745: Development of a novel ron receptor targeted antibody-drug conjugates using cysteine bridging technology for potential treatment of pancreatic cancer
Authors: Suthe Sreedhar Reddy , Yao Hang-Ping , Trippier Paul C. , Wang Ming-Hai 
Published: August 2018

Abstract
Therapeutics targeting known oncoproteins have been applied for pancreatic cancer treatment but clinical outcomes are not promising. Hence, there is an urgent need to identify novel targets and develop effective drugs to improve pancreatic cancer therapeutic index. Antibody-drug conjugates (ADC) represent a promising class of drugs for targeted cancer therapy. Here we developed a novel ADC targeting RON receptor tyrosine kinase for potential pancreatic cancer treatment. To this end, we have synthesized a bis-alkylating linker (BL), attached to a lysosomal protease-cleavable dipeptide with payload Monomethyl auristatin E (MMAE). The BL-MMAE was then conjugated to Zt/g4 (anti-RON mAb) through cysteine bridging technology to produce Zt/g4-BL-MMAE with a homogeneous conjugation profile and an antibody to drug ratio of 1:4. Zt/g4-BL-MMAE showed significant improvement in drug conjugation homogeneity and serum stability over conventional ADCs prepared through maleimide based linkers. In pancreatic cancer cell lines overexpressing RON, Zt/g4-BL-MMAE specifically targeted RON-expressing tumor cells and was effective in rapid induction of cell surface RON endocytosis. Functional analysis revealed that Zt/g4-BL-MMAE caused cell cycle arrest at G2/M phase, reduction of cell viability and subsequently resulted in massive cell death. The calculated IC50 is in the range of 1 to 2 µg/ml. We conclude that Zt/g4-BL-MMAE is a novel anti-RON ADC with excellent conjugation profile, serum stability, and selective cytotoxicity for pancreatic cancer cells. This work provides a pharmaceutical opportunity for evaluating potentials of RON-targeted ADCs in pancreatic cancer treatment in the future.
Citation Format: Sreedhar Reddy Suthe, Hang-Ping Yao, Paul C. Trippier, Ming-Hai Wang. Development of a novel ron receptor targeted antibody-drug conjugates using cysteine bridging technology for potential treatment of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 745.
Abstract 750: Modular coiled-coil masking domains for tumor-specific antibody activation
Authors: Trang Vivian H. , Zhang Xinqun , Dominguez Melissa M. , Zeng Weiping , Cochran Julia H. , Stone Ivan J. , Senter Peter D. , Levengood Matthew R. 
Published: August 2018

Abstract
The power of monoclonal antibody therapeutics arises from their remarkable selectivity for a particular antigen. However, antibody therapies can still be limited by serious side effects that result from target-mediated toxicity when the antigen is also expressed on non-diseased tissue. An emerging concept in the field of therapeutic antibodies is to restrict antibody binding in healthy tissues while empowering the antibody at sites of disease. This has previously been accomplished by fusing masking groups to the antibody through cleavable sequences that can be activated upon hydrolysis by disease-associated proteases. Here, we present a novel approach to mask antibodies utilizing a variety of leucine zipper coiled-coil peptides fused to the N-termini of antibody heavy and light chains. An optimized heterodimeric coiled-coil masking domain was identified that significantly impaired the binding of multiple antibodies to their cognate receptors with no antibody-specific optimization required. Protease-cleavable linkers were introduced between the coiled-coil peptides and antibody termini, and protease-catalyzed removal of the coiled-coil domains restored antibody binding affinity to that of the unmasked parent antibody. The coiled-coil mask did not impair production of antibody-drug conjugates (ADCs) of varying drug-to-antibody ratios, and masked antibodies and ADCs had similar stability and pharmacokinetic profiles to unmasked counterparts. However, coiled-coil masked ADCs and antibodies displayed decreased functional activity in biological assays, commensurate with the decrease in affinity afforded by masking, and this activity could be restored upon cleavage of the mask. Lastly, coiled-coil masked antibodies and ADCs had been tested in vivo and had demonstrated improved safety benefits as well as equivalent antitumor activity compared to the unmasked counterparts. Coiled-coil masked antibodies represent an advance in the field of antibody pro-drugging, as this modular domain can be rapidly applied to an array of therapeutic antibodies and ADCs.
Citation Format: Vivian H. Trang, Xinqun Zhang, Melissa M. Dominguez, Weiping Zeng, Julia H. Cochran, Ivan J. Stone, Peter D. Senter, Matthew R. Levengood. Modular coiled-coil masking domains for tumor-specific antibody activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 750.
Abstract 761: The role of PI3 kinase pathway in the the skin of Sezary syndrome
Authors: Cristofoletti Cristina , Bresin Antonella , Picozza Mario , Picchio Maria Cristina , Passarelli Francesca , Monzo Francesca , Citterich Mauro Helmer , Monopoli Alessandro , Benucci Roberto , Cantonetti Maria , Frezzolini Alessandra , Scala Enrico , Caprini Elisabetta , Russo Giandomenico , Narducci Maria Grazia 
Published: August 2018

Abstract
Sezary Syndrome (SS) is an aggressive variant of cutaneous T cell lymphoma (CTCL) characterized by an accumulation of malignant T lymphocytes - the Sezary (SS) cells - in the skin, lymph nodes and blood. Until now, most studies on the characterization of this lymphoma have been performed on circulating SS cells because of the easy availability of tumor material from this compartment. For this reason, the role of skin microenvironment has not been characterized although it might play a fundamental role in the pathogenesis and in the disease progression of this neoplasia. According to this view, we recently demonstrated that PTEN downregulation, due to genetic loss and microRNA deregulation, commonly observed in SS patients, mainly activates AKT in skin-resident respect to blood-derived SS cells. This data underline how microenvironment signals amplify genetic abnormalities. Based on these observations, we investigated the effect of the skin microenvironment on SS cells in vivo. Comparing skin and blood-derived SS cells concurrently obtained from SS patients, we demonstrate that skin milieu promotes proliferation and PI3K/AKT/mTORC1 activation, a pathway that we prove to have multiple copy number (CN) alterations in our cohort of forty-three patients, thus indicating these genetic lesions as valid therapeutic targets to treat SS. At the end, we also demonstrate that the progressive increase of these CN alterations is associated to the shortening of overall survival of SS patients.
Citation Format: Cristina Cristofoletti, Antonella Bresin, Mario Picozza, Maria Cristina Picchio, Francesca Passarelli, Francesca Monzo, Mauro Helmer Citterich, Alessandro Monopoli, Roberto Benucci, Maria Cantonetti, Alessandra Frezzolini, Enrico Scala, Elisabetta Caprini, Giandomenico Russo, Maria Grazia Narducci. The role of PI3 kinase pathway in the the skin of Sezary syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 761.
Abstract 768: Identification of signal transduction pathways specific for mutant KRas-dependent tumors
Authors: Puli Oorvashi Roy , Yang Hua , Fang Bin , Jiang Hong Yuan (Rays) , Koomen John , Sebti Said M. 
Published: August 2018

Abstract
Targeting KRas directly has proven difficult. Therefore, identifying vulnerabilities specific for mutant KRas tumors is an important alternative approach to target mutant KRas-driven tumors. Towards this goal, we used phosphoproteomics to dissect key differences in signaling pathways between mutant KRas-dependent and mutant KRas-independent human cancer cells. Mass spectrometry analysis led to the identification of 25 proteins with significantly higher (up to 410 fold) phosphorylation levels in mutant KRas-dependent cells. Among these, 25 proteins- 8, 8 and 3 were tyrosine (Y), Serine (S) and Threonine (T) phosphorylated, and 6 were phosphorylated on both S and T. Presently, CRISPR-Cas9 knockout and siRNA depletion studies are ongoing to identify which of these 25 hits are required for the survival of mutant KRas-dependent human cancer cells. These studies can lead to identifying signaling circuits that can be targeted to treat mutant KRas-driven cancers.
Citation Format: Oorvashi Roy Puli, Hua Yang, Bin Fang, Hong Yuan (Rays) Jiang, John Koomen, Said M. Sebti. Identification of signal transduction pathways specific for mutant KRas-dependent tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 768.
Abstract 773: A heterochromatin gene signature unveils HP1α mediating neuroendocrine prostate cancer development and aggressiveness
Authors: Ci Xinpei , Hao Jun , Dong Xin , Choi Stephen Y. , Xue Hui , Qu Sifeng , Fazli Ladan , Crea Francesco , Ong Christopher , Zoubeidi Amina , He Housheng H. , Gleave Martin E. , Collins Colin C. , Lin Dong , Wang Yuzhuo 
Published: August 2018

Abstract
Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer (PCa) arising mostly from adenocarcinoma via NE transdifferentiation following androgen deprivation therapy. However, mechanisms contributing to both NEPC development and its aggressiveness remain elusive. In light of the fact that hyperchromatic nuclei is a distinguishing histopathological feature of NEPC, we identified 36 heterochromatin-related genes that are significantly enriched in NEPC by transcriptomic analyses of our patient-derived xenograft (PDX) models, multiple clinical cohorts, and genetically engineered mouse models. Longitudinal analysis using our unique, first-in-field PDX model of adenocarcinoma-to-NEPC transdifferentiation revealed that, among those 36 heterochromatin-related genes, heterochromatin protein 1α (HP1α) expression is increased early and steadily during NEPC development and remain elevated in the developed NEPC tumor. Its elevated expression is further confirmed in multiple PDX and clinical NEPC samples. Functional studies showed that HP1α knockdown in the NCI-H660 NEPC cell line dramatically inhibits proliferation, completely ablates colony formation, and induces apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promotes NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. Mechanistically, HP1α reduces expression of androgen receptor (AR) and RE1 silencing transcription factor (REST), two crucial transcription factors silenced in NEPC, and enriches the repressive histone mark trimethylation of histone H3 at Lys9 (H3K9me3) on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1α as an early functional mediator and a potential therapeutic target for NEPC prevention and/or management.
Citation Format: Xinpei Ci, Jun Hao, Xin Dong, Stephen Y. Choi, Hui Xue, Sifeng Qu, Ladan Fazli, Francesco Crea, Christopher Ong, Amina Zoubeidi, Housheng H. He, Martin E. Gleave, Colin C. Collins, Dong Lin, Yuzhuo Wang. A heterochromatin gene signature unveils HP1α mediating neuroendocrine prostate cancer development and aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 773.
Abstract 806: KI2011 is a novel potent FLT3 tyrosine kinase inhibitor in acute myeloid leukemia cells with FLT3-mutation
Authors: Ryu Hwani , Song Jie-Young , Ahn Jiyeon 
Published: August 2018

Abstract
More than 30% of patients with acute myeloid leukemia (AML) harbor a mutation with internal tandem duplication (ITD) in the juxtamembrane domain and point mutations in the tyrosine kinase domain of FMS-like tyrosine kinase-3 (FLT3), which results in aberrant activation FLT3 by auto-phosphorylation, and confers poor prognosis. To develop novel FLT3 inhibitors, ten novel oxazole amine derivatives were designed and synthesized based on FLT3 protein structure. Among the synthesized small molecule compounds, KI2011 exhibited selectively inhibitory activities of the class III receptor tyrosine kinases, especially FLT3, wile-type, FLT3-D835Y mutant and FLT3-internal tandem duplication (ITD) mutant isoforms with IC50 values of 25, 9, and 1.2 nM, respectively, determined by an in vitro kinase activity assay. The compound decreased FLT3 phosphorylation and its downstream signaling in MV4-11 cells harboring FLT3-ITD mutation. Treatment of KI2011 selectively inhibited cell proliferation and induced apoptosis of MV411 cells in a concentration-dependent manner, but not in K562 (FLT3 negative) cells. In addition, we found that KI2011 enhanced radiosensitivity of MV4-11 cells. The results suggest that KI2011 is a novel potent FLT3 inhibitor that may be further developed in the preclinical studies as a therapeutic agent in AML treatments.
Citation Format: Hwani Ryu, Jie-Young Song, Jiyeon Ahn. KI2011 is a novel potent FLT3 tyrosine kinase inhibitor in acute myeloid leukemia cells with FLT3-mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 806.
Abstract 815: New approach for old target: W0101 antibody drug conjugate effectively inhibits tumor growth in preclinical models of IGF-1R overexpressing solid tumors
Authors: Akla Barbara , Loukili Noureddine , Robert Alain , Beau-Larvor Charlotte , Malissard Martine , Haeuw Jean-Francois , Beck Alain , Perez Michel , Dreyfus Cyrille , Pavlyuk Mariya , Chetaille Eric , Corvaia Nathalie 
Published: August 2018

Abstract
Insulin-like growth factor type 1 receptor (IGF-1R) has been recognized for decades for its role in tumorigenesis and growth1. In addition, overexpression of this receptor has been largely documented in numerous tumor tissues. However, so far, previous therapeutic approaches based on monoclonal antibodies and tyrosine kinase inhibitors failed to show clinical benefit in the overall patient population2. Here we disclose for the first time a novel IGF-1R targeted Antibody Drug Conjugate (ADC), W0101, designed to deliver highly potent cytotoxic drugs selectively to IGF-1R over-expressing tumor cells.
The naked antibody for our ADC was selected on the basis of its specific binding properties to IGF-1R compared to insulin receptor (IR), and for its internalization properties.
After coupling of a proprietary auristatin derivative to the naked antibody, neither the binding nor the internalization properties of W0101 evaluated by FACS analysis, were modified.
Interestingly, the capacity of W0101 to induce cytotoxicity was evaluated in vitro in various cell lines and was demonstrated to be independent of effector functions.
Mouse efficacy studies with various doses and schedules of administration were conducted in several models expressing different level of IGF-1Rin order to determine their sensitivity to W0101. The sensitivity of W0101 was correlated to the expression level of IGF-1R evaluated by IHC. And in a 3+ MCF-7 breast cancer model, a single injection of W0101 at 3mg/kg led to more than 90% tumor growth inhibition (TGI), associated with a modulation of the IGF-1R expression on the tumor cells (IHC study).
The first in-human trial of W0101 is currently on going to address clinical safety. We believe that W0101 will bring a new therapeutic option for patients that overexpress IGF-IR.
1Pollak M. Insulin and insulin-like growth factor signaling in neoplasia. Nat Rev Cancer, 2008,8:915-928.
2Corvaia N, Beck A, Caussanel V, Goetsch L. Insulin-like growth factor receptor type I as a target for cancer therapy. Frontiers in Bioscience, Scholar, 5, 439-450, January 1, 2013
Citation Format: Barbara Akla, Noureddine Loukili, Alain Robert, Charlotte Beau-Larvor, Martine Malissard, Jean-Francois Haeuw, Alain Beck, Michel Perez, Cyrille Dreyfus, Mariya Pavlyuk, Eric Chetaille, Nathalie Corvaia. New approach for old target: W0101 antibody drug conjugate effectively inhibits tumor growth in preclinical models of IGF-1R overexpressing solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 815.
Abstract 82: Epigenetic reader ZMYND8 bridges BRD4 and hypoxia-inducible factors to mediate breast cancer progression and metastasis
Authors: Chen Yan , Zhang Bo , Bao Lei , Jin Lai , Yang Mingming , Peng Yan , Wang Jennifer , Wang Chenliang , Zou Xuan , Wang Yingfei , Luo Weibo 
Published: August 2018

Abstract
Metastatic breast cancer has high rates of relapse and mortality. The absence of definitive prognostic biomarker and effective therapeutic target is the major obstacle to end this aggressive disease. Epigenetic dysregulation plays a crucial role in breast cancer metastasis. However, the mechanism by which epigenetic dysregulation stimulates the hypoxia-mediated breast cancer progression and metastasis remains unknown.
Based on luciferase reporter assays and analysis of expression changes of 720 epigenetic genes in three microarray datasets, we identified epigenetic reader ZMYND8 as a novel hypoxia-inducible factor (HIF) target gene. Human breast cancer tissue microarray data indicated that ZMYND8 is highly expressed in invasive breast tumors and this overexpression is significantly correlated with poor clinical outcomes in patients with breast cancer. ZMYND8 depletion dramatically attenuates the tumorigenic potential of breast cancer cells in colony formation, migration and invasion in vitro, and suppresses breast tumor growth and metastasis in mice. To elucidate the underlying mechanism, we performed co-immunoprecipitation, chromatin immunoprecipitation and quantitative PCR assays and found that ZMYND8 interacts with HIF complex and acetyl lysine 16 of histone H3 at the hypoxia inducible elements (HREs) to provoke the expression of HIF target genes LOX, AGR2, AQP1 and VEGFA. ZMYND8 controls breast cancer growth and metastasis through HIF in mice. We further found that p300 binds and acetylates ZMYND8 in breast cancer cells. Acetylated ZMYND8 interacts with and recruits BRD4 to the HREs to stimulate RNA polymerase II phosphorylation, thereby promoting transcriptional elongation of HIF target genes. ZMYND8 acetylation is necessary and sufficient for breast tumor growth and metastasis in vitro and in mice. Together, p300-ZMYND8-BRD4-HIF axis is critical for breast cancer progression and metastasis.
In summary, ZMYND8 represents a positive feedback mechanism that amplifies HIF-mediated breast cancer progression and metastasis, and provides a potential epigenetic target for the prognosis and treatment of breast cancer.
Citation Format: Yan Chen, Bo Zhang, Lei Bao, Lai Jin, Mingming Yang, Yan Peng, Jennifer Wang, Chenliang Wang, Xuan Zou, Yingfei Wang, Weibo Luo. Epigenetic reader ZMYND8 bridges BRD4 and hypoxia-inducible factors to mediate breast cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 82.