bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 459: Therapy-induced senescence is reversible in vitro and in vivo
Authors: Saleh Tareq , Alotaibi Moureq R. , Kyte Sarah L. , Cudjoe Emmanuel K. , Kawale Ajinkya , Xu Jingwen , Elsayed Zeinab , Landry Joseph W. , Henderson Scott C. , Yakovlev Vasily , Elmore Lynne W. , Gewirtz David A. 
Published: August 2018

Abstract
While cellular senescence has long been recognized as an irreversible form of growth arrest, evidence in the literature has suggested that subpopulations of senescent tumor cells may retain proliferative capacity. To directly address this question, H460 non-small cell lung cancer cells induced into senescence by exposure to etoposide, and enriched based on β-galactosidase staining and size, were shown to recover reproductive capacity, which was accompanied by resolution of the DNA-damage-response (downregulation of p53 and p21Waf1/Cip1 induction), attenuation of the senescence-associated secretory phenotype (SASP) as well as downregulation of miRNA34 expression and an increase in c-myc. The senescence-enriched lung cancer cells were also capable of tumor growth upon transplantation into immunodeficient mice. Re-emergence from etoposide-induced senescence was also observed using HCT116 colon cancer cells, as evidenced by concomitant downregulation of a senescence-associated reporter (BTG1-RFP). Collectively, these findings indicate that therapy-induced senescence (TIS) may ultimately be a transient process in that at least a subpopulation of tumor cells can resume proliferation. We propose that some forms of tumor dormancy that lead to disease recurrence may reflect cells that enter into and ultimately escape from senescence.
Citation Format: Tareq Saleh, Moureq R. Alotaibi, Sarah L. Kyte, Emmanuel K. Cudjoe, Ajinkya Kawale, Jingwen Xu, Zeinab Elsayed, Joseph W. Landry, Scott C. Henderson, Vasily Yakovlev, Lynne W. Elmore, David A. Gewirtz. Therapy-induced senescence is reversible in vitro and in vivo [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 459.
Abstract 4599: Detecting MSI phenotype in circulating blood DNA
Authors: Stern Marc-Henri , Silveira Amanda B. , Bieche Ivan , Melaabi Samia , Cabel Luc , Buecher Bruno , Pierga Jean-Yves , Bidard Francois-Clement , Proudhon Charlotte 
Published: August 2018

Abstract
Background: Microsatellite instability (MSI) is a hypermutator phenotype occurring in gastrointestinal, endometrial and colorectal tumors, and more rarely, in urinary tract, ovarian, breast, prostate, lung, head and neck, liver and glioblastoma tumors. The diagnosis of MSI phenotype has recently emerged as the first pan-tumor biomarker likely to predict clinical benefit from immune-checkpoint blockade therapy, making its precise identification primordial for treatment decisions and disease monitoring. Current diagnosis of MSI is performed by multiplex PCR of five microsatellite markers, followed by capillary electrophoresis to detect shifts in allele size. An important limitation of this method is its low sensitivity preventing its use when tumor content is below 10%.
Methods: We designed ddPCR assays examining 3 microsatellites. Analytical performance was assessed in vitro. Clinical performance was evaluated in a series of FFPE and body fluid DNA samples obtained from patients with Stage IV colorectal or endometrial carcinomas, previously classified as MSI-H or MSS using the standard pentaplex PCR method. Mutant allele frequencies (MAF) quantified with the ddPCR MSI assay were also compared with the MAFs reported by ddPCR assays targeting specific BRAF or PIK3CA mutations.
Results: The ddPCR assays for the 3 microsatellites were found to have high specificity and reached a limit of detection of &lt;0.1%. A perfect concordance with the MSI status determined by the pentaplex assay was observed in the 50 tumor samples tested (25 MSI-H and 25 MSS). Importantly, the ddPCR assays diagnosed the MSI phenotype in the plasma of all patients with MSI-H tumors, without false positives in MSS cases. Furthermore, an excellent correlation was observed in the 6 FFPE (R2:0.81) and 8 body fluid (R2:0.99) MSI-H samples were the MAFs measured by our assay could be compared with the ones obtained by ddPCR assays targeting specific mutations in BRAF or PIK3CA genes.
Conclusion: This technique allows a cost-effective, sensitive and large scale screening of the MSI phenotype, as well as the follow-up of MSI patients using liquid biopsies.
Citation Format: Marc-Henri Stern, Amanda B. Silveira, Ivan Bieche, Samia Melaabi, Luc Cabel, Bruno Buecher, Jean-Yves Pierga, Francois-Clement Bidard, Charlotte Proudhon. Detecting MSI phenotype in circulating blood DNA [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 4599.
Abstract 4601: Dissecting the spatial heterogeneity of circulating tumor cells reveals CCL5-Treg-mediated immune evasion in hepatocellular carcinoma
Authors: Wu Liang , Jiang Miaomiao , Sun Yunfan , Yang Xinrong , Hou Yong , Fan Jia , Liu Shiping 
Published: August 2018

Abstract
The prognosis of hepatocellular carcinoma (HCC) is closely linked to the occurrence of recurrent, metastatic disease. Metastasis has been proposed to be initiated by circulating tumor cells (CTCs); however, the transcriptomic plasticity and adaptive mechanisms of CTCs in systemic circulation are not well defined. Here, we established single-cell RNA-sequencing profiles of 113 CTCs isolated from four key vascular sites along the dissemination route in ten HCC patients. In our study, we found that single CTCs displayed profound spatial transcriptional heterogeneity within the circulatory system, which is associated with increased transcriptional activity, cell cycle progression, and chemokine-induced immune escape programs. In particular, CTCs dynamically drove chemokine (C-C motif) ligand 5 (CCL5) expression over the course of circulation. We demonstrated that increased CCL5 expression in turn recruited regulatory T cells to facilitate immune evasion and metastatic progression, as rigorously validated by our in vitro and in vivo models. Finally, we identified an inherently dormant CTC subset with an epithelial-mesenchymal transition and immune-evasive phenotype, and demonstrated its potential prognostic implications. Collectively, our results reveal the previously unappreciated spatial heterogeneity of CTCs, and define its role in diverse regulatory programs and cellular states. Our study offers new insight into metastatic mechanisms, highlighting the potential utility of anti-CTC therapeutic strategies.
Citation Format: Liang Wu, Miaomiao Jiang, Yunfan Sun, Xinrong Yang, Yong Hou, Jia Fan, Shiping Liu. Dissecting the spatial heterogeneity of circulating tumor cells reveals CCL5-Treg-mediated immune evasion in hepatocellular carcinoma [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 4601.
Abstract 4621: Risk stratification and biomarker discovery in HPV-positive oropharynx squamous cell carcinoma determined by HPV and human gene expression profile associations
Authors: Gleber-Netto Frederico O. , Rao Xiayu , Erikson Kelly , Akagi Keiko , Johnson Faye M. , Wang Jing , Califano Joseph , Gillison Maura L. , Myers Jeffrey N. , Pickering Curtis R. 
Published: August 2018

Abstract
Determining which HPV+ oropharyngeal squamous cell carcinoma (OPSCC) patients will respond to therapy is of utmost important for implementation of treatment de-escalation to reduce morbidity or testing of novel therapeutic approaches. Due to the lack of reliable indicators of treatment response, we explored the gene expression profile of OPSCC in order to better understand the biology of these tumors and identify novel biomarkers. In this study, we investigated human genes associated with HPV transcription in 80 OPSCC samples from The Cancer Genome Atlas (TCGA). This exploratory analysis provided a list of 582 human genes associated with HPV biology. Hierarchical clustering analysis using the 582 human genes was used to separate HPV+ OPSCC in two groups with significantly distinct survival (log-rank test p &lt; 0.001) and differential expression of HPV genes. A refinement of this analysis generated a prognostic gene expression signature for HPV+ OPSCC containing 41 human genes. These results were validated in two independent cohorts of HPV+ OPSCC (n=83 and n=47) and one independent cohort of cervical cancer (n=83). In all three validation cohorts our 41 gene expression signature was able to identify a group of HPV+ OPSCC patients with worse survival. Further refinement and validation of the signature is ongoing. In order to understand the biology related to poor outcome in HPV+ OPSCC, a whole transcriptome analysis between the two initial HPV+ OPSCC TCGA groups was performed. Pathway analysis identified cell metabolism, cell stress, and DNA damage related genes were highly associated with poor outcome. Similar patterns of gene expression were found in vitro in a panel of 10 HPV+ cell lines, and markers of the poor outcome were found to be associated with reduced radiation sensitivity in vitro. Our study has identified prognostic biomarkers in HPV+ OPSCC with potential clinical importance. These biomarkers may be useful for selection of low risk patients for treatment de-escalation or selection of high risk patients for novel therapeutic approaches. These biomarkers are also functionally linked to radiation sensitivity and may include new therapeutic targets.
Citation Format: Frederico O. Gleber-Netto, Xiayu Rao, Kelly Erikson, Keiko Akagi, Faye M. Johnson, Jing Wang, Joseph Califano, Maura L. Gillison, Jeffrey N. Myers, Curtis R. Pickering. Risk stratification and biomarker discovery in HPV-positive oropharynx squamous cell carcinoma determined by HPV and human gene expression profile associations [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 4621.
Abstract 4630: Characterizing oncogene addiction in alveolar rhabdomyosarcoma reveals novel strategies for combination therapy
Authors: Ommer Johannes , Wachtel Marco , Schaefer Beat W. 
Published: August 2018

Abstract
Rhabdomyosarcoma is the most common soft tissue sarcoma in children. The aggressive alveolar subtype (aRMS) is characterized by chromosomal translocations, most often a t(2;13) resulting in the expression of the oncogenic fusion protein PAX3-FOXO1 which is critical for tumorigenesis and cell survival. Our aim here was to identify a pharmacological combination therapy approach interfering with PAX3-FOXO1 biology at different levels.
Since loss of the fusion protein results in cell death, we first aimed to pharmacologically enhance this effect. To this end, we screened aRMS tumor cells with a library of 208 drugs while simultaneously silencing PAX3-FOXO1 by shRNA. This identified the BH3-mimetic ABT-263 to sensitize aRMS cells to cell death after PAX3-FOXO1 depletion. To further characterize the cell death mechanisms we used combined shRNA and CRISPR approaches to perform a BH3 protein profiling. In accordance with identification of ABT-263 we demonstrate that aRMS cells undergo intrinsic apoptosis in a NOXA-dependent manner upon depletion of PAX3-FOXO1.
In a parallel approach, and to identify drugs altering PAX3-FOXO1 protein stability, we screened the same drug library directly measuring fusion protein levels as read-out. This revealed that inhibition of Aurora kinase A negatively affects PAX3-FOXO1 protein levels.
Finally, using both aRMS cell lines and patient-derived xenografts we demonstrate that combination treatment of Aurora kinase A inhibitors together with ABT-263 synergistically induces cell death and greatly slows tumor growth in vitro and in vivo.
Taken together, these data show a novel functional interaction of Aurora kinase A and PAX3-FOXO1 and suggest new opportunities for targeted combination treatment of aRMS.
Citation Format: Johannes Ommer, Marco Wachtel, Beat W. Schaefer. Characterizing oncogene addiction in alveolar rhabdomyosarcoma reveals novel strategies for combination therapy [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 4630.
Abstract 4638: Predictive computational approaches to guide the covalent targeting of cysteine residues in drug discovery
Authors: Ward Richard A. , Lonsdale Richard 
Published: August 2018

Abstract
Targeted covalent inhibition is an established approach for increasing the potency and selectivity of potential drug candidates, and has also been used to identify tool compounds for target validation studies. It is evident that binding to reversible recognition elements within the pocket is essential for selective covalent inhibition, but this must also be achieved with the appropriate level of inherent reactivity of the covalent functionality and compatible geometry and reactivity of the target amino acid. We have assessed the ability of several experimental and computational approaches to predict the intrinsic reactivity of a range of cysteine targeting warheads, some of which can be used in prospective compound design. In addition, molecular dynamics (MD) simulations in combination with pKa prediction methods have been used to investigate the accessibility and potential reactivity of target cysteines towards covalent inhibition. As part of this work a number of case studies will be reported including retrospective examples from covalent drug discovery efforts along with prospective use towards novel targets. Finally, a dataset of osimertinib analogues along with other EGFR inhibitors of varying reactivity will be discussed to enable further insight into the impact of reversible and covalent interactions on inhibitor binding.
Citation Format: Richard A. Ward, Richard Lonsdale. Predictive computational approaches to guide the covalent targeting of cysteine residues in drug discovery [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 4638.
Abstract 464: Cell death and senescence: Role of protein kinase C in promoting senescence
Authors: Livneh Etta , Ari Assaf Ben , Zurgil Udi 
Published: August 2018

Abstract
Senescence is characterized by permanent cell cycle arrest and loss of proliferative capacity, despite continued viability and metabolic activity. Senescent cells undergo massive genome modulation including induction of the senescence-associated secretory phenotype (SAPS). Components of SASP can implement cell cycle arrest or recruit the immune system to clear senescent cells, thus contributing to tumor suppression. However, some secreted pro-inflammation molecules, act as pro-tumorigenic agents contributing to tumor progression, suggesting that elimination of senescent cells could be beneficial. Very few studies showed a role for PKC in senescence. Here we show that PKCeta, an epithelial specific and anti-apoptotic kinase (epithelia is the origin of about 90% of human tumors), promotes senescence induced by oxidative stress and DNA damage. Using PKCeta-knockdown breast adenocarcinoma MCF-7 cells we show that PKCeta promotes senescence induced by oxidative stress and DNA damage via its ability to upregulate the expression of the cell cycle inhibitors p21Cip1 and p27Kip1 and to modulate transcription of major components of SASP such as IL-6 and IL-8. Moreover, we demonstrate that PKCeta creates a positive loop for reinforcing senescence by increasing the transcription of both IL-6 and IL-6 receptor. Thus, the expression of PKCeta modulates major components of SASP. Furthermore, our studies demonstrate that PKCeta interferes with γH2AX phosphorylation, which mark DNA double-strand breaks for repair. The phosphorylation of γH2AX may reflect the extent of DNA breaks but also the cellular response to DNA damage. Our experiments suggest that the response to DNA damage (repair processes) was more efficient in PKCeta-knockdown cells. The phosphorylation on ATM and Chk2 was also lower in PKCeta expressing cells. Revealing the molecular regulators of senescence will improve our ability to develop new therapeutic strategies for clearing tumor cells. Our studies showing a role for PKCeta in senescence could identify PKCeta and/or its activated signaling cascades as targets for intervention senescence induction. Since PKCeta is highly expressed in epithelia that are the origin of about 90% of human tumors, this may provide critical inhibitors as therapeutic adjuvants for different types of carcinomas.
Citation Format: Etta Livneh, Assaf Ben Ari, Udi Zurgil. Cell death and senescence: Role of protein kinase C in promoting senescence [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 464.
Abstract 4640: Sustained co-delivery of dendritic cells and oncolytic adenovirus co-expressing IL-12 and GM-CSF using biodegradable polymer matrix for cancer immunotherapy
Authors: Oh Eonju , Oh Jung-Eun , Hong JinWoo , Chung YoonHo , Lee Yunki , Park Ki Dong , Kim Sung Wan , Yun Chae-Ok 
Published: August 2018

Abstract
Administration of dendritic cells (DCs) combined with oncolytic adenovirus (Ad) expressing antitumor cytokines induces a potent antitumor effect and antitumor immunity by ameliorating the immunosuppressive tumor microenvironment. However, this combination therapy has significant limitations due to rapid dissemination and inactivation of the therapeutics at the tumor site, necessitating multiple injections of both therapeutics. In this study, we investigated injectable and biodegradable gelatin-based hydrogel as a carrier for oncolytic Ad co-expressing interleukin (IL)-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF) (oAd) and DCs to elicit a potent antitumor effect with single administration. Gel matrix enabled sustained release of both oAd and DCs while preserving their biological activity over a considerable time period, leading to efficient retention of both therapeutics in tumor tissue. Further, tumors treated with oAd- and DC-loaded gel (oAd+DC/gel) showed a significantly greater expression level of IL-12, GM-CSF, and interferon-γ (IFN-γ) than either single treatment (oAd or DC) or oAd in combination with DC (oAd+DC), resulting in efficient activation of both endogenous and exogenous DCs, migration of DCs to draining lymph nodes, and tumor infiltration of CD4+ and CD8+ T cells. Moreover, oAd+DC/gel resulted in a significantly higher number of tumor-specific IFN-γ-secreting immune cells compared with oAd+DC. Lastly, oAd+DC/gel significantly attenuated tumor-mediated thymic atrophy, which is associated with immunosuppression in the tumor microenvironment, compared with oAd+DC. Taken together, these results demonstrate that gelatin gel-mediated co-delivery of oncolytic Ad and DCs might be a promising strategy to efficiently retain both therapeutics in tumor tissue and induce a potent antitumor immune response for an extended time period via a single administration.
Citation Format: Eonju Oh, Jung-Eun Oh, JinWoo Hong, YoonHo Chung, Yunki Lee, Ki Dong Park, Sung Wan Kim, Chae-Ok Yun. Sustained co-delivery of dendritic cells and oncolytic adenovirus co-expressing IL-12 and GM-CSF using biodegradable polymer matrix for cancer immunotherapy [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 4640.
Abstract 4649: Targeting the cancer cell lysosome with transformable self-assembling peptide nanoparticles
Authors: Baehr Christopher M. , Wang Lei , Lam Kit S. 
Published: August 2018

Abstract
Lysosome-mediated cell death has recently become of great interest to the cancer community as several compounds have been shown to preferentially induce cancer cell death via lysosomal membrane permeabilization (LMP) (e.g., oleocanthal, salinomycin, and TiO2 nanoparticles). Further, many cancer cell lines that are resistant to traditional cancer therapeutics are highly susceptible to lysosome-mediated cell death. Here, we develop transformable peptide nanoparticles (NP) designed to traffic to cancer cell lysosomes, form aggregates, and induce LMP. The peptide consists of three motifs: 1) a hydrophilic, cell penetrating, and pH-responsive poly-d-Arg motif, 2) a hydrogen-bonding motif derived from beta amyloid (KLVFF); and 3) hydrophobic bis(pyrene) that fluoresces upon aggregation. The peptides initially self-assemble into NPs (50nm via TEM) in PBS, but when exposed to a lysosomal pH of 4.5, form much larger aggregates. We show that these nanoaggregates colocalize with the lysosome, leading to cell death, suggesting the induction of LMP. Moreover, utilizing bis(pyrene) we show that while these aggregates form in the lung carcinoma cell line, A549, they do not form in 3T3 fibroblasts. Additionally, we demonstrate that these nanoaggregates are highly toxic to A549 cells with IC50 in the low micromolar range (~2μM). This offers a novel organelle-specific strategy to preferentially target and kill cancer cells.
Citation Format: Christopher M. Baehr, Lei Wang, Kit S. Lam. Targeting the cancer cell lysosome with transformable self-assembling peptide nanoparticles [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 4649.
Abstract 4687: Double positive (DP) CD4+CD8+ T cells with an exhausted phenotype in renal cell carcinoma (RCC) patients
Authors: Menard Laurence , Fischer Paul , Kakrecha Bijal , Lee Deborah , Penhallow Becky , Orduno Nataly Manjarrez , Nadler Steven 
Published: August 2018

Abstract
Checkpoint inhibitors target the inhibitory receptors expressed by tumor infiltrating T cells in order to reinvigorate an anti-tumor immune response. Therefore, understanding T cell composition and phenotype in human tumors is crucial. We analyzed by flow cytometry tumor infiltrating lymphocytes from two independent cohorts of patients with different cancer types, including RCC, lung and colon cancer. T cells are usually either CD4+ or CD8+ with a small percentage of CD4+ CD8+ DP cells (&lt;5%). Compared to several other cancer types, including lung and colorectal cancers, about a third of RCC patients showed an increased proportion of DP CD4+CD8+ T cells (&gt;5%, reaching 30-50% of T cells in some patients). These DP T cells express high level of PD1 and TIM-3 that tend to correlate with higher expression of PD1 and TIM-3 in conventional CD8 T cells. DP T cells also express markers of antigen-experienced T cells such as CD38 and HLA-DR. These results suggest that double positive T cells might be exhausted tumor specific T cells with the potential to be reactivated by checkpoint inhibitors.
Citation Format: Laurence Menard, Paul Fischer, Bijal Kakrecha, Deborah Lee, Becky Penhallow, Nataly Manjarrez Orduno, Steven Nadler. Double positive (DP) CD4+CD8+ T cells with an exhausted phenotype in renal cell carcinoma (RCC) patients [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 4687.