bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4513: Notch inhibitors relieve growth suppression by TGF-β and promote growth and metastasis of triple-negative breast cancers
Authors: Saikumar Pothana , Singha Prajjal K. , Pandeswara Srilakshmi , Venkatachalam Manjeri A. 
Published: August 2018

Abstract
The paradoxical behavior of Notch1 and transforming growth factor-beta (TGF-β) is puzzling as they were shown to have both tumor-suppressive and tumor-promoting activities. We addressed the interaction between these two signaling pathways in cancer development and progression in a systematic way. Towards this goal, we utilized primary human mammary epithelial cells (HMEC) and various triple-negative breast cancer (TNBC) cells and examined the molecular crosstalk between TGF-β1 and Notch signaling pathways using biochemical, molecular and cell biology techniques. First, we observed lower expression of Notch1 in most of the TNBC cells compared to normal cells. Most of these TNBC cells also overexpressed TMEPAI (transmembrane prostate androgen induced), which we previously showed switches TGF-β from tumor-suppressive to a tumor-promoting role in breast cancer. Surprisingly, treatment of TNBC with Notch inhibitors increased their growth rate both in the absence and presence of TGF-β, while Notch inhibitors relieved normal cells from TGF-β mediated growth suppression. Both normal and TNBC cells showed increased growth in the presence of Notch inhibitors with decreased TGF-β signaling activity. In fact, normal cells that express very low levels of TMEPAI both at mRNA and protein levels, overexpressed TMEPAI in presence of various Notch inhibitors, suggesting that Notch1 negatively regulates TMEPAI expression. Correspondingly, knockdown of TMEPAI in TNBC cell lines showed increased expression of Notch1 and Jagged 1, suggesting a negative regulation of Notch1 by TMEPAI. In fact, TMEPAI, which binds to E3 ligases, promoted increased turnover of Notch1. In contrast to notch inhibitors, overexpression of active Notch1 in MDA-MB-231 cells inhibited tumor cell growth both in vitro and in vivo. Our results clearly suggest that a crosstalk between TGF-β and Notch1 signaling exists through TMEPAI. Importantly, these studies should be taken into consideration while contemplating the use of Notch inhibitors in triple-negative breast cancer therapy.
Citation Format: Pothana Saikumar, Prajjal K. Singha, Srilakshmi Pandeswara, Manjeri A. Venkatachalam. Notch inhibitors relieve growth suppression by TGF-β and promote growth and metastasis of triple-negative breast cancers [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 4513.
Abstract 4527: Major pathologic response and biomarker predict survival in lung cancer patients receiving neoadjuvant chemotherapy
Authors: Pataer Apar , Shao Ruping , Correa Arlene M. , Wistuba Ignacio I. , Swisher Stephen G. 
Published: August 2018

Abstract
In a previous study, we determined that major pathologic response (MPR) as indicated by the percentage of residual viable tumor cells predicted overall survival (OS) in patients with non-small cell lung cancer (NSCLC) who received neoadjuvant chemotherapy. In this study, we assessed whether 2 gene and 5 protein biomarkers could predict MPR and OS in 98 NSCLC patients receiving neoadjuvant chemotherapy. We assessed whether gene mutation status or protein expression was associated with MPR or OS. We observed that KRAS mutation tended to be associated with OS (p = 0.06), but EGFR mutation was not associated with OS. We found that patients with high RAD51 expression levels had a poorer prognosis than did those with low RAD51 expression. We also observed that RAD51 expression was associated with MPR. MPR and RAD51 expression were associated with OS in univariate and multivariate analyses (p = 0.04 and p = 0.02, respectively). Combination of MPR with RAD51 is a significant predictor of prognosis in NSCLC patients who received neoadjuvant chemotherapy. No association of MPR or VEGFR2, EZH2, ERCC1, RAD51, or PKR expression with KRAS or EGFR mutation was found. We demonstrated that MPR or RAD51 expression was associated with OS in NSCLC patients receiving neoadjuvant chemotherapy. Prediction of a patient's prognosis could be improved by combined assessment of MPR and RAD51 expression.
Citation Format: Apar Pataer, Ruping Shao, Arlene M. Correa, Ignacio I. Wistuba, Stephen G. Swisher. Major pathologic response and biomarker predict survival in lung cancer patients receiving neoadjuvant chemotherapy [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 4527.
Abstract 4559: KY-B602, a humanized anti-human OX40 antibody, enhances CD4+T cell activation and inhibits tumor growth in a syngeneic model
Authors: hao feng , he feng , ning mingxuan , bai zhaoshuai , ning jinying 
Published: August 2018

Abstract
OX40, a member of the tumor necrosis factor (TNF) receptor superfamily, is mainly expressed on activated T cells. As a secondary costimulatory molecule, activated OX40 can increase effector T-cell survival, proliferation, and memory. Anti-OX40 monoclonal antibodies have shown anti-tumor efficacy. Recent preclinical studies further support the potential synergistic effects of agonist OX40 immunotherapy in combination with cancer vaccination or in sequential co-administration with PD1 antibody to revert PD1 resistance. Several anti-OX40 agonistic monoclonal antibodies are currently tested in early phase cancer clinical trials either in monotherapy or in combination with other immune modulators. KY-B602 is a novel humanized IgG1 anti-OX40 antibody under pre-clinical development. It was generated from hybridoma and humanized by CDR grafting and structure simulation. KY-B602 specifically binds to the extracellular domain of human OX40 with high affinity (KD = 5.1 nM, determined by Biacore). FACS study showed KY-B602 also binds to both human and cynomolgus monkey OX40 over-expressed on 293T cells (EC50 =4.6nM, EC50=6.1nM, respectively). Another, in HT1080 cell reporter assay, KY-B602 significantly increased IL-8 secretion through OX40 pathway. In addition, KY-B602 dose-dependently augmented IL-2 and IFN-gamma secretion from CD4+T cells, that were pre-stimulated with IL-2 and PHA. However, in FACS competition assay, KY-B602 did not affect OX40L binding to OX40, suggesting that KY-B602 binds to a different epitope with that of OX40L. Moreover, KY-B602 inhibits in vivo tumor growth in MC38 syngeneic model. In summary, the current data of KY-B602 support its potency for cancer therapy.
Citation Format: feng hao, feng he, mingxuan ning, zhaoshuai bai, jinying ning. KY-B602, a humanized anti-human OX40 antibody, enhances CD4+T cell activation and inhibits tumor growth in a syngeneic model [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 4559.
Abstract 4576: Combination of a label independent CTC enrichment platform with fluorescence in situ hybridization for the molecular characterization of CTCs in non-small cell lung cancer patients
Authors: Ntzifa Aliki , Zavridou Martha , Pollakis Pavlos , Bardi Georgia , Georgoulias Vasilis , Kotsakis Athanasios , Lianidou Evi 
Published: August 2018

Abstract
Background: Patients with EGFRmt non-small cell lung cancer (NSCLC) develop resistance to first (erlotinib/ gefitinib) and second (afatinib) generation EGFR tyrosine kinase inhibitors (EGFR TKIs). Circulating tumor cells (CTCs) may be used as a potential biological material to monitor genetic alterations during the clinical course of the disease. We used the ParsortixTM (ANGLE) system, a label-independent microfluidic-based technology platform, to enrich CTCs from whole blood of NSCLC patients to evaluate the presence of HER-2 and c-MET amplification using fluorescence in situ hybridization (FISH). Materials and methods: Peripheral blood (PB) (15mL) from 42 patients with EGFRmt and resistant to 1st and 2nd generation EGFR TKIs NSCLC was obtained before, during and after treatment with osimertinib. CTCs were isolated using the ParsortixTM system and were further analyzed for HER-2 and c-MET amplification by FISH. Results: PB samples were obtained before (n=42), after one cycle (n=12) and at PD (n=7) during treatment with Osimertinib. One patient had HER-2 amplified CTCs whereas in total, 5 patients had marginally HER-2-positive CTCs; HER-2-positive CTCs were observed in 1/42 baseline sample but in none post-1st cycle and PD samples. Similarly, c-MET amplification was detected in 3/42 patients at baseline whereas in total 4 patients had marginally c-MET-positive CTCs. Treatment with Osimertinib resulted in a decrease of the number of c-MET amplified CTCs in these patients. In all c-MET and HER-2 amplified CTCs there was no HER-2 or c-MET amplification in the primary tumor. c-MET amplification in the primary tumor was detected only in one patient, however this patient had no detectable CTCs. Conclusions: Our preliminary results indicate that in selected patients with EGFRmt NSCLC, detection of HER-2 or c-MET amplified CTCs may be correlated with tumor resistance to EGFR TKIs. The ParsortixTM system can be successfully combined with downstream FISH analysis for the molecular characterization of CTCs in NSCLC patients. More samples are currently being analyzed in order to reveal the implication of HER-2 and c-MET amplification in resistance to therapy with first, second and third generation EGFR TKIs.
Citation Format: Aliki Ntzifa, Martha Zavridou, Pavlos Pollakis, Georgia Bardi, Vasilis Georgoulias, Athanasios Kotsakis, Evi Lianidou. Combination of a label independent CTC enrichment platform with fluorescence in situ hybridization for the molecular characterization of CTCs in non-small cell lung cancer 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 4576.
Abstract 458: Relationship between autophagy, activation and senescence in normal and cancer-associated human oral fibroblasts
Authors: Tan May Leng , Parkinson Eric K. , Yap Lee Fah , Paterson Ian C. 
Published: August 2018

Abstract
Cancer-associated fibroblasts (CAFs) isolated from oral squamous cell carcinoma (OSCC) display an activated phenotype in that they express α-smooth muscle actin (αSMA) and are frequently prematurely senescent. OSCC cell lines can induce senescence in normal fibroblasts in vitro by a mechanism that involves TGF-β and reactive oxygen species. Another phenotype closely associated with senescence is autophagy, but the relationship between autophagy, activation and senescence in CAFs has not been examined in detail. We first examined autophagosome accumulation in normal human oral fibroblasts (NHOFs; n=3) and in a panel of CAFs (n=8) that exhibited different degrees of senescence. Autophagosome accumulation was observed in senescent CAFs, as shown by the increased expression of the LC3B-II protein and by the number of LC3B cytoplasmic puncta, which were quantified using immunofluorescence. The number of LC3B puncta was significantly greater (p&lt;0.01) in senescent CAFs compared to NHOFs, and senescent CAFs contained a higher fraction of autophagic fibroblasts than NHOFs, as indicated by increased number of LC3B puncta per cell. Further, the number of LC3B puncta correlated positively with the degree of senescence, as demonstrated by senescence-associated β-galactosidase (SA β-Gal) activity. To investigate whether autophagy, activation and senescence develop simultaneously when fibroblasts are stimulated to undergo senescence, we examined the temporal induction of these phenotypes in NHOFs in response to TGF-β1. NHOFs were treated with TGF-β1 (4 ng/ml) for up to 10 days to induce autophagy, αSMA expression and SA β-Gal activity. The results showed that autophagic flux preceded fibroblast activation, which in turn was followed by senescence. In summary, our results demonstrate that CAFs from OSCC concomitantly display autophagic, activated and senescent phenotypes and that the induction of autophagy occurs before fibroblast activation and sensecence. Taken together, these data suggest that autophagy, activation and sensecence in fibroblasts may be part of a unified programme leading to the development of CAFs.
Citation Format: May Leng Tan, Eric K. Parkinson, Lee Fah Yap, Ian C. Paterson. Relationship between autophagy, activation and senescence in normal and cancer-associated human oral fibroblasts [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 458.
Abstract 4582: Capturing T cell receptor clones from circulating free DNA in cancer patients with solid malignancies
Authors: McGrath Lara , Maloney Elizabeth , Stetson Daniel , Lubinski Tristan J. , Kirchner Rory , Dougherty Brian , Barrett J. Carl 
Published: August 2018

Abstract
Introduction Understanding the tumor microenvironment is challenging in situations where a tumor biopsy is unavailable. In these situations, liquid biopsies provide a less invasive alternative that can be collected at multiple timepoints throughout treatment. In particular, analyses of circulating free DNA (cfDNA) from plasma samples can distinguish genomic alterations from shed tumor DNA (ctDNA) within the cfDNA population. In this study, we aim to better understand the origin of cfDNA as well as its potential in understanding the intratumoral immune infiltration by developing and validating a strategy for identifying T cell receptor β (TCR β) rearrangements in the cfDNA from patients with solid malignancies. Methods We devised a target enrichment approach for high-throughput DNA sequencing that employs a hybridization capture strategy to bait germline variable (V) and joining (J) gene sequences in the TCR β loci. The target sequences are proximal to rearrangement sites flanking the CDR3, the principal site of contact for recognition specificity with foreign antigens presented by the major histocompatibility complex (MHC). We controlled for amplification bias by tagging DNA fragments with unique molecular indices (UMI). We validated our approach on dilutions of T cell lines in non-T cell lines, compared T cell levels determined from our method to those derived from flow cytometry, and compared data complexity at DNA input levels from 100 ng to 2 ng. Finally, we analyzed 27 pre-treatment plasma samples from cancer patients with solid malignanices, including quantification of total cfDNA concentrations, analyzing somatic genomic alterations using whole exome sequencing (WES), and employing our method for capture of TCR β rearrangements. Results Results indicate we are able to capture T cell rearrangements from cfDNA in cancer patient plasma. T cell rearrangements were identified in more than 25% of samples (7/27). Interestingly, the total cfDNA levels were not correlated to the number of T cell rearrangements detected, but all samples with detectable somatic alterations in the cfDNA (3/27) were also those with T cells identified. These preliminary results suggest a connection between apoptosis of lymphocytes and solid tumors that shed DNA into the bloodstream, and demonstrate potential utility as liquid biopsy for identifying tumor infiltrating lymphocytes.
Citation Format: Lara McGrath, Elizabeth Maloney, Daniel Stetson, Tristan J. Lubinski, Rory Kirchner, Brian Dougherty, J. Carl Barrett. Capturing T cell receptor clones from circulating free DNA in cancer patients with solid malignancies [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 4582.
Abstract 4596: Early noninvasive prediction of response to targeted therapy in non-small cell lung cancer
Authors: Phallen Jillian A. , Leal Alessandro , Woodward Brian D. , Forde Patrick M. , Naidoo Jarushka , Marrone Kristen , Brahmer Julie , Fiksel Jacob , Palsgrove Doreen N. , Cristiano Stephen , Bruhm Daniel , Weihe Elizabeth , Adleff Vilmos , Keshavarzian Parissa , Anagnostou Valsamo , Scharpf Robert B. , Velculescu Victor E. , Husain Hatim 
Published: August 2018

Abstract
There is an unmet need for improved methods of rapidly identifying responses to targeted therapies. Liquid biopsy approaches have potential as early biomarkers of response based on noninvasive, real-time monitoring of disease burden. We have used the ultrasensitive targeted error correction sequencing (TEC-Seq) approach to analyze 58 cancer driver genes in patients with metastatic non-small cell lung cancer undergoing treatment with targeted tyrosine kinase inhibitors. As a proof-of-principle study, liquid biopsies were obtained from sixteen patients immediately prior to treatment, 6-22 days after treatment, and at serial timepoints until disease progression. Tumor derived alterations and copy number changes were directly detected in plasma and tracked over timepoints analyzed. Based on the dynamics of cell-free circulating tumor DNA (ctDNA) mutations identified, we developed a noninvasive measure of cell-free clonal tumor load (cfTL) to evaluate real-time response to treatment. These analyses revealed that patients with a radiographic response to therapy had a significant drop in cfTL from an average mutant allele fraction of 3.59% to 0.13% within 6-22 days (P &lt; 0.05) as well as in the number of detectable mutations and aneuploidy scores, while radiographic non-responders had limited to no changes. Analyses of residual cfTL 6-22 days after treatment stratified patients into ctDNA responders and ctDNA non-responders. ctDNA responders had improved progression-free survival (12.4 vs 1.7 months, P &lt; 0.001), which was detected on average 38 days earlier and was as predictive as CT imaging. These analyses provide an approach for rapid evaluation of response to targeted therapies and have important clinical implications for the management of cancer patients.
Citation Format: Jillian A. Phallen, Alessandro Leal, Brian D. Woodward, Patrick M. Forde, Jarushka Naidoo, Kristen Marrone, Julie Brahmer, Jacob Fiksel, Doreen N. Palsgrove, Stephen Cristiano, Daniel Bruhm, Elizabeth Weihe, Vilmos Adleff, Parissa Keshavarzian, Valsamo Anagnostou, Robert B. Scharpf, Victor E. Velculescu, Hatim Husain. Early noninvasive prediction of response to targeted therapy in non-small cell lung 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 4596.
Abstract 4604: Long noncoding RNA Linc00162, as a novel prognostic marker, modulates cancer stem cell properties in triple-negative breast cancer
Authors: Sun Lichao , Lin ChangChing , Burnett Joseph , Yuan Hebao , Sun Duxin 
Published: August 2018

Abstract
Trastuzumab is an effective treatment for HER2+ breast cancer. However, trastuzumab resistance in HER2+ breast cancer may induce the epithelial-to-mesenchymal transition (EMT), transforming HER2+ to triple-negative breast cancer with cancer stem cell properties in some cancer cell populations. Long noncoding RNAs (lncRNAs) have been reported to be upregulated in many types of cancer tissues, and might play significant regulatory roles in cancer progression. However, the mechanisms of lncRNA in trastuzumab resistance still remain largely unknown. Here, we systematically analyzed the levels of LincRNA between BT474 (HER2+trastuzumab-sensitive) and the PTEN-deficient trastuzumab-resistant derivative (BT474-PTEN-LTT) by using RNA-sequencing, and identified that Linc00162 was significantly overexpressed in BT474 PTEN- LTT cells. In vitro functional assay indicated that downregulation of Linc00162 in BT474 PTEN-LTT cells completely inhibited the cell proliferation. To further evaluate the role of Linc00162 in BCSC self-renewal, we found that inhibition of Linc00162 led to a significant reduction in the number and the size of LTT cells sphere by using the mammosphere formation assay. Next, we examined Linc00162 expression levels in breast cancer tissues, and identified that Linc00162 was markedly increased. Clinicopathologic relevance analysis showed that Linc00162 expression was correlated with advanced clinical stage, lymph node metastasis and the depth of invasion. Furthermore, upregulation of Linc00162 was correlated with TRNB phenotype. In Kaplan-Meier survival analysis, high levels of Linc00162 was significantly associated with unfavorable survival in breast cancer patients. These findings suggest that Linc00162 can be used as a clinically relevant novel biomarker in breast cancer and may serve as a target for future drug development.
Citation Format: Lichao Sun, ChangChing Lin, Joseph Burnett, Hebao Yuan, Duxin Sun. Long noncoding RNA Linc00162, as a novel prognostic marker, modulates cancer stem cell properties in triple-negative breast 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 4604.