bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-203: VXL100, a MUC1 signal peptide based immunotherapy, acts through a neoantigen-like mechanism, and shows promising effects in hematological cancers
Authors: Chen Limor , Kovjazin Riva , Shapira Michael 
Published: July 2017

Abstract
VXL100 (ImMucin®), a 21mer peptide, pan-HLA vaccine derived from the MUC1 signal peptide (SP) domain, has been shown to be safe and to elicit a robust and specific T and B-cell responses in stable and progressive multiple myeloma patients in a phase I/II clinical trial. It is now becoming recognized that the advantages of using the signal peptide domain for immunization stem from its unique B and T cells epitope restriction density and TAP independent presentation. Additionally, the low avidity of signal peptides as antigens, is believed to result in escaping negative selection in the thymus during development, and preservation of active clones in the peripheral blood. This may allow signal peptides to be presented as true neoantigens during tumor development and generate a robust immune response. To prove the neoantigenic properties of MUC1 SP, we have recently tested endogenous levels of specific anti-VXL100 T-cells by staining for VXL100-specific or control multimers. We also performed proliferation assays for patient TIL and normal donors PBMCs using cells stimulated with VXL100 or other MUC1 antigenic control peptides. VXL100 specific T-cell were found in 100% of patients (1.3-6%), VS. 0% in normal donors. We have found a direct correlation between the MUC1 signal peptide expression levels on tumor cells and levels of endogenous VXL100 specific T-cells. Positive signals were observed for multimers of other MUC1 peptides as well, but these were also seen in normal donors,
suggesting a non-specific binding. Moreover, we were able to show that VXL100 specific exhausted CD8 cells exist at a non-significant levels as compared to the total exhausted CD8. When stimulated in-vitro with VXL100, PBMCs from 70% of naive normal donors and 94% of cancer patients showed a strong proliferative response (average of 8.9% and 16.5% proliferating cells, respectively). When stimulated with control peptides 0.5% - 5.2% of patients and 0 - 13% of donors showed positive proliferation response.
Conclusions: VXL100, a novel immunotherapy agent shows the capacity to elicit a specific and robust T-cell response in healthy individuals and hematological cancer patients. These features suggest that MUC1 SP is a native sequence functioning as a cancer neoantigen and preserved through normal and tumor development. It presents an attractive opportunity for the development of an effective cancer immunotherapy.
Citation Format: Limor Chen, Riva Kovjazin, Michael Shapira. VXL100, a MUC1 signal peptide based immunotherapy, acts through a neoantigen-like mechanism, and shows promising effects in hematological cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-203. doi:10.1158/1538-7445.AM2017-LB-203
Abstract LB-217: Microenvironment mediated mechanisms of resistance to HER2 inhibitors differ between HER2+ breast cancer subtypes
Authors: Watson Spencer , Gray Joe , Korkola James , Dane Mark , Hesier Laura , Chin Koei , Mills Gordon 
Published: July 2017

Abstract
Clinical responses of HER2+ breast cancers to tyrosine kinase inhibitors (TKIs) are often limited by de novo and acquired resistance. Recent studies have shown that the tumor microenvironment has a substantial capacity to generate signals and create niches that enable otherwise sensitive cells to avoid therapeutic control. We describe here the use of MicroEnvironment MicroArrays (MEMAs) to identify specific signals from the tumor microenvironment that reduce sensitivity to small molecule HER2 targeted TKIs. We show here that responses to these signals differ between HER2+ cells that express transcriptional signatures associated with basal (HER2E) or luminal (L-HER2+) HER2+ subtypes. Specifically, we show that HER2E cell lines are rescued from the TKIs lapatinib and neratinib by hepatocyte growth factor (HGF), while L-HER2+ cell lines are rescued by neuregulin1-β1 (NRG1β). We further show that these divergent responses are due to differential use of the PI3K and MAPK pathways, and expression of receptors HER3 and MET. This is supported by transcriptomics of human tumors performed by The Cancer Genome Atlas. HGF and NRG1β are expressed in the stroma of primary mammary tumors, but can also be highly expressed in common sites of both HER2E and L-HER2+ metastasis. We show that NRG1β mediated resistance in L-HER2+ lines is reversed by inhibiting HER2-HER3 dimers with pertuzumab, while HGF mediated resistance in HER2E lines is reversed with the MET inhibitor crizotinib. These studies suggest that L-HER2+ and HER2E tumors should be treated as separate diseases and that treatments should be tailored to counter microenvironment mediated resistance mechanisms that may differ between metastatic locations based on local production and action of growth factors.
Citation Format: Spencer Watson, Joe Gray, James Korkola, Mark Dane, Laura Hesier, Koei Chin, Gordon Mills. Microenvironment mediated mechanisms of resistance to HER2 inhibitors differ between HER2+ breast cancer subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-217. doi:10.1158/1538-7445.AM2017-LB-217
Abstract LB-220: A microfluidic model for real-time monitoring of tumor-lymphocyte interactions
Authors: Moore Nathan , Doty Daniel , Santos Jose , Kratchman Louis B. , Angione Stephanie , Mott Vienna , Zielstroff Mark , Chen Hongmin , Gimbel Alla , Borenstein Jeffrey 
Published: July 2017

Abstract
The emergence of immune checkpoint inhibitors and the promise of increased patient survival reinforces the potential for targeting the tumor microenvironment as a drug development strategy. The tumor microenvironment consists of a heterogeneous composition of cancer cells, vascular cells, fibroblasts, and immune cells that are regulated by both intrinsic and extrinsic chemical and physical stimuli. Within this microenvironment, aberrant blood vessel formation and extra cellular matrix (ECM) restructuring lead to increased interstitial fluid flow and shear stress that stimulate differential gene expression, reorganization of tumor cell structure, and suppression of local cytotoxic T-cell activity. Elevated levels of fluid pressure and shear stress have also been demonstrated to alter cell sensitivity and response to therapeutic agents. Traditional static 2D in vitro models fail to adequately address tumor-immune cell interactions and flow mediated change in sensitivity, contributing to inaccurate predictions of in vivo therapeutic response. The development of 3D microfluidic systems have greatly enhanced the ability to model components of the tumor microenvironment, such as fluid flow, and capture the dynamics of tumor and immune cell responses to emerging therapeutic compounds. Here, we have developed a medium throughput microfluidic device which is constructed using bioinert materials that are also compatible with real-time confocal imaging, to model the effects of therapeutic treatment on tumor viability. In addition to exposing tumors to a dynamic flow environment, this model system enables the introduction of flowing lymphocytes, permitting tracking of tumor-lymphocyte interactions in real-time. As a test case, we demonstrate the ex vivo binding and cytotoxic activity of MC38-derived tumor infiltrating lymphocytes (TILs) on tumor fragments. These results highlight the power of a dynamic microfluidic flow system to model the tumor-lymphocyte microenvironment and the potential of this system to more accurately evaluate novel therapeutic agents.
Citation Format: Nathan Moore, Daniel Doty, Jose Santos, Louis B. Kratchman, Stephanie Angione, Vienna Mott, Mark Zielstroff, Hongmin Chen, Alla Gimbel, Jeffrey Borenstein. A microfluidic model for real-time monitoring of tumor-lymphocyte interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-220. doi:10.1158/1538-7445.AM2017-LB-220
Abstract LB-223: Whole genome sequencing of rhabdomyosarcoma germline cohort identifies low frequency of pathogenic mutations
Authors: Light Nicholas , Lupo Philip , Khan Javed , Schiffman Joshua , Hawkins Douglas , Shlien Adam , Malkin David 
Published: July 2017

Abstract
Introduction: Rhabdomyosarcoma (RMS) is among the most frequently occurring tumors in Li-Fraumeni syndrome patients and is often observed in patients with a strong family history of cancer. Recent studies suggest that at least 10% of children with cancer harbor an underlying pathogenic germline mutation, although the frequency in children with RMS is not well characterized. In this study we sought to determine the rate of likely pathogenic germline mutations in rhabdomyosarcoma patients, unselected for family history.
Methods: Of 275 RMS patients enrolled on one clinical trial (COG ARST0531), whole-genome sequencing was performed on blood-derived DNA of an initial set of 50 using the Illumina HiseqX to an average sequencing depth of 44.9X [34.2-58.4]. Single nucleotide variants (SNVs) and Indels were called and filtered to select only those occurring in exons or splicing regions. Variants were further filtered to include only those with a frequency of &lt;0.5% in the ExAC database and lying in one of 99 genes identified as a cancer predisposition gene in the COSMIC Cancer Gene census. Nonsynonymous SNVs were required to be predicted as deleterious by one or more of Polyphen, mutation assessor or sift.
Results: Across the 50 initial samples, a total of 290 variants ([0-17], median of 5) passed the described filters. Notably, no point mutations were identified in TP53 in the initial 50 samples. Two samples contained variants annotated as pathogenic in ClinVar - a frameshift deletion in CHEK2 and a rare SNP in MUTYH. Also notable was a potentially pathogenic frameshift deletion in MSH6 that lacked previous annotation.
Conclusions: Our preliminary analysis suggests a lower incidence of causative TP53 mutations in RMS than previously suggested. Whole genome sequencing of the remaining samples in the cohort along with analysis of copy number and structural variants is ongoing. Statistical analysis of the entire cohort of 275 patient samples will allow for the most complete characterization of the germline genomic landscape of rhabdomyosarcoma to date. This information will better inform clinical surveillance and management parameters for RMS patients and families.
Citation Format: Nicholas Light, Philip Lupo, Javed Khan, Joshua Schiffman, Douglas Hawkins, Adam Shlien, David Malkin. Whole genome sequencing of rhabdomyosarcoma germline cohort identifies low frequency of pathogenic mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-223. doi:10.1158/1538-7445.AM2017-LB-223
Abstract LB-226: Dual inhibition of CD47 and HER2 to radiosensitize breast cancer cells
Authors: Candas Demet , Zhang Lu , Menaa Cheikh , Fan Ming , Zhang Yanhong , Liu Lin , Zhou Weibing , Azghadi Soheila , Sweeney Colleen , Shen Rulong , Lin Tzu-yin , Pan Chong-xian , Vaughan Andrew T. , Wang Ji Ming , Chen Hong-Wu , Lam Kit , Sun Lun-Quan , Monjazeb Arta M. , Murphy William J. , Li Jian Jian 
Published: July 2017

Abstract
Accumulating studies are aimed to combine immunoregulation with the standard of treatment such as radiotherapy in anti-cancer therapy. A potential cross resistance of tumor cells will be a barrier in furthering the long-term control by such combined treatment. CD47, an immunoglobulin-like transmembrane protein, enables cancer cells to escape the immune surveillance by flagging them with a ‘don’t eat me’ signal, which is recognized by the signal regulatory protein α (SIRPα) on macrophages. Here, we report that CD47 expression is enhanced by radiation in breast cancer cells and in vivo irradiated xenograft tumors via NF-κB regulation. In addition, CD47 and HER2 are co-induced by radiation and CD47 expression is specially enhanced by radiation in HER2-expressing cells. Contrasted with primary tumors, co-expression of CD47 and HER2 is elevated in the recurrent breast tumors. Anti-HER2 treatment inhibits CD47 transcription and protein expression with increased macrophage phagocytosis. Likewise, anti-CD47 not only augments macrophage phagocytosis but also reduces the capacity of tumorsphere formation. Radiation with anti-CD47 synergistically suppresses clonogenic survival and the maximal inhibition was achieved by dual inhibition of CD47 and HER2 with radiation. The synergy of in vivo tumor inhibition is established in mouse breast tumor model via local tumor radiotherapy combined with anti-CD47 treatment. These results demonstrate that the HER2-NF-κB-CD47 loop is responsible the cross-resistance of breast tumor against immune surveillance and radiation. Thus dual inhibition of CD47 and HER2 is a potential target to enhance tumor response to immune-radiotherapy. Funding: This study was partially supported by National Cancer Institute RO1 grant R01CA213830-01 (JJL).
Note: This abstract was not presented at the meeting.
Citation Format: Demet Candas, Lu Zhang, Cheikh Menaa, Ming Fan, Yanhong Zhang, Lin Liu, Weibing Zhou, Soheila Azghadi, Colleen Sweeney, Rulong Shen, Tzu-yin Lin, Chong-xian Pan, Andrew T. Vaughan, Ji Ming Wang, Hong-Wu Chen, Kit Lam, Lun-Quan Sun, Arta M. Monjazeb, William J. Murphy, Jian Jian Li. Dual inhibition of CD47 and HER2 to radiosensitize breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-226. doi:10.1158/1538-7445.AM2017-LB-226
Abstract LB-230: Oncogenic PKC epsilon and Pten loss converge on activating CXCL13 via atypical NF-κB transcriptional signaling in prostate cancer progression
Authors: Garg Rachana , Blando Jorge , Perez Carlos , Abba Martin , Benavides Fernando , Kazanietz Marcelo 
Published: July 2017

Abstract
Protein Kinase C epsilon (PKCϵ), a pro-oncogenic member of the PKC family of phorbol ester/diacylglycerol receptors, has been shown to be up-regulated in most epithelial cancers, including prostate cancer. PKCϵ transgenic overexpression in the mouse prostate causes preneoplastic lesions, however when intercrossed with mice haploinsufficient for Pten, the resulting compound mice (PB-PKCϵ;Pten+/-) develops invasive adenocarcinoma. We found that Pten-deficient prostate cell lines engineered to overexpress PKCϵ (CaP8-PKCϵ) cells become highly invasive and tumorigenic. Microarray gene expression profiling in this cell line revealed marked changes in the expression of genes implicated in proliferation, migration, adhesion, EMT, angiogenesis and metabolism. In particular, the chemokine CXCL13 was identified as the top-most up-regulated gene in CaP8-PKCϵ cells. Measurements of either CXCL13 mRNA, protein release to the culture medium (CM), or Cxcl13 promoter activity showed clear enhancements in cells overexpressing PKCϵ or Pten depleted, and these effects were enriched synergistically in CaP8-PKCϵ cells. CaP8-PKCϵ subjected to CXCL13 RNAi depletion showed reduced motility and tumorigenic growth. Similar results were observed upon silencing of CXCR5, the CXCL13 receptor. CXCL13 expression and promoter activity in CaP8-PKCϵ cells were significantly reduced by GF109203X (PKC inhibitor), IKK16, wedelolactone (NF-κB inhibitors), and BKM120 (PI3K inhibitor), but were insensitive to BX795 (PDK1 inhibitor). RNAi-mediated depletion of NIK or IKKα significantly blunted Cxcl13 luciferase promoter activity in CaP8-PKCϵ cells, but the effect was partially inhibited by IKKβ RNAi, suggesting the role of the atypical NF-κB pathway. Mutation of a responsive element for atypical NF-κB in the CXCL13 promoter abolished CXCL13 reporter activity in CaP8-PKCϵ cells. Taken together, our study identifies a novel paradigm depicting atypical NF-κB as the transcriptional signaling pathway by which PKCϵ overexpression/Pten loss regulates overproduction of the chemokine CXCL13 in prostate cancer cells.
Citation Format: Rachana Garg, Jorge Blando, Carlos Perez, Martin Abba, Fernando Benavides, Marcelo Kazanietz. Oncogenic PKC epsilon and Pten loss converge on activating CXCL13 via atypical NF-κB transcriptional signaling in prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-230. doi:10.1158/1538-7445.AM2017-LB-230
Abstract LB-241: Quantification of EGFR allele frequency predicts tumor response to EGFR tyrosine kinase inhibitors
Authors: Kim Jin-Soo , Kim Mi Young , Kim Sung-Su , Choi Hyun-jeung , Lee Yunsu , Lee In-Seon , Park Jin-Hyun , Kim Ki Hwan , Kim Hoon Gu , Kim Bong Seog , Shin Young Kee 
Published: July 2017

Abstract
Background: EGFR tyrosine kinase inhibitors (TKIs) are current standard treatments for non-small cell lung cancers (NSCLCs) with EGFR mutation. Current diagnostic tests for EGFR mutation include direct sequencing, pyrosequencing or real-time PCR based technology. We have developed a digital droplet PCR based analysis, GenesWell™ ddEGFR Mutation Test (IUO version 5.2. Gencurix Inc., Seoul, Korea). Methods: We have analyzed a total of 325 archived tissue from 233 lung cancer patients treated with gefitinib or erlotinib in the participating 3 hospitals from 2008 to 2013. Samples were analyzed with GenesWell™ ddEGFR Mutation Test and the results were compared with in-house results recorded in each institutional EMR. Results: Since we have analyzed left-over archived tissue, the amount of DNA was inappropriate for analysis in few cases (n=5, 1.5%), which had less than 2ng/uL concentration of DNA. ddEGFR test detected additional EGFR mutations in patients with EGFR wild-type (WT) (N=4), exon 19 deletion (19del) (N=4) and exon 21 L858R (L858R) (N=3) by in-house EGFR test. ddEGFR test detected EGFR mutations in cytology-base samples, such as pleural effusion or ascites. Small amount of sample from CSF and plasma was also detectable with ddEGFR test. Based on in-house EGFR mutation results, response rates (RRs) and disease control rates (DCRs) were as follows: 15.8% and 26.9% in WT, 71.4% and 91.8% in 19del, and 55.9% and 91.2% in L858R. Similarly, RRs and DCRs were as follows, based on ddEGFR results: 13.4% and 43.9% in wild-type (WT), 77.6% and 93.9% in 19del and 54.1% and 86.5% in exon 21 L858R (L858R). Mean allele frequencies were 48.6 (0 - 180.5) in PR, 27.4 (0 - 287.5) in SD, and 9.5 (0-159.6) in PD (P-value, PR vs SD: .0078, PR vs PD: &lt;.000001, SD vs. PD: .029, respectively, Student T-test) Conclusion: The GenesWell™ ddEGFR Mutation demonstrate a high sensitivity for EGFR mutation detection. RRs and DCRs were comparable between in-house EGFR test and ddEGFR. Quantitative analysis of EGFR mutant allele could predict responses to EGFR TKIs. Plasma-based detection of EGFR mutations with ddEGFR are being tested in patients with EGFR mutant lung cancers. Supported by the R&D Program for Society of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning (Grant number : 2013M3C8A1078499)
Citation Format: Jin-Soo Kim, Mi Young Kim, Sung-Su Kim, Hyun-jeung Choi, Yunsu Lee, In-Seon Lee, Jin-Hyun Park, Ki Hwan Kim, Hoon Gu Kim, Bong Seog Kim, Young Kee Shin. Quantification of EGFR allele frequency predicts tumor response to EGFR tyrosine kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-241. doi:10.1158/1538-7445.AM2017-LB-241
Abstract LB-244: Implication of secretory mucin MUC5AC and its glycan modification for detection of pancreatic cancer
Authors: Hayashi Chihiro , Carmicheal Joseph , Krasnoslobodtsev Alexey , Haung Ying , Brand Randall E. , Batra Surinder K. , Kaur Sukhwinder 
Published: July 2017

Abstract
Background and Aims
Pancreatic Cancer (PC) is often discovered in late stages, which contributes to its extreme
lethality. Early detection is key to improved curative response and increased survival. This study
explored the potential of secretory mucin MUC5AC and its glycosylation (Sialyl-Lewis A and
Disialyl-Lewis A) states in combination with carbohydrate antigen CA19.9 for early diagnosis of
PC.
Methods
Sandwich ELISA and radioimmunoassay were utilized to measure patient serum for levels of
MUC5AC and CA19.9, respectively. A blinded reference set was obtained from the NCI’s Early
Detection Research Network Program (n=242): healthy control (HC, N=50), chronic pancreatitis
(CP, N=59), acute biliary obstruction (ABO, N= 30), stage IA/IB/IIA (N=52), and stage IIB PC
(N=41), to assess the diagnostic performance of MUC5AC. Further, glycans on MUC5AC
(Disialyl Lewis A, Lewis A, Blood group H (BGH) antigen) were measured via Surface
Enhanced Raman Spectroscopy (SERS).
Results
MUC5AC levels were significantly increased in patients with stage IA/IB/IIA/IIB PC in
comparison to HC, ABO and CP. MUC5AC efficiently differentiated stage IA/IB/IIA PC from
healthy controls [AUC- 0.707], ABO [AUC- 0.662], and CP [AUC- 0.745]. CA19.9
differentiated stage IA/IB/IIA PC from healthy controls [AUC- 0.727], ABO [AUC-0.537] and
CP [AUC- 0.675]. The MUC5AC combination with CA19.9 significantly improved the
performance of CA19.9 alone: healthy controls [AUC- 0.761], ABO [AUC-0 .679], and CP
[AUC- 0.753]. Further, PC serum was shown to express MUC5AC with greater Sialyl-Lewis A
glycosylation in comparison to Disialyl-Lewis A glycosylation. Further, the reverse trend for
these glycosylation was observed in CP and BC group.
Conclusions
MUC5AC is an early-stage PC biomarker that offers improved performance with CA19.9 for the
detection of PC. Also, measurement of MUC5AC glycan modification will aid in the better
differentiation of PC from healthy controls and high risk groups (CP, ABO). Further, the ratio of
disialyl to CA19.9 glycosylation of MUC5AC is a novel way to differentiate between PC and
benign conditions.
Citation Format: Chihiro Hayashi, Joseph Carmicheal, Alexey Krasnoslobodtsev, Ying Haung, Randall E. Brand,, Surinder K. Batra, Sukhwinder Kaur. Implication of secretory mucin MUC5AC and its glycan modification for detection of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-244. doi:10.1158/1538-7445.AM2017-LB-244