bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5052: CD44 inhibits the transition of ductal carcinoma in situ to invasive breast carcinoma
Authors: Liu Fang , Zhou Jun , Kundu-Roy Tanima , Wahler Joseph , So Jae Young , Lin Yong , Lou You-Rong , Barnard Nicola J. , Matsuura Isao , Suh Nanjoo 
Published: September 2020

Abstract
Ductal carcinoma in situ (DCIS) transition to invasive tumor is a big problem for breast cancer. The human MCF10DCIS.com cell line (abbreviated as MCF10DCIS) is derived from the human MCF10A breast epithelial cell line. The MCF10DCIS xenografts are similar to human high grade comedo DCIS. In the xenograft assay, MCF10DCIS cells form DCIS-like lesion, remain as DCIS-like lesion in the first several weeks, and then progress into invasive carcinoma. Thus, it is an excellent model to study human breast cancer transition from DCIS to invasive carcinoma. We investigated the role of CD44 in breast cancer transition from DCIS to invasive carcinoma by knockdown the expression of CD44 in the MCF10DCIS xenograft model. Our results show that knockdown of CD44 expression in the MCF10DCIS cells promotes DCIS transition to invasive carcinoma. Our finding is supported by a previous study that showed CD44 expression is higher in DCIS than in invasive breast carcinomas for human patients. Furthermore, we will present our ongoing studies for the underlying mechanisms. Our findings have important implications for breast cancer.
Citation Format: Fang Liu, Jun Zhou, Tanima Kundu-Roy, Joseph Wahler, Jae Young So, Yong Lin, You-Rong Lou, Nicola J. Barnard, Isao Matsuura, Nanjoo Suh. CD44 inhibits the transition of ductal carcinoma in situ to invasive breast carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5052.
Abstract 5097: Pancreatic cancer cells derived exosomes stimulate pericyte phenotype switching in the tumor microenvironment
Authors: Delgado Alexander , Jacobson Reed , Wrede Dylan , Ha Sangdeuk , Kim Jiha 
Published: September 2020

Abstract
In pancreatic cancer (PC), most conventional and targeted therapies fail to provide substantial response partly due to the limited delivery efficacy of cytotoxic drugs. Poor vascular structure and stroma-rich tumor microenvironment (TME) likely contribute to such failure. We have previously shown that in breast cancer, differential perivascular investment significantly impacts vascular functionality and drug delivery efficacy. Considering unique pancreatic cancer TME, it is a promising approach to "re-invest" perivascular cells in which blood vessels are in their optimal functional status.
As a first attempt to understand the perivascular phenotype of pancreatic tumors, we utilized a multiplex imaging analysis technique to map out differential pericyte markers expression on several mouse model systems for PC as well as tumor microarray (TMA) of patients with PC. Among pericyte markers examined, alpha-smooth muscle actin (α-SMA) expression was significantly increased in all cases of PC compared to normal pancreas tissues, which skewed the ratio between Desmin (mature pericyte marker) and α-SMA.
To determine if eliminating pathological pericytes can normalize vascular phenotype of pancreatic tumor, we utilized PDGFRβ-TK transgenic mice in which proliferating pericytes that express PDGFRβ are depleted. However, eliminating these pericytes resulted in increased metastasis accompanied by increased vascular leakiness. This result indicates that elimination tumor-associated pericyte might result in an adverse effect instead of vascular normalization. Therefore, we hypothesize that normalizing vascular phenotype by re-investment of perivascular cells will likely contribute to improving TME for a better outcome.
To understand the molecular mechanism governing pericyte phenotype switching, we established in vitro vascular cell culture system. The results indicate that PC cells derived exosomes can modify pericyte phenotype that resembles tumor-associated pericyte. Such phenotype conversion was even further enhanced in a hypoxic environment. Currently, we are investigating global gene expression changes of pericyte upon exposure to PC cell exosomes using a single-cell RNA sequencing method to have a comprehensive understanding of pericyte phenotype switching. Currently, we are performing in vivo perivascular re-investment using our candidate molecules to prove our hypothesis that perivascular re-investment will improve vascular performance and consequently enhance drug delivery efficacy.
Citation Format: Alexander Delgado, Reed Jacobson, Dylan Wrede, Sangdeuk Ha, Jiha Kim. Pancreatic cancer cells derived exosomes stimulate pericyte phenotype switching in the tumor microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5097.
Abstract 5166: In silico identification of specific inhibitor(s) of tumor associated Vacuolar ATPase ‘a2' isoform: A critical target for anti-cancer drug development
Authors: Kulshrestha Arpita , Katara Gajendra K. , Kumar Awanish , Beaman Kenneth D. 
Published: September 2020

Abstract
The discovery of effective anti-cancer therapies has immense consequences on global health. Vacuolar (H+)-ATPases (V-ATPases) are multi-subunit nano-motors that acidify the lumen of intracellular organelles in normal physiology. In cancer cells, the plasma membrane V-ATPases acidify the extracellular space. This is critical in tumor invasion, metastasis, and chemo-resistance. The `a2` isoform of V-ATPase (a2V) is the major pH sensing unit of this complex and is distinctly overexpressed on the surface of cancer cells making it an excellent drug target. The chemical inhibitors such as bafilomycin/concanamycin target V-ATPase subunits also critical in normal cell function. Currently, there are no selective a2V inhibitors commercially available as anti-cancer agents. Here, we employed in silico molecular modeling to analyze specific a2V binding sites in order to design targeted small molecules a2V inhibitors. We have identified several natural compounds as a2V ligands which inhibit specifically a2V in cancer. Employing human ovarian and breast epithelial cells (normal or tumor), in vitro studies measured each a2V ligand(s) effects on cancer cell proliferation. We selected five a2V ligands showing the most potent anti-proliferative activity in cancer cells and were least toxic to normal cells. We further measured each ligand(s) effects on specific ATPase activity in vitro by determining the decrease in inorganic phosphate levels. Next, the two most potent a2v ligands (KDB001, KDB002) which belonged to alkaloid and mono-terpenoid phenol groups, were selected to measure the changes in cytosolic and extracellular pH- SNARF assay and pH of cell supernatants. KDB001 induced cytosolic pH acidification in a dose-dependent manner indicating inhibition of V-ATPase activity. Based on the above experiments, the best ligand with most prominent effect on a2V activity (KDB-001) was further validated in vivo for anti-ovarian cancer efficacy in an athymic nude mouse model. KDB001 administration resulted in a significant delay in in vivo ovarian tumor growth. Studies are underway to design and synthesize more efficient analogs for KDB001 molecular modelling, toxicity assessment and chemical synthesis approach. In conclusion, the study has discovered new inhibitors of V-ATPase-a2V, positioning these promising compounds to enter the anti-cancer drug development pipeline.
Citation Format: Arpita Kulshrestha, Gajendra K. Katara, Awanish Kumar, Kenneth D. Beaman. In silico identification of specific inhibitor(s) of tumor associated Vacuolar ATPase ‘a2' isoform: A critical target for anti-cancer drug development [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5166.
Abstract 5300: A survey of EphA2 expression by immunohistochemistry (IHC) in tumor tissue microarrays (TMAs) to support BT5528 indication selection
Authors: Campbell Carly T. , Smale Robert , Lee James , Ragheb Josette William , Rigby Michael , Gelb Tara , Mahnke Lisa , Bennett Gavin , Blakemore Stephen J. 
Published: September 2020

Abstract
Introduction: BT5528 is a Bicycle® Toxin Conjugate (BTC) which contains an EphA2 binding peptide (Bicycle) conjugated through a molecular spacer and cleavable linker to the antimitotic toxin MMAE. EphA2 is an attractive tumor target; overexpression has been reported in multiple tumor types. Preclinical activity of BT5528 has been described previously, demonstrating increased efficacy is associated with high EphA2 tumor cell expression levels in xenograft models. Enrollment to a Phase I dose escalation study with BT5528 (BT5528-100) has started in patients with advanced solid tumors associated with EphA2 expression. Here we describe the analysis of TMAs stained using an EphA2 IHC assay developed for retrospective analysis of archive tumor from the BT5528-100 clinical trial.
Methods: A clinical grade EphA2 IHC assay was developed on the Dako platform using R&D Systems EphA2 primary antibody (AF3035) at 10 µg/mL and the Dako FLEX detection kit. TMAs of indications reported to have high EphA2 including pancreatic, bladder, head & neck, stomach, NSCLC, TNBC, and ovarian cancer were stained and scored for EphA2 expression. H-scores (the product of stain intensity on a scale of 0-3 and % positive tumor cells) were generated by a pathologist independently for tumor cell membrane (TM) and tumor cytoplasm (TC). H-scores ≥20 were considered positive for EphA2.
Results: The pattern of EphA2 expression was different across indications tested with pancreas having the greatest frequency of EphA2 expression. In contrast to the other indications assessed, pancreas and bladder had a greater percentage of cores positive for TM over TC. These differences may be relevant for BT5528 indication selection given that the mechanism of BTCs may be enhanced in cases which are TM positive.
Conclusion: Use of an IHC assay assessing expression of EphA2 across multiple TMAs and scoring TM and TC individually may help guide indication selection for the BT5528 clinical program.
EphA2 expression by IHC in multiple indicationsIndicationTotal cores (N)TM Positive N (%)TC Positive N(%)TM or TC Positive N (%)Pancreatic9248 (52)14 (15)48 (52)Bladder14242 (30)37 (26)51 (36)Head & Neck6914 (20)17 (25)22 (32)Stomach5310 (19)15 (28)15 (28)NSCLC22145 (20)52 (24)60 (27)Ovarian838 (10)13 (16)17 (20)TNBC1243 (2)25 (20)25 (20)
Citation Format: Carly T. Campbell, Robert Smale, James Lee, Josette William Ragheb, Michael Rigby, Tara Gelb, Lisa Mahnke, Gavin Bennett, Stephen J. Blakemore. A survey of EphA2 expression by immunohistochemistry (IHC) in tumor tissue microarrays (TMAs) to support BT5528 indication selection [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5300.
Abstract 5363: A direct amplicon-based targeted sequencing assay for mutation analysis of single circulating tumor cells and correlation with circulating tumor DNA
Authors: Ericson Nolan G. , Kapoor Vidushi , Liu Guoying , Clein Alisa C. , Sabath Daniel E. , Kaldjian Eric P. , George Tad 
Published: September 2020

Abstract
There is increasing interest in sequence analysis of circulating tumor cells (CTCs) to identify actionable mutations that may complement circulating tumor DNA (ctDNA) findings. Because the amount of DNA present in a single cell is miniscule (~6 pg), whole genome amplification (WGA) is typically performed prior to next generation sequencing (NGS) library preparation. Existing WGA methods have inherent amplification biases leading to non-uniform genome coverage that can cause dropout of desired targets, as well as replication errors that can lead to false positive results. Targeted sequencing is an alternative approach that does not require WGA. We modified the CleanPlex® OncoZoom® Cancer Hotspot Panel protocol to perform targeted sequencing of single CTCs isolated by the RareCyte platform using A549 cell line spike-in and patient samples. We also used the CleanPlex panel to evaluate ctDNA from plasma isolated by blood collection tubes from two manufacturers (RareCyte and Streck). In both cases we compared OncoZoom results with and without prior WGA. Increased uniformity of coverage with decreased target dropout was observed when CleanPlex NGS libraries were prepared directly from cell lysates without WGA. Median read depth increased 48-fold when compared to the WGA method. On average, 23 out of 29 (79%) variants present in bulk A549 genomic DNA were observed without WGA in single model CTCs, while 15 of 29 (52%) were observed after WGA. Additionally, the false positive error frequency of non-WGA samples was 8-fold lower than in the WGA samples. CTCs and cell-free DNA from two metastatic breast cancer patients were also sequenced using OncoZoom. In one patient, PIK3CA E542K, a well-documented oncogenic mutation, was observed in 3 of 5 CTCs. In the other, ERBB2 L755S, a known HER2-reactivating mutation associated with chemoresistance, was found in 3 of 5 CTCs. Both patients' variants were present at similar allelic frequencies in plasma isolated from RareCyte and Streck cell-free DNA BCT tubes. Single-cell CleanPlex amplicon-based sequencing without prior WGA resulted in libraries with more complete and consistent coverage and lower error frequencies, enabling efficient and accurate assessment of somatic mutations in CTCs. This approach shows promise for cell-based liquid biopsy diagnostic applications.
Citation Format: Nolan G. Ericson, Vidushi Kapoor, Guoying Liu, Alisa C. Clein, Daniel E. Sabath, Eric P. Kaldjian, Tad George. A direct amplicon-based targeted sequencing assay for mutation analysis of single circulating tumor cells and correlation with circulating tumor DNA [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5363.
Abstract 5402: Inhibition of RET via BLU-667 in an in vitro model of neuroblastoma
Authors: Gutierrez Jessica , Flynn Sean , Huo Yuchen , Lesperance Jacqueline , Zage Peter 
Published: September 2020

Abstract
Neuroblastoma is the most common extracranial solid tumor of childhood. Despite aggressive treatment, outcomes in patients with high-risk disease remains poor and new therapeutics are needed to address their needs. Rearranged during Transfection (RET) is a tyrosine kinase that is a known oncogenic driver of multiple human tumors. RET is expressed on neural crest derived cells, including neuroblastoma cells, and has been shown to play a role in neuroblastoma proliferation and survival as well. Recent studies have shown RET inhibition to be a promising new therapeutic target in neuroblastoma. BLU-667 is a selective RET inhibitor with a higher potency and specificity for RET than the current inhibitors that have been previously tested. We hypothesize that this increased potency and specificity will result in greater efficacy against neuroblastoma in preclinical models with fewer off target effects. Thus, to investigate this we evaluated BLU-667 at different concentrations against a panel of established human neuroblastoma cell lines to assess its effects on neuroblastoma cell proliferation, differentiation, and viability. We found that inhibition of RET resulted in a significant decrease in cell proliferation and viability in vitro. Further, given the increased specificity of BLU-667 to RET, we hope to use western blot protein analysis to establish the specific downstream pathways through which RET inhibition leads to decreased neuroblastoma cell survival, potentially revealing further therapeutic targets.
Citation Format: Jessica Gutierrez, Sean Flynn, Yuchen Huo, Jacqueline Lesperance, Peter Zage. Inhibition of RET via BLU-667 in an in vitro model of neuroblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5402.
Abstract 5430: Deep learning-based prognosis prediction in T3N1 nasopharyngeal carcinoma patients treated with induction chemotherapy followed by concurrent chemoradiotherapy
Authors: Zhong Lianzhen , Dong Di , Tang Linglong , Han Shuyan , Tian Jie 
Published: September 2020

Abstract
Purpose: To estimate the value of deep learning on magnetic resonance (MR)-base radiomics for T3N1 nasopharyngeal carcinoma (NPC) patients receiving induction chemotherapy (ICT) followed by concurrent chemoradiotherapy (CCRT).
Methods: A total of 672 NPC patients with T3N1 disease (training cohort: n = 470; test cohort: n = 202) were enrolled and underwent MRI scan prior to receiving ICT+CCRT. Primary endpoint was disease-free survival (DFS). From each of three sequences of MR images of the primary tumor at baseline, a survival model based on SE-ResNeXt was developed to predict DFS end-to-end. Incorporating three deep learning-based radiomic signatures, a radiomic model was built using multivariable Cox proportional hazard model. Harrell's concordance indices (C-index) were applied to evaluate the predictive power of radiomics nomogram.
Results: Three deep learning-based radiomic signatures were significant associated with DFS in the training (C-index: 0.609-0.616) and test (C-index: 0.587-604) cohorts. The radiomic model had the best result for predicting DFS (train cohort: C-index, 0.647, 95% CI, 0.587-0.708, p &lt; 0.001; test cohort: C-index, 0.647, 95% CI, 0.552-0.741, p = 0.002). In addition, the radiomic model also had a significant predictive value for secondary endpoints in the entire dataset (overall survival: C-index, 0.622, p &lt; 0.001; distant metastasis-free survival: C-index, 0.578, p = 0.044; locoregional relapse-free survival: C-index, 0.648, p &lt; 0.001).
Conclusion: Deep learning MR-based radiomic signatures may serve as a powerful tool for prognosis prediction in T3N1 nasopharyngeal carcinoma patients receiving ICT + CCRT treatment.
Citation Format: Lianzhen Zhong, Di Dong, Linglong Tang, Shuyan Han, Jie Tian. Deep learning-based prognosis prediction in T3N1 nasopharyngeal carcinoma patients treated with induction chemotherapy followed by concurrent chemoradiotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5430.
Abstract 5567: In vivo administration of the STING agonist, JNJ-67544412, leads to complete regression of established murine subcutaneous tumors
Authors: Smith Melissa , Chin Diana , Chan Szeman , Mahady Sally , Campion Liam , Morgan Caitlin , Patel Shefali , Chu Gerald , Hughes Anna , Bignan Gilles , Connolly Pete , Emanuel Stuart , Packman Kathryn , Luistro Leopoldo L. 
Published: September 2020

Abstract
STING (Stimulator of Interferon Genes) is an important mediator of innate and adaptive immunity that responds to invading cytosolic bacterial and viral pathogens, and double stranded DNA from transformed cells. Activation of the cGAS-STING pathway leads to pleiotropic cytokine (IFN-α, IFN-β, TNF-α, IL-6) production, maturation and activation of macrophages, and MHC class II expressing dendritic cells (DCs) with generation of CD8+ T cells. JNJ-67544412 (JNJ-4412) is a cyclic dinucleotide (CDN) developed as a STING agonist. JNJ-4412 binds both mouse and human STING and is more potent binding all the major human STING alleles than most other STING CDN agonists. JNJ-4412 phosphorylate STING and IRF3 and induces high levels of IFNβ and other cytokines in M1 and M2 macrophages, dendritic cells, and monocytes.
In syngeneic mouse tumor studies, JNJ-4412 was dosed intratumorally (i.t.) on a q3d x 3 or qweekly schedule resulting in significant tumor regression, complete cures and long-lasting antitumor immunity. Body weight loss (&lt;20%) was observed but was transient and recoverable and could be mitigated by utilizing a qweekly schedule with no loss of activity. Proinflammatory cytokines such as IFN-α, IFN-β, IP-10, TNF-α, IL-6 and MCP-1 were detected in tumor and plasma after dosing. Combination studies with anti-PD-1 resulted in enhanced dose-dependent efficacy in treated tumors. In bilateral tumor studies, JNJ-4412 inhibited growth of contralateral un-injected tumors. Pharmacodynamic (PD) and mechanism of action (MOA) studies revealed increased number of CD8+ T cells in the treated tumors; increased apoptosis (cleaved caspase 3); loss of vascularization; decreased tumor cell proliferation and pronounced hemorrhagic necrosis in tumors. Rechallenge of cured mice demonstrated long-lasting antitumor immunity.
Thus, in vivo administration of JNJ-4412 potently activates the STING pathway resulting in inflammatory cytokine induction, activation of dendritic cells, proliferation of CD8+ T cells, increased apoptosis and curative antitumor efficacy with immunologic memory.
Citation Format: Melissa Smith, Diana Chin, Szeman Chan, Sally Mahady, Liam Campion, Caitlin Morgan, Shefali Patel, Gerald Chu, Anna Hughes, Gilles Bignan, Pete Connolly, Stuart Emanuel, Kathryn Packman, Leopoldo L. Luistro. In vivo administration of the STING agonist, JNJ-67544412, leads to complete regression of established murine subcutaneous tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5567.