bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3739: Characterization of the effects of DIM (3,3’-Diindolylmethane) on irradiated tumors and anti-tumor immunity
Authors: Chen Renxiang , Li Lijun , Lin Lorreta Yun-Tien , Fornace Albert J. , Li Heng-Hong 
Published: August 2019

Abstract
The overall goal of this project is to determine the efficacy of DIM (3,3’-Diindolylmethane) to protect normal tissues during radiotherapy but not enhance the survival of irradiated tumors. We tested expression change of p53-downstream genes in the absence and presence of DIM after radiation exposure using hTERT-immortalized human mammary epithelial cells. Radiation-induced gene inductions for both p21 and Wip1 were found attenuated in cells pretreated with various concentrations of DIM compared to the vehicle control. To reveal DIM’s effects on the global transcriptome of irradiated cells, we performed whole genome gene expression microarray analysis. Pathway analysis results showed that the differentially expressed genes are involved in cell cycle, p53 network, DDR, and related pathways. Gene regulation pattern at the later post-radiation time point in the presence of DIM shows similarity with that of early time point with no DIM, which suggests that DIM treatment delays responses of cell-cycle-related genes. We monitored tumor growth after localized radiation in tumor xenograft models of MDA-MB-231 and HCC1937 human breast carcinoma cell lines using immunocompromised NSG mice. The fractionated regimen consists of a total dose of 24 Gy in four fractions (6 Gy per fraction given every other day) with administration of DIM or vehicle at one hour prior to each fraction. DIM showed no significant effect on the growth of irradiated tumors, i.e. DIM did not affect the treatment efficacy of radiation on tumors. To investigate effects of DIM on tumor microenvironment, we treated tumors with fractioned radiation in an E0771 syngeneic tumor model. DIM treatment enhanced tumor infiltration of lymphocytes population. These studies support the goal of developing DIM as a clinical radioprotector in order to improve the therapeutic index by allowing higher doses of radiation to improve local tumor control by reducing late dose-limiting normal tissue toxicity by radiation.
Citation Format: Renxiang Chen, Lijun Li, Lorreta Yun-Tien Lin, Albert J. Fornace, Heng-Hong Li. Characterization of the effects of DIM (3,3’-Diindolylmethane) on irradiated tumors and anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3739.
Abstract 3747: Radium 223 inhibits prostate cancer in bone via zonal cytotoxicity
Authors: Dondossola Eleonora , Casarin Stefano , Paindelli Claudia , De-Juan-Pardo Elena , Hutmacher Dietmar , Logothetis Christopher , Friedl Peter 
Published: August 2019

Abstract
Bone metastases are the initial site of progression and account for many complications experienced by men with metastatic prostate cancer (PCa), with limited therapeutic options. Targeting the bone environment has recently resulted in the approval of Radium-223 (Rad-223), a new life-prolonging therapy for patients with metastatic castrate-resistant prostate cancer. Rad-223 is a rare earth metal radioisotope that displays chemical properties similar to calcium, becomes enriched in bone after in vivo administration and emits alpha particles with locally high energy but limited penetrance in tissues (&lt;100 µm). Confoundingly, the clinical response to Radium-223 is often followed by detrimental relapse and progression, and whether Radium-223 causes tumor-cell directed cytotoxicity in vivo remains unclear. We hypothesized that limited radiation penetrance in situ defines outcome and addressed the principles discriminating Radium-223 efficacy from failure by combining 3D intravital microscopy, in silico modeling and end-point analysis in preclinical PCa models in bone. Radium-223 induced profound but zonally confined cancer cell lethality along the bone interface (200-300 µm), while the more distant tumor core remained unperturbed. As consequence, macro-lesions persisted and grew, whereas micro-tumors in the bone niche showed severe growth delay or eradication. The relative inefficacy in controlling large tumors points to application of Radium-223 in secondary prevention of early bone-metastatic disease and regimens co-targeting the tumor core or broadening the zonal toxicity.
Citation Format: Eleonora Dondossola, Stefano Casarin, Claudia Paindelli, Elena De-Juan-Pardo, Dietmar Hutmacher, Christopher Logothetis, Peter Friedl. Radium 223 inhibits prostate cancer in bone via zonal cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3747.
Abstract 3749: Metabolic reprogramming by GCN1 mediates metastatic reactivation and outgrowth at liver metastatic site in response to glutamine deprivation in pancreatic cancer
Authors: Sinha Surajit , Hernandez Jonathan , Ayabe Reed , Wach Michael , Ruff Samantha , Ranjan Alok , Remmert Kirsten , Alexander Imani 
Published: August 2019

Abstract
Introduction: Disseminated tumor cells in the circulation upon extravasation into a secondary organ like the liver encounter hostile conditions like nutrient deprivation and oxidative stress and may undergo dormancy or growth arrest. The molecular drivers and mechanisms that enable disseminated tumor cells to overcome such adverse growth conditions and revert to proliferative stage are unknown.
Method: To identify these molecular drivers, a retroviral cDNA library was generated from a highly metastatic pancreatic cell line (M-4964Liv) derived from a KPC mouse which forms macroscopic liver lesions upon splenic injection in mice. The cDNA library was then transduced into a dormant pancreatic KPC cells (D-4964Liv) cells which does not give liver lesions upon splenic injection in mice. This methodology will allow all the cDNA’s from the metastatic cells to express in the dormant cells but only those cDNA’s which can trigger the dormant cells to outgrow will give rise to a metastatic liver lesion.
Results: The screening strategy led to the identification of general control of amino-acid synthesis 1-like 1 (GCN1L1). The human homologue GCN1 has been shown to regulate the activation of mammalian amino acid sensor general control non-derepressible 2 (GCN2) under amino acid starvation in budding yeast but how GCN1 regulates metastatic reactivation is not known. We show that GCN1 is activated under physiologic glutamine levels in the liver which is around 0.5 mM compared to standard tissue culture levels of 2-4 mM. Mechanistic interrogation revealed that GCN1 activates both the mammalian amino acid sensors: the general control nonderepressible 2 (GCN2) and the mechanistic target of rapamycin complex 1 (mTORC1) leading to metastatic outgrowth in vivo. Contrary, knockdown of GCN1 dramatically impairs the activation of GCN2 and mTORC1 and abrogates liver metastatic outgrowth upon splenic injection in immunocompetent mice.
Conclusions: These results suggest that under physiologic glutamine levels, induction of GCN1 activates two different pathways: One pathway impinges on ATF4 and the other on mTORC1. While ATF4 activation promotes metabolic homeostasis by inducing de novo amino acid synthesis, the activation of mTOR pathway ensures re-entry in to the cell cycle leading to metastatic reactivation and outgrowth.
Citation Format: Surajit Sinha, Jonathan Hernandez, Reed Ayabe, Michael Wach, Samantha Ruff, Alok Ranjan, Kirsten Remmert, Imani Alexander. Metabolic reprogramming by GCN1 mediates metastatic reactivation and outgrowth at liver metastatic site in response to glutamine deprivation in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3749.
Abstract 3752: Fabrication and validation of an in vitro bone marrow microenvironment for the study of prostate cancer progression
Authors: Kozminsky Molly , Sohn Lydia 
Published: August 2019

Abstract
Metastasis is responsible for the vast majority of cancer deaths, motivating the investigation of how the disease progresses in the face of each obstacle put forth by the body. While disseminated tumor cells (DTCs) are detected in the bone marrow of many prostate cancer patients, only 1% of DTCs yield macrometastases. There is pressing need for an in vitro system to study the characteristics of the interactions with the microenvironment that influence prostate cancer progression. High-throughput DNA-directed single-cell patterning was used to create an in vitro bone-marrow microenvironment that provides replicates of these miniature systems within an easy-to-images conventional chamber slide. This system enables the study of the contributions of several cell types present in the bone marrow microenvironment. Cell types in the in vitro system to be represented by cell lines include bone cells (osteoblasts and osteoclasts), cells of hematopoietic lineage (macrophages, osteoclasts), and endothelial cells. Optimization strategies for cell culture conditions, pattern design, and fabrication parameters will be described as well the incorporation of prostate cancer cells to study cell-cell interactions. Applying high-throughput DNA-directed cell-patterning system yielded a highly complex cellular system that can be used to answer open questions about prostate cancer metastasis.
Citation Format: Molly Kozminsky, Lydia Sohn. Fabrication and validation of an in vitro bone marrow microenvironment for the study of prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3752.
Abstract 3761: Regulation of metastasis by CD8 T lymphocytes
Authors: Joseph Robiya , Soundararajan Rama , Vasaikar Suhas , Yang Fei , Isgandarova Sevinj , Tian Lin , Haemmerle Monika , Mino Barbara , Zhou Tieling , Raja Geraldine Vidhya , Pena Esmeralda Ramirez , Hollander Petra Den , Bhangre Neeraja , Shin Crystal , Martinez Melisa , Canales Jaime Rodriguez , Chang Jeffrey , Sood Anil , Wistuba Ignacio Ivan , Gibbons Don L. , Rosen Jeffrey M. , Acharya Ghanashyam , Varadarajan Navin , Zhang Xiang H. , Mani Sendurai A. 
Published: August 2019

Abstract
Metastatic breast cancer is the most dreadful malignant disease that accounts for the majority of cancer-related deaths worldwide among women. A number of studies have shown that the tumor microenvironment (TME) plays a crucial role in regulating metastasis. It is therefore imperative to understand the dynamic interactions between cancer cells and their microenvironment to examine the molecular interaction and to effectively target cancer cells. TME comprises a variety of cells including immune cells which can influence tumor survival, growth and metastasis. Tumor-infiltrating lymphocytes (TILs), in particular, the CD8 T lymphocytes, has emerged as a promising prognostic marker for immunotherapy in a variety of cancers. However, the key molecular factors that regulate the cross-talk between tumor cells and CD8 T lymphocytes and its impact on metastatic traits in breast cancer is still inconclusive. Platelets are crucial components of the tumor microenvironment that are known to modulate tumor promotion and metastasis. The contribution of platelets and platelet secreted molecules are also carefully examined in metastasis of various cancers. The primary objective of this study is to investigate the role of CD8 T lymphocytes and platelets in breast tumor progression using isogenic tumor lines that form identical primary tumors but differ in their ability to develop metastasis.
Citation Format: Robiya Joseph, Rama Soundararajan, Suhas Vasaikar, Fei Yang, Sevinj Isgandarova, Lin Tian, Monika Haemmerle, Barbara Mino, Tieling Zhou, Geraldine Vidhya Raja, Esmeralda Ramirez Pena, Petra Den Hollander, Neeraja Bhangre, Crystal Shin, Melisa Martinez, Jaime Rodriguez Canales, Jeffrey Chang, Anil Sood, Ignacio Ivan Wistuba, Don L. Gibbons, Jeffrey M. Rosen, Ghanashyam Acharya, Navin Varadarajan, Xiang H. Zhang, Sendurai A. Mani. Regulation of metastasis by CD8 T lymphocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3761.
Abstract 3771: Oncogenes and tumour-suppressors drive differential retinoblastoma evolution
Authors: Salcedo Adriana , Watson John D. , Racher Hilary , Rushlow Diane , Espiritu Shadrielle Melijah G. , Sendorek Doroto H. , Prokopec Stephenie D. , Matveski Donco , Yousif Fouad , Livingstone Julie , Gallie Brenda L. , Boutros Paul C. 
Published: August 2019

Abstract
Unlike any other tumour type, retinoblastomas can be driven by only two tumour-initiating events: bi-allelic loss of the tumour suppressor RB1 or amplification of the MYCN oncogene. These mutations drive morphologically indistinguishable tumours that arise at different ages, providing a unique model system to evaluate the influence of initiating mutation on tumour evolution. We performed high-resolution copy number analysis of 101 retinoblastoma and whole genome sequencing of 23. These data reveal that different initiating mutations cause probabilistic changes in somatic point and copy number mutations, but large changes in genomic rearrangements and mitochondrial number. Independent of the initiating mutation, retinoblastomas harbour multiple subclonal populations that preferentially accrue point mutations after subclonal diversification. These subclonal structures suggest caution when choosing chemotherapeutic strategies for primary treatment. Overall, initiating mutations influence evolutionary trajectory more than specific driver mutations: RB1- and MYCN-driven tumours harbour distinct mutational processes, sequences of mutation acquisition and patterns of subclonal diversification. These data show how tumour-initiating mutations drive clinical behaviour by subtly biasing multiple evolutionary processes. Validation in other tumour types is underway.
Citation Format: Adriana Salcedo, John D. Watson, Hilary Racher, Diane Rushlow, Shadrielle Melijah G. Espiritu, Doroto H. Sendorek, Stephenie D. Prokopec, Donco Matveski, Fouad Yousif, Julie Livingstone, Brenda L. Gallie, Paul C. Boutros. Oncogenes and tumour-suppressors drive differential retinoblastoma evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3771.
Abstract 3787: Reduced expression of INPP4B by promoter hypermethylation in Epstein-Barr virus-associated gastric carcinoma
Authors: Ma Yiwen , Tan Jichao , Dai Weihong , Zhang Yu , Zhang Yu , Lin Rongjin , Xu Yan 
Published: August 2019

Abstract
Background: Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is attracting increasing attention due to distinct molecular and clinical characteristics. However, its carcinogenesis still remains unclear. Previous studies demonstrated that aberrant DNA methylation is one of the pathogenic mechanisms of EBVaGC. Inositol polyphosphate 4-phosphatase type II (INPP4B), as a component of PI3K/AKT pathway, is implicated in the regulation of crucial cellular processes and tumorigenesis. This study aims to reveal the correlation between INPP4B expression and EBV infection, as well as investigate the inactivation mechanism of INPP4B in EBVaGC.
Methods: EBV status and INPP4B expression were examined in gastric carcinoma (GC) tissue microarray (301 cases) using EBV RNA probe and immunohistochemistry, respectively. The correlation of EBV status and INPP4B expression was analyzed in GC by Chi-Squared Test. The INPP4B promoter methylation was investigated in GC cell lines: SNU-719 (EBV positive), AGS (EBV negative) and SGC-7901 (EBV negative) with methylation-specific polymerase chain reaction (MSPCR). After treatment with 5-Aza-2′-deoxycytidine, the INPP4B promoter methylation and expression were detected using MSPCR, western blot, and qPCR.
Results: INPP4B expression is decreased in 146 of 301 GC cases (48.5%). In 272 evaluable GC cases, EBV was present in 40 cases (14.71%). In addition, Lower expression of INPP4B is significantly correlated with EBV infection (p&lt;0.05). There was a significantly decreased expression of INPP4B in EBV positive cell line (SNU-719) compared to EBV negative cell line (AGS and SGC-7901). Moreover, aberrant CpG island hypermethylation of INPP4B was found in SNU-719 rather than AGS and SGC-7901. After treatment with 5-Aza-2′-deoxycytidine, INPP4B protein and mRNA are dramatically up-regulated, while unmethylated DNA became detectable in SNU-719.
Conclusions: Our results suggest that the reduction of INPP4B expression is commonly found in GC, particularly in EBVaGC. Promoter hypermethylation may be one of the mechanisms of INPP4B inactivation.
Citation Format: Yiwen Ma, Jichao Tan, Weihong Dai, Yu Zhang, Yu Zhang, Rongjin Lin, Yan Xu. Reduced expression of INPP4B by promoter hypermethylation in Epstein-Barr virus-associated gastric carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3787.
Abstract 3799: Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer
Authors: Lee Haeseung , Kwon Ok-Seon , Kim Wankyu , Cha Hyuk-Jin 
Published: August 2019

Abstract
Even when targets responsible for chemoresistance are identified, drug development is often hampered due to the poor druggability of these proteins. We systematically analyzed therapy-resistance with a large-scale cancer cell transcriptome and drug-response datasets and predicted the candidate drugs based on the gene expression profile. Our results implicated the epithelial-mesenchymal transition as a common mechanism underlying resistance to chemotherapeutic drugs. Notably, we identified ITGB3, whose expression was abundant in both drug resistance and mesenchymal status, as a promising target to overcome chemoresistance. We also confirmed that depletion of ITGB3 sensitized cancer cells to conventional chemotherapeutic drugs by modulating the NF-κB signaling pathway. Considering the poor druggability of ITGB3 and the lack of feasible drugs to directly inhibit this protein, we took an in silico screening for drugs mimicking the transcriptome-level changes caused by knockdown of ITGB3. This approach successfully identified atorvastatin as a novel candidate for drug repurposing, paving an alternative path to drug screening that is applicable to undruggable targets.
Citation Format: Haeseung Lee, Ok-Seon Kwon, Wankyu Kim, Hyuk-Jin Cha. Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3799.
Abstract 3812: Overcoming de novo and acquired modes of cetuximab resistance by broad-spectrum receptor tyrosine kinase inhibitors
Authors: Singh Bhuminder , Graves-Deal Ramona , Bogatcheva Galina , Coffey Robert J. 
Published: August 2019

Abstract
MEK inhibition has been shown to delay emergence of cetuximab resistance in colorectal cancer (CRC) (Nat Commun 22;6:8305, 2015). By exploiting a novel 3D culture system, we herein show that three broad-spectrum tyrosine kinase inhibitors overcome de novo and acquired resistance to cetuximab. By culturing a CRC cell line, HCA-7 in 3D in type I collagen, we previously identified two novel modes of cetuximab resistance. In 3D culture, HCA-7-derived CC are sensitive to cetuximab, while SC exhibit de novo cetuximab resistance (PNAS 114:E2852-E2861, 2017). Continuous exposure of CC to cetuximab resulted in colonies that acquired resistance to cetuximab, designated CC-CR, which was dependent in part on increased levels of lncRNA MIR100HG that leads to increased WNT signaling (Nat Med 23:1331-1341, 2017). We previously showed increased MET and RON tyrosine phosphorylation in SC cells and that MET/RON inhibitor, crizotinib overcomes SC cetuximab resistance. We now show that crizotinib also overcomes acquired cetuximab resistance in CC-CR. A phospho-RTK array showed increased phosphorylation of several RTKs, including MET and RON, in SC and CC-CR cells compared to cetuximab-sensitive CC counterparts. Furthermore, other multi-RTK inhibitors cabozantinib and BMS-777607 helped overcome cetuximab resistance, as measured by 3D colony growth and activation state of key signaling molecules. Conversely, addition of RTK ligands HGF and NRG1 induced cetuximab resistance in CC cells, which could be blocked by addition of crizotinib and this was associated with disorganized spindle positioning during cell division, leading to multi-layering of CC cultures. By FACS analysis, we observed increased cell cycle arrest in G1 phase in SC and CC-CR cultures treated with cetuximab and crizotinib. Furthermore, we show that crizotinib overcomes cetuximab resistance in vivo in SC nude mice xenografts. Finally, in a direct comparison between vertical suppression (EGFR/MEK inhibition) and parallel inhibition (EGFR/multi-RTK inhibition), we observed a higher degree of synergy with the latter strategy. The non-overlapping toxicities of cetuximab and crizotinib warrants consideration for its clinical deployment.
Note: This abstract was not presented at the meeting.
Citation Format: Bhuminder Singh, Ramona Graves-Deal, Galina Bogatcheva, Robert J. Coffey. Overcoming de novo and acquired modes of cetuximab resistance by broad-spectrum receptor tyrosine kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3812.