bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3735: An anti-tumor immune response is evoked by partial-volume single dose radiation
Authors: Haimovitz-Friedman Adriana , Humm Johnn , Deasy Joseph O. , Wolchok Jedd , Merghoub Taha , Russell James , Li Hongyan , Samstein Robert , Budhu Sadna , Powell Simon , Bodden Chloe , Markovsky Ela , Chen Qing 
Published: August 2019

Abstract
Purpose: To study tumor growth delay resulting from partial irradiation in preclinical mouse models.
Methods and Materials: We investigated 67NR murine orthotopic breast tumors in both immunocompetent and nude mice. Treatment was delivered to 50% or 100% of the tumor using a 2x2 cm collimator on a micro-irradiator. Radiation response was modulated by treating with anti-CD8 and anti-ICAM antibodies. Similar experiments were performed using the less immunogenic Lewis Lung Carcinoma (LLC) mouse model. Tumor growth delay and γH2AX phosphorylation were measured and immune response was assessed by immunofluorescence and flow cytometry at 1 and 7 days post-radiotherapy (RT). Tumor expression of cellular adhesion molecules was also measured at different times post-RT.
Results: Partial irradiation led to tumor responses similar to fully exposed tumors in immunocompetent mice, but not in nude mice. After a single dose of 10Gy, infiltration of CD8+ T cells was observed, along with increased expression of ICAM. The response to 10Gy in hemi-irradiated tumors was abrogated by treatment with either anti-CD8 or anti-ICAM antibodies. Similar responses were obtained in the less immunogenic LLC mouse model delivering 15Gy to half the tumor volume. Treatment with FTY720, a compound that inhibits T cell egress from lymph nodes, did not affect tumor response at the time of CD8+ T cells infiltration in the non-irradiated area of the tumor, indicating that the most likely source of these cells is the irradiated portion of the hemi-irradiated tumors. In addition, a significant abscopal effect was observed after partial irradiation with a single dose of 10Gy in the 67NR model.
Conclusions: In these models, radiation controls tumor growth both directly through cell killing and indirectly through immune activation. This raises the possibility that this effect could be induced in the clinic.
Citation Format: Adriana Haimovitz-Friedman, Johnn Humm, Joseph O. Deasy, Jedd Wolchok, Taha Merghoub, James Russell, Hongyan Li, Robert Samstein, Sadna Budhu, Simon Powell, Chloe Bodden, Ela Markovsky, Qing Chen. An anti-tumor immune response is evoked by partial-volume single dose radiation [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 3735.
Abstract 3769: Detection of allele specific loss of heterozygosity in 70,000 patients with ctDNA
Authors: Zhao Jing , Fairclough Stephen R. , Chudova Darya , Lanman Richard , Talasaz AmirAli , Hardin Aaron 
Published: August 2019

Abstract
Background: Loss of Heterozygosity (LoH) is a common feature of tumor biology. LoH frequently arises from defects in Homologous Recombination Repair (HRR) and results in uni-parental deletions that manifest as (LoH). In the absence of a driving force, the likelihood of allelic loss is equal, so in a population, the rate of retention and loss of a given allele is equal, but allele specific loss (or retention) is known to occur.
Methods: Using a novel analysis method incorporating observed allele frequency and copy number variation, we investigated the Guardant Health database of variants detected from 70,000+ samples from whole blood samples from patients with advanced solid tumors that were tested using a 73-gene cell-free DNA next-generation sequencing panel (Guardant360, Guardant Health, Redwood City, CA) to identify allele specific loss.
Results: Analysis of the Guardant Health database revealed that LoH frequently manifests as allele imbalance with the observed mutation allele frequency (MAF) of the retained allele exceeding an observed allele frequency of 50% and the lost allele having observed mutation allele frequencies below 50% in an individual sample. This imbalance occurs because allele frequency is a relative measurement and loss of one allele causes the relative abundance of the remaining allele to increase in a proportional amount. Population analysis reveals that the majority of of alleles are lost without preference, but certain alleles may be more prone to retention or loss.
Conclusions: The detection of allele specific loss from ctDNA provides insight into the underlying tumor biology and the selective pressures shaping tumor evolution over the course of treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Jing Zhao, Stephen R. Fairclough, Darya Chudova, Richard Lanman, AmirAli Talasaz, Aaron Hardin. Detection of allele specific loss of heterozygosity in 70,000 patients with ctDNA [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 3769.
Abstract 3800: HDAC8 regulates plasticity and escape from therapy in BRAF mutant melanoma
Authors: Emmons Michael , Flores Fernanda , Koomen John , Seto Edward , Messina Jane , Lau Eric , Licht Jonathan , Smalley Keiran 
Published: August 2019

Abstract
Melanoma cells are highly plastic and have the ability to switch to a dedifferentiated, invasive phenotype in response to multiple stimuli. We here show that exposure to melanoma cell lines and patient specimens to multiple stresses including BRAF-MEK inhibitor therapy, hypoxia and UV-irradiation leads to an increase in HDAC8 expression/activity, and in turn, the adoption of a drug-resistant, invasive phenotype. Systems level analyses using mass spectrometry-based phosphoproteomics and RNA-Seq demonstrated HDAC8 to be involved in pathways that regulated cell cycle entry, ribosome function, RNA binding, regulation of the cytoskeleton and MAPK pathway signaling. Introduction of HDAC8 into drug-naïve melanoma cells conveyed resistance in vitro and in in vivo xenograft models. The HDAC8-mediated BRAF inhibitor resistance was mediated through upstream receptor tyrosine kinase (RTK) activation, Ras/CRAF/MEK/ERK signaling and the suppression of apoptosis through increased stabilization of Mcl-1 and the inhibition of pro-apoptotic BIM. Among the multiple RTKs increased by HDAC8, EGFR emerged as a direct transcriptional target, and it was found that EGFR inhibition could overcome HDAC8-mediated tolerance to BRAF inhibition. Although it is known that HDACs primarily function at the histone level, they can also regulate signaling through the modulation of cytoplasmic protein acteylation. In line with this, we observed that HDAC8 introduction decreased the acetylation of c-JUN, leading to an increase in its transcriptional activity and the enrichment for an AP-1 gene signature. Mutation of putative acetylation sites in c-JUN (K268R, K271R, K273R) reduced the transcriptional activation of c-JUN in melanoma cells and conveyed resistance to BRAF inhibition through increased MAPK pathway activity. In vivo xenograft studies confirmed the key role of HDAC8 in therapeutic adaptation, with either a pan-HDAC inhibitor (panobinostat) or an HDAC8 inhibitor (PCI-34051) enhancing the durability of response to BRAF inhibitor therapy. We have thus identified HDAC8 as a key driver of phenotype switching in melanoma that regulates the responses to multiple cellular stresses and conveys resistance to BRAF inhibition. Our studies demonstrate that isoform-specific HDAC8 inhibitors could be an excellent strategy to limit the adaptation of melanoma cells to multiple stresses and therapeutic interventions, including the BRAF-MEK inhibitor combination.
Citation Format: Michael Emmons, Fernanda Flores, John Koomen, Edward Seto, Jane Messina, Eric Lau, Jonathan Licht, Keiran Smalley. HDAC8 regulates plasticity and escape from therapy in BRAF mutant melanoma [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 3800.
Abstract 3815: Overcoming acquired resistance of Lapatinib in breast cancer with Palbociclib
Authors: Jeong Da Eun , Min Ahrum , Kim Seongyeong , Kim So Hyeon , Park Yoonjung , Yang Yaewon , Lee Kyung-Hun , Im Seock-Ah 
Published: August 2019

Abstract
Background : Lapatinib is a dual tyrosine kinase inhibitor that interrupts the ErbB family pathways in many solid tumors. However, the vast majority of patients who initially respond to the treatment will eventually relapse due to acquired resistance. The defects in cell cycle regulation via increased levels of cyclin D-CDK4/6 complex is well known mechanism of the acquired resistance to lapatinib. Thus, CDK4/6 inhibition can be considered as an attractive strategy to overcome lapatinib resistance. In this study, we investigated whether palbociclib, a palbociclib can overcome the resistance to lapatinib by modulating cell cycle regulation.
Methods : Acquired resistant SK-BR-3-cells was established by treating lapatinib consistently. The features of lapatinib resistance (LR) cell lines were evaluated by MTT, FACS, Western blotting, qPCR, methylation assay and WES. The antitumor effects of palbociclib in LR cell lines were evaluated through changes in cell cycle progression, proliferative ability and signaling transduction.
Results : In LR cell lines, the change of the molecules that were related to G1/S transition of cell cycle was prominent. It was confirmed that cell cycle progression and proliferation were significantly faster in LR cells compared to parental cells. Upregulation of cyclin D1, CDK4, CDK6 was shown in LR cells but cyclin-dependent kinase inhibitor, p16 was downregulated. The increase of Cyclin D1, CDK4, and CDK6 occur at the transcription level, and the epigenetic alteration of CDKN2A was observed. We identified that the palbociclib inhibited the cell cycle progression and reduced the cell viability significantly in LR cells by cell cycle arrest via blocking hyperphosphorylation of Rb. It was also confirmed that these changes resulted in apoptosis.
Conclusion : The changes of cell cycle molecules that were related to G1/S transition was observed in LR cells. Upregulation of cyclin D1, CDK4, CDK6, and deficiency in CDKN2A led to the increasing cell cycle progression and prolfieration in LR cells. Therefore, inhibition of these molecules by palbociclib could be an effective strategies for overcoming lapaitnib resistance.
Citation Format: Da Eun Jeong, Ahrum Min, Seongyeong Kim, So Hyeon Kim, Yoonjung Park, Yaewon Yang, Kyung-Hun Lee, Seock-Ah Im. Overcoming acquired resistance of Lapatinib in breast cancer with Palbociclib [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 3815.
Abstract 3834: Epigenetic modification of oncogenes or tumor suppressor genes by thymoquinone in triple negative breast cancer
Authors: Khan Md. Asaduzzaman , Zheng Meiling , Fu Junjiang 
Published: August 2019

Abstract
Background and Objective: Triple negative breast cancer (TNBC) is a molecular subtype, and most aggressive and deadly among breast cancers. Different molecular subtypes of breast cancer have distinct molecular mechanisms, and in case of TNBC, the mechanisms are complex, and still obscure. Development of therapeutic strategies are thus also difficult against TNBC. Thymoquinone (TQ) is a natural compound, which has been found effective against TNBC cells, but the mechanism of TQ action in TNBC is not clear. In this study, we have focused on TQ’s genome-wide epigenetic effect on TNBC cell line BT549. Methods: The BT549 cells were treated with 1-10 µM of TQ for cellular growth analysis, and isolated DNA for dot blot analysis with anti-5-methyl cytosine (anti-5MC) antibody to observe whole genome methylation status affected by TQ. Also the chromatin immunoprecipitation (ChIP) was performed with anti-methyl binding domain protein (anti-MBD1) to identify DNA sections, of which methylation status is changed by TQ.
Results: Cell viability assay showed that TQ dose-dependently reduced BT549 cell growth. DNA dot blot analysis results indicated no obvious changes in total methylation status change in genomic DNA. However, ChIP-seq confirmed that methylation level was affected (either increased or decreased) in certain genomic locations by TQ treatment. Some of the locations are proximal or close to some genes, indicating that this epigenetic modification might have influence on these genes’ expression pattern.
Conclusion: Thus, here in this preliminary research study, we indicate some genes, which might be epigenetically targeted by TQ in TNBC cells. Funding support: National Natural Science Foundation of China (Grant No. 81850410555, 81672887, 81172049)
Citation Format: Md. Asaduzzaman Khan, Meiling Zheng, Junjiang Fu. Epigenetic modification of oncogenes or tumor suppressor genes by thymoquinone in triple negative breast 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 3834.
Abstract 3842: Co-targeting BET and MEK as salvage therapy for MAPKi and checkpoint inhibitor resistant melanoma
Authors: Villanueva Jessie , Echevarria-Vargas Ileabett M. , Reyes-Uribe Patricia I. , Guterres Adam , Ronghe Amruta , Burgos Delaine M. Zayas-Bazan , Liu Qin , Xu Xiaowei , Speicher David W. 
Published: August 2019

Abstract
Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that the BET family member BRD4 is expressed at high levels in NRAS-mutant melanoma, and that high levels of BRD4 are associated with poor patient survival. Combining BET and MEK inhibitors synergistically curbed the growth of NRAS mutant melanoma and prolonged the survival of mice bearing tumors refractory to MAPK inhibitors and immunotherapy. Transcriptomic analysis revealed that combining BET and MEK inhibitors mitigated a MAPK- and checkpoint-inhibitor resistance transcriptional signature, downregulated the transcription factor TCF19, and induced apoptosis. Notably, TCF19 levels were downregulated in post-treatment biopsies from patients that responded to targeted or immunotherapies. In contrast, TCF19 levels were upregulated in tumor samples from non-responder patients. Furthermore, global proteomic analysis of PDX derived from patients resistant to immune checkpoint inhibitor indicate that the major downstream effects of concurrent BET and MEK inhibition is lipid metabolism. We are investigating the impact and mechanism whereby lipids modulate therapy response. Together our studies demonstrate that co-targeting MEK and BET can offset therapy resistance, offering a potential salvage strategy for melanomas with no other therapeutic options, and possibly other treatment-resistant tumor types.
Citation Format: Jessie Villanueva, Ileabett M. Echevarria-Vargas, Patricia I. Reyes-Uribe, Adam Guterres, Amruta Ronghe, Delaine M. Zayas-Bazan Burgos, Qin Liu, Xiaowei Xu, David W. Speicher. Co-targeting BET and MEK as salvage therapy for MAPKi and checkpoint inhibitor resistant melanoma [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 3842.
Abstract 3852: Development of1,2-bis(hydroxymethyl)benzo[g]pyrrolo[2,1-a]phthalazine hybrids as potent anticancer agents to small cell lung cancer
Authors: Chen Tai-Lin , Jain Vicky , Lin Yi-Wen , Su Tsann-Long , Lee Te-Chang 
Published: August 2019

Abstract
Angiogenesis is a hallmark of cancer development, especially in lung cancer and colorectal cancer. Unfortunately, the rapid development of resistance to anti-angiogenesis agents has limited the clinical benefits for the treatment. To improve the efficacy of anti-angiogenesis agents, we designed and synthesized a series of new hybrid molecules that are composed of benzophthalazine (anti-angiogenesis moiety) and bis(hydroxymethyl)pyrrole (DNA interstrand crosslinking moiety). We demonstrate that these compounds are the dual function inducing DNA crosslinking and anti-angiogenesis. 1,2-Bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazine derivatives displayed potent cytotoxicity to leukemia and a batch of solid tumor cell lines. Among them, small cell lung cancer (SCLC) cells were the most susceptible cells with the IC50 values ranged from dozens of nanomolar to submicromolar. Significantly, we observed total tumor remission by treatment of SCLC H526 (TP53 WT) xenografts with formulated compound 8 at the dose of 20mg/kg, 5 times/week for 2 weeks. In addition, compound 8 was also more potent than cisplatin in suppression of growth of SCLC H211 (TP53 mutant) xenografts. Combination treatment of H211 cells with compound 8 and cisplatin displayed the synergistically cell killing. Our preliminary results further showed that co-treatment of compound 8 and low dose cisplatin significantly suppressed tumor growth and prolonged the survival rate of mice bearing H211 xenografts. In contract to cisplatin, treatment of mice with compound 8 did not cause body weight lost, indicating low systematic toxicity of compound 8. In summary, our results indicate that bis(hydroxymethyl)benzopyrrolo[2,1-a]phthalazine hybrids, either alone or in combination with other therapeutic drugs, are potent anticancer agents against SCLC and deserve for future development.
Note: This abstract was not presented at the meeting.
Citation Format: Tai-Lin Chen, Vicky Jain, Yi-Wen Lin, Tsann-Long Su, Te-Chang Lee. Development of1,2-bis(hydroxymethyl)benzo[g]pyrrolo[2,1-a]phthalazine hybrids as potent anticancer agents to small cell 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 3852.
Abstract 3866: Decursin inhibits tumor growth, migration and invasion through the regulation of CXCR7 expression in gastric cancer
Authors: Kim Solbi , Kim Nayoung , Joo Mina , Jeon HueungJin , Ryu Hyewon , Lee Hyo Jin 
Published: August 2019

Abstract
Background: CXCR7 is overexpressed in a variety of cancer and is known to promote cell migration, invasion and metastasis. Therefore, inhibition of CXCR7 can prevent tumor progression. In this study, we investigated the role of decursin on the CXCR7 expression and its antitumor effects in gastric cancer.
Methods: CXCR7-overexpressing gastric cell lines were established, and the expression of membrane CXCR7 was confirmed by flow cytometry and immunocytochemistry. Cell viability and anoikis assay were performed using CCK-8 reagent. The effect of decursin on cell migration and invasion was tested using transwell system, and the cleavage of PARP and caspase-3 was performed in western blotting and was confirmed by flow cytometry using apoptosis detection kit. The inhibition of tumor growth by decursin was also demonstrated in vivo by measuring tumor growth using subcutaneous injection mouse model.
Results: CXCR7 overexpression significantly increased the invasion and migration, and tumor growth in gastric cancer cells. Administration of decursin decreased the membrane expression of CXCR7 in a concentration dependent manner and significantly inhibited tumor progression by suppressing cell migration, invasion and proliferation. In addition, decursin treatment impeded in vivo tumor growth in BALB/c nude mice. CXCR7-induced STAT3 and c-Myc activation were inhibited by decursin, whereas pro-apoptotic pathway was activated.
Conclusion: Decursin inhibited the cell growth, migration and invasion via downregulating the membrane expression of CXCR7 in gastric cancer in vitro and suppressed tumor growth in vivo suggesting that decursin might be used as a therapeutic agent alone or in combination with other anticancer agents in gastric cancer.
Citation Format: Solbi Kim, Nayoung Kim, Mina Joo, HueungJin Jeon, Hyewon Ryu, Hyo Jin Lee. Decursin inhibits tumor growth, migration and invasion through the regulation of CXCR7 expression in gastric 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 3866.
Abstract 3879: Inhibition of CXCR4 driven colorectal cancer progression by Nef-M1 peptide
Authors: Katkoori Venkat R. , Anderson Zeynoire , Manne Upender , Bumpers Harvey 
Published: August 2019

Abstract
Introduction: The Nef-M1 peptide (Nef-M1) competes effectively with the natural ligand of CXCR4, SDF-1α, and exhibits anti-tumorigenic activity in human colorectal cancer (CRC). However, the molecular mechanisms of action of Nef-M1 on CRC remain unclear. In this study, we evaluated the inhibition of CXCR4 driven molecular signaling mechanisms that is involved in CRC progression.
Experimental Design: Cell line derived xenografts (CDX), patient derived explant (PDE) and in vitro cell based models were used to examine the mechanisms of action of Nef-M1. The severe combined immunodeficient (SCID) mice with tumor were treated intraperitoneally with either Nef-M1 or scrambled amino acids sequence Nef-M1 (sNef-M1) that is the control. Preparation of CRC tissue, explant complete media, and cultures and treatment for 48 hours were performed for the PDE study. Sections from tumors were evaluated by immunostaining (IHC) for signaling proteins thus, implicating CRC progression. Western blot (WB) analyses were also performed on lysates of both cell lines and tumors to assess the effect of Nef-M1 on the signaling pathways that promote CRC progression.
Results: The present study revealed that PDE recapitulate multiple biological features of the disease and these were found to be very similar to the corresponding original CRC. CXCR4 overexpressing CRC cells displayed activation of CXCR4/CREB signaling as demonstrated by an increased activation of CREB, and expression of B-Myb and APOBEC3B (A3B). IHC analysis for Ub-H2B, a stem cell signaling protein that correlates with advanced disease and metastasis indicated that Nef-M1 treated CDX or PDE tumors had low expression of Ub-H2B. However, sNef-M1 treated tumors had high expression of Ub-H2B. WB analyses indicated that Nef-M1 not only suppressed the expression of Ub-H2B, but also significantly suppressed the expression of A3B. Cells expressing CXCR4 became susceptible to Nef-M1-induced inhibition of Akt, mTOR activation and Ub-H2B expression.
Conclusions: These results indicate that Nef-M1 suppresses CXCR4 driven activation of CXCR4/CREB signaling and the expression of Ub-H2B. Therefore, Nef-M1 inhibition of these signaling pathways may be a promising therapeutic strategy for CRC. This work was supported by NIH/NCI Workforce Diversity Grant R21-CA171251.
Citation Format: Venkat R. Katkoori, Zeynoire Anderson, Upender Manne, Harvey Bumpers. Inhibition of CXCR4 driven colorectal cancer progression by Nef-M1 peptide [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 3879.