bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3682: Expression levels of genes in primary melanoma associated with clinically meaningful characteristics
Authors: Berwick Marianne , Gorlov Ivan P. , Orlow Irene , Ringelberg Carol , Ernstoff Marc , Parker Joel , Gerstenblith Meg , Thompson Cheryl , Hernando Eva , Busam Klaus , Lezcano Cecilia , Corrales Sergio , Leong Siok , Thomas Nancy E. , Amos Christopher I. 
Published: August 2018

Abstract
Melanoma survival appears to be improving; however, between 13-68% of individuals with melanoma diagnosed with Stages II-III ultimately die from their melanoma. Factors influencing melanoma survival include sex, age, clinical stage, lymph node involvement and several primary tumor characteristics, such as Breslow thickness, presence of infiltrating lymphocytes (TILs), mitotic rate and ulceration. Identification of genes whose expression in primary tumors is associated with these key tumor/patient characteristics can shed light on molecular mechanisms of melanoma survival. Here we show results from a gene expression analysis of 32 formalin-fixed, paraffin embedded (FFPE) primary melanomas with extensive clinical annotation. We extracted RNA, and measured the expression of 760 genes selected based on published evidence of association with melanoma initiation or outcome using NanoString. The Cancer Genome Atlas (TCGA) data on primary melanomas was used for validation of nominally significant associations. We identified 5 genes that were significantly associated with the presence of TILs in the combined analysis of both datasets after adjustment for multiple testing using the Benjamini-Hochberg false discovery rate method: IL1R2, PPL, PLA2G3, RASAL1, and SGK2. We also identified two genes significantly associated with lymph node status (PIK3CG and IL2RA), and two genes significantly associated with sex (KDM5C and KDM6A). We found that LEF1 was significantly associated with Breslow thickness and CCNA2 with mitosis. These results demonstrate that genetic expression in primary tumors is associated with clinically meaningful characteristics of cutaneous melanoma.
Citation Format: Marianne Berwick, Ivan P. Gorlov, Irene Orlow, Carol Ringelberg, Marc Ernstoff, Joel Parker, Meg Gerstenblith, Cheryl Thompson, Eva Hernando, Klaus Busam, Cecilia Lezcano, Sergio Corrales, Siok Leong, Nancy E. Thomas, Christopher I. Amos. Expression levels of genes in primary melanoma associated with clinically meaningful characteristics [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 3682.
Abstract 3685: The BET inhibitor INCB057643 suppresses ALDH activity by targeting the ALDH1A1 super-enhancer in high-grade serous ovarian cancer
Authors: Karakashev Sergey 
Published: August 2018

Abstract
The emergence of tumor cells with certain stem-like characteristics such as high aldehyde dehydrogenase (ALDH) activity due to ALDH1A1 expression contributes to chemotherapy resistance and tumor relapse. However, clinically applicable inhibitors of ALDH activity have not been reported. There is evidence to suggest that epigenetic regulation of stem-related genes contributes to the efficacy of chemotherapy. Here we show that the bromodomain and extra-terminal (BET) inhibitor INCB57643 suppresses ALDH activity by abrogating BRD4-mediated ALDH1A1 expression through a super-enhancer element and its associated enhancer RNA. INCB57643 suppressed the outgrowth of platinum-treated ovarian cancer cells in a concentration-dependent manner. Consistently, INCB57643 synergizes with carboplatin in suppressing the growth of ovarian cancer cells with BRD4 expression, which was accompanied by induction of apoptosis. These phenotypes correlate with inhibition of ALDH1A1 expression through a super-enhancer element and additional stem-related genes, including LIF, HES1 and WNT5a in promoter regions bound by BRD4. Thus, targeting the BET protein BRD4 using small molecule BET inhibitor INCB057643 is a promising strategy for targeting ALDH activity in epithelial ovarian cancer.
Citation Format: Sergey Karakashev. The BET inhibitor INCB057643 suppresses ALDH activity by targeting the ALDH1A1 super-enhancer in high-grade serous ovarian 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 3685.
Abstract 3691: Collagen 1 fiber content may predict for recurrence in non-small cell lung cancer
Authors: Kakkad Samata , Huang Peng , Brock Malcolm , Krishnamachary Balaji , Bhujwalla Zaver M. 
Published: August 2018

Abstract
Non-small cell lung carcinoma (NSCLC) comprises 85% of all lung cancers. Approximately 30-50% of NSCLC recur despite curative resection. There is a major unmet need to identify NSCLC that are likely to recur so that these patients may be treated with more aggressive therapies. Collagen 1 (Col1) fibers are a major structural component of the extracellular matrix (ECM) of tumors. While increased Col1 fibers have been associated with increased metastasis in breast cancer, the role of Col1 in NSCLC and its relationship to recurrence has not been previously examined. We performed a blinded second harmonic generation (SHG) microscopy study on tumor tissue obtained from 5 patients with nonrecurrent NSCLC and 5 patients with recurrent NSCLC. Col1 fibers were detected with SHG microscopy that detects an intrinsic signal derived from the noncentrosymmetric molecular structure of Col1 fibers. SHG microscopy of tumor regions was performed on the H&E sections to quantify Col1 fiber volume and inter fiber distance in the tumors. At least 10 fields of view were analyzed from 1-2 sections obtained from each tumor. We additionally performed Haralick feature analyses to further analyze Col1 fiber patterns. Adjacent sections were immunostained for CD44 and α-SMA to identify cancer associated fibroblasts (CAFs) and understand their role in these tumors. We observed a significant increase of Col1 fiber volume and a significant decrease of inter fiber distance in recurrent NSCLC. Four Haralick features (orientation, contrast, energy and homogeneity) were also significantly higher in the recurrent tumors compared to the non recurrent tumors. We are currently analyzing the CAFs in the tumor sections to understand their role in the significant differences observed in Col1 fibers between recurrent and nonrecurrent tumors. If these preliminary data are confirmed in an expanded sample set, Col1 fiber analysis may provide a companion diagnostic test that can be performed rapidly on H&E tumor sections, using a confocal microscope, to evaluate the likelihood of tumor recurrence. These studies provide new insights into the role of the tumor microenvironment in NSCLC recurrence, and identify new targets for future therapeutic strategies. This work was supported in part by NIH R35CA209960.
Citation Format: Samata Kakkad, Peng Huang, Malcolm Brock, Balaji Krishnamachary, Zaver M. Bhujwalla. Collagen 1 fiber content may predict for recurrence 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 3691.
Abstract 3694: Measuring oncogene signaling with transferrin-based PET: From bench to bedside
Authors: Evans Michael J. , Truillet Charles , Ruggero Davide , Lewis Jason S. , Aggarwal Rahul , Behr Spencer C. 
Published: August 2018

Abstract
Background: Non-invasive tools that measure the activity of central oncogenes could be broadly useful for cancer detection and management. We have shown that radiolabeled transferrin molecules can be used to measure mTORC1 and MYC signaling in prostate cancer models, because the transferrin receptor is a MYC target gene. The purpose of this study was to complete the preclinical assessment of 89Zr-transferrin, as well as demonstrate that clinical disease harbors avidity for transferrin using 68Ga-citrate. Methods: Human prostate cancer cell lines have been manipulated pharmacologically and genetically to alter mTORC1 and/or MYC signaling, and radiolabeled transferrin has been used to study the impact of aberrant oncogene signaling on transferrin biology. A first in man study with 68Ga-transferrin PET was also performed at UCSF using a GE SIGNA PET/MR. A dose escalation study was performed in eight patients with castration resistant prostate cancer to identify the optimal signal to noise ratio. Results: Activation of mTORC1 or MYC resulted in higher transferrin receptor expression and higher transferrin uptake into cells, as expected. Pharmacological inhibition of either oncogene suppressed transferrin uptake in vitro and in vivo. 68Ga-transferrin PET/MR resolved ~75% of lesions that were detectable by CT or bone scan. Approximately 4 mCi and &gt;3.5 hours post injection was required to visualize tumor lesions. Conclusions: These experiments establish that like MYC, mTOR activity can be quantified in prostate cancer models with 89Zr-transferrin. Moreover, our first in human study with 68Ga-transferrin shows that human disease is generally avid for the radiotracer, but the uptake is variable among lesions, consistent with a molecularly diverse disease.
Citation Format: Michael J. Evans, Charles Truillet, Davide Ruggero, Jason S. Lewis, Rahul Aggarwal, Spencer C. Behr. Measuring oncogene signaling with transferrin-based PET: From bench to bedside [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 3694.
Abstract 3729: Developing cetuximab-staurosporine conjugate as the therapeutic medicine in KRAS/BRAF mutated colon cancer cells
Authors: Chao Wei-Ting , Sun Wei-Ting , Chiu Hsiang-Ling , Wei Wan-Chen , Wu Yi-Che , Kao Ling-Yi , Chung Yuan-Chiang , Chuang Shih-Hsien 
Published: August 2018

Abstract
Epidermal growth factor receptor (EGFR) is the key receptor for cancer cell growing, cetuximab is the monoclonal antibody that targets EGFR and was approved for treatment of colorectal, head and neck cancer. However, patients with KRAS /BRAF mutation are screened for the resistance. Kinases activities in the signal axes have been demonstrated the role in drug resistance in colon cancer cells. In this study, cetuximab was conjugated with kinases inhibitor staurosporine and the efficacy was examined in KRAS/BRAF mutated colon cancer cells. The cetuximab and staurosprone conjugate was prepared based on the amide bond formation or the thioether bond formation. Both cleavable and non-cleavable linkers were applied to the conjugate. KRAS and BRAF mutated colon cancer cell lines SW480 and HT-29 were treated with cetuximab, staurosporine, cetuximab and Staurosporine combination, cetuximab-staurosporine conjugate, cell viability and the molecular expression were monitored. In the result, staurosporine was demonstrated to suppress cetuximab induced Src activation which may contribute to drug resistance. Wild type cell (SW48) is sensitive (63% viability) to cetuximab treatment compared to BRAF and KRAS mutated cells. Cetuximab-staurosporine conjugate showed twice efficacy than cetuximab on wild type cell, and also resulted in greater toxicity (50% viability) in BRAF/KRAS mutated cells which are resistant to cetuximab treatment. Taken together, cetuximab-staurosporine conjugate has therapeutic potential in BRAF/KRAS mutated colon cancer cells.
Citation Format: Wei-Ting Chao, Wei-Ting Sun, Hsiang-Ling Chiu, Wan-Chen Wei, Yi-Che Wu, Ling-Yi Kao, Yuan-Chiang Chung, Shih-Hsien Chuang. Developing cetuximab-staurosporine conjugate as the therapeutic medicine in KRAS/BRAF mutated colon cancer cells [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 3729.
Abstract 3733: Combined targeting of estrogen receptor alpha and nuclear transport pathways remodel metabolic pathways to induce autophagy and overcome endocrine resistance
Authors: Erdogan Zeynep Madak , Cotul-Kulkoyluoglu Eylem , Wrobel Kinga , Sahoo Sunati , Haley Barbara , Landesman Yosef 
Published: August 2018

Abstract
Majority of breast cancer specific deaths in women with ERα (+) tumor occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to resensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and XPO1, a nuclear transport protein in overcoming endocrine resistance. Selinexor (SXR), an XPO1 antagonist, has been evaluated in multiple later stage clinical trials in patients with relapsed and /or refractory hematological and solid tumor malignancies. Using Cignalfinder to profile kinase signaling pathways, we found that 4-OH-Tam, SXR or their combination induced differential Akt phosphorylation profiles, changing the localization and activity of the kinase. Since we observed dramatic changes in Akt activity we hypothesized that metabolic profile of breast cancer cells would change in the presence of 4-OH-Tam and SXR. Using Seahorse metabolic profiler and cell viability experiments in limited media conditions we showed that tamoxifen resistant cells were more dependent on mitochondria for energy production. Their glucose and fatty acid dependency decreased in the presence of SXR and cells were more dependent on glutamine as the mitochondrial fuel source. In order to examine metabolic pathways that might result in the observed phenotype we performed transcriptomics and GC/MS whole metabolite profiling and identified aminoacid metabolism pathways to be upregulated when cells were treated with SXR+4-OH-Tam. We demonstrated that combined targeting of XPO1 and ERα rewires metabolic pathways and shuts down both glycolytic and mitochondrial pathways that would eventually lead to autophagy. Remodelling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and given the need for better strategies for improving therapy response of relapsed ERα(+) tumors, our findings show great promise for uncovering the role ERα-XPO1 crosstalk plays in reducing cancer recurrences.
Citation Format: Zeynep Madak Erdogan, Eylem Cotul-Kulkoyluoglu, Kinga Wrobel, Sunati Sahoo, Barbara Haley, Yosef Landesman. Combined targeting of estrogen receptor alpha and nuclear transport pathways remodel metabolic pathways to induce autophagy and overcome endocrine resistance [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 3733.
Abstract 3740: Functional cross-talk between nuclear receptor LRH-1 and androgen receptor signalling in prostate cancer
Authors: You Wenxing , Wang Yuliang , Chan Leung 
Published: August 2018

Abstract
Liver Receptor Homolog 1 (LRH-1, NR5A2) is an orphan nuclear receptor that is over-expressed in cancers in tissues such as the breast, colon and pancreas. In prostate cancer, LRH-1 is reported as a potent transcription factor to facilitate the formation of CRPC (castration-resistant prostate cancer cells) which is resistant to androgen deprivation therapy (ADT). However, it is still elusive how LRH-1 responses to ADT and facilitates the growth of CRPC. After deprivation of androgen in mouse prostate cancer xenograft model, LRH-1 mRNA was upregulated dramatically at a very low androgen level. After CRPC formation, LRH-1 mRNA was downregulated when androgen level recovered. KLK3/PSA is an important downstream target of activated AR (Androgen receptor), whose expression level at 4 days after castration is downregulated, while upregulated after relapse. Since PSA level/AR signaling activity showed an opposite expression pattern to LRH-1, we hypothesized that LRH-1 was suppressed by androgen in a negative-feedback manner. With androgen treatment of an androgen-sensitive prostate cancer cell line LNCaP, LRH-1 was downregulated in both dose- and time-dependent manner, while PSA shows an opposite expression pattern. And knocking down of AR blocked the suppression of androgen on LRH-1, indicating that androgen suppresses LRH-1 through AR. Furthermore, AR antagonist Enzalutamide can block the binding of androgen to AR thus upregulate LRH-1. According to ChIP-seq data, AR binds to the promoter and enhancer of LRH-1,and the binding intensity increased with androgen treatment. Through ChIP-qPCR, several binding sites of AR on LRH-1 promoter and enhancer were validated. The transcription activity of luciferase reporter with these AR binding sites was also suppressed by treatment of androgen. In the future work, to find out the epigenetics modifiers in the AR complexes when suppressing LRH-1 will be critical for the understanding of the detailed mechanism.
Citation Format: Wenxing You, Yuliang Wang, Leung Chan. Functional cross-talk between nuclear receptor LRH-1 and androgen receptor signalling in prostate 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 3740.
Abstract 3743: Translational regulation by ERα in hormone-dependent cancers
Authors: Lorent Julie , Hoef Vincent van , Rebello Richard , Lawrence Mitchell , Topisirovic Ivan , Larsson Ola , Furic Luc 
Published: August 2018

Abstract
The estrogen receptor α (ERα) activities are complex: in the cytoplasm ERα can directly stimulate survival signalling at the cell membrane, while in the nucleus ERα activates and represses the transcription of target genes. We recently showed that in prostate cancer ERα expression is associated with increased proliferation and higher clinical grade.
Here we explore the role of ERα in coordinating transcription and mRNA translation. Unexpectedly, loss of ERα expression leads to decoupling of transcription and translation events. Namely, mRNAs whose levels are induced by ERα loss exhibit reduced translation efficiency and, vice versa, mRNAs whose levels are reduced by ERα loss exhibit enhanced translation efficiency. Such regulation is manifested at the protein level and targets a range of key cellular functions including translation and metabolism.
Our detailed mechanistic assessment reveal that while ERα-regulated microRNA levels contribute to global changes in mRNA levels, translational buffering is explained by changes in ribosome processivity and elongation rate.
Overall, we have recently identified a process by which ERα drastically impacts the translation of a subset of mRNAs in cancer cells. We propose that this new regulatory pathway plays a major role in mediating biological effects of ERα in neoplastic tissues. Moreover, our findings have important implications in understanding alterations in gene expression programs following treatment with ERα antagonists.
Citation Format: Julie Lorent, Vincent van Hoef, Richard Rebello, Mitchell Lawrence, Ivan Topisirovic, Ola Larsson, Luc Furic. Translational regulation by ERα in hormone-dependent 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 3743.
Abstract 375: Origins of fractional control in regulated cell death
Authors: Santos Luis C. , Vogel Robert , Chipuk Jerry E. , Birtwistle Marc , Stolovitzky Gustavo , Meyer Pablo 
Published: August 2018

Abstract
Fractional killing of a population of cancer cells is often linked to cell-to-cell variability due to stochastic gene expression and fluctuations in protein levels. We found that mitochondria abundance is a major source of cell-to-cell variability that determines the fraction of cells that live or die in response to TNF-related apoptosis-inducing ligand (TRAIL). We show that the IC50 of TRAIL of clonogenic cancer cell populations correlates with mitochondria abundance, and cell-to-cell variability in mitochondria abundance controls up to 40% of the response to TRAIL. Our coarse-grained quantitative model of apoptosis reveals that increasing the mitochondrial surface area decreases the density of proapoptotic Bax pores, which in turn decreases the sensitivity of cells to TRAIL. We demonstrate that the clinically relevant small-molecule inhibitor of antiapoptotic Bcl-2 proteins ABT-263 reduces the IC50 of TRAIL by reducing the contribution of mitochondria to variability in apoptosis.
Citation Format: Luis C. Santos, Robert Vogel, Jerry E. Chipuk, Marc Birtwistle, Gustavo Stolovitzky, Pablo Meyer. Origins of fractional control in regulated cell death [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 375.
Abstract 3751: Inhibition of A2AR by AZD4635 induces anti-tumor immunity alone and in combination with anti-PD-L1 in preclinical models
Authors: Borodovsky Alexandra , Wang Yanjun , Ye Minwei , Shaw Joseph C. , Sachsenmeier Kris , Deng Nanhua , Goodwin Kelly , Clarke James D. , Goodwin Richard , Strittmatter Nicole , Hay Carl , Sah Vasu , Deborah Lawson , Reimer Corinne , Congreve Miles , Mason Jonathan , Marshall Fiona , Lyne Paul , Woessner Richard 
Published: August 2018

Abstract
Adenosine signaling through the high affinity adenosine 2A receptor (A2AR) on immune cells elicits a range of immunosuppressive effects which can promote tumor growth and limit the efficacy of immune checkpoint inhibitors. AZD4635 (HTL-1071) is a potent and selective oral A2AR antagonist, currently in a Phase 1 clinical trial as a single agent and in combination with durvalumab (anti-PD-L1 Ab) in patients with solid malignancies. In functional in vitro assays, the IC50 of AZD4635 for inhibition of A2AR signaling is dependent on adenosine concentrations and ranges from 1, 10.0, 143 nM in the presence of 0.1, 1, 10 μM adenosine, respectively. However, full understanding of the impact of adenosine on AZD4635 mediated anti-tumor responses requires characterization of intratumoral adenosine concentration and spatial heterogeneity. Using a novel LC/MS based method, measurement of intratumoral adenosine concentrations in a panel of syngeneic tumor models demonstrated a wide range of adenosine levels (5-122 μM). Additionally, measurement of intratumoral adenosine by desorption electrospray ionisation - mass spectroscopy (DESI-MS) demonstrated that adenosine levels are spatially heterogeneous, with levels varying up to 50-fold among regions of a single tumor. High intratumoral adenosine concentrations were correlated with decreased intratumoral CD8 infiltration in vivo. The therapeutic benefit of A2AR blockade alone and in combination with anti-PD-L1 was evaluated in a panel of syngeneic mouse tumor models with varying adenosine concentrations. In sensitive models, inhibition of A2AR signaling with AZD4635 led to a dose dependent reduction in tumor growth alone and in combination with checkpoint inhibitors. Tumors harvested from the treated mice exhibited increases in the functional activity of T cell and myeloid subsets. These results demonstrate that AZD4635 is a potent and selective A2AR inhibitor, that blockade of A2AR signaling with an inhibitor such as AZD4635 can reduce tumor burden and enhance antitumor immunity.
Citation Format: Alexandra Borodovsky, Yanjun Wang, Minwei Ye, Joseph C. Shaw, Kris Sachsenmeier, Nanhua Deng, Kelly Goodwin, James D. Clarke, Richard Goodwin, Nicole Strittmatter, Carl Hay, Vasu Sah, Lawson Deborah, Corinne Reimer, Miles Congreve, Jonathan Mason, Fiona Marshall, Paul Lyne, Richard Woessner. Inhibition of A2AR by AZD4635 induces anti-tumor immunity alone and in combination with anti-PD-L1 in preclinical models [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 3751.