bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT217: POLO: Homologous recombination repair gene mutations (HRRm) in metastatic pancreatic cancer (mPaC) tumors
Authors: Lai Zhongwu , Golan Talia , Kindler Hedy L. , Dougherty Brian , Matakidou Athena , Dong Liqin , Locker Gershon , Harrington Elizabeth A. 
Published: September 2020

Abstract
mPaC patients (pts) with HRRm, including BRCA1 and/or BRCA2 mutations (BRCAm), derive benefit from platinum-based treatment (Pishvaian. J Clin Oncol 2019). In the Phase III POLO trial (NCT02184195) maintenance olaparib conferred a progression-free survival benefit over placebo in pts with a germline (g) BRCAm and mPaC. A prespecified exploratory analysis was conducted to determine the prevalence of tumor tissue biomarkers in pts screened for inclusion in POLO.
Archival tumor samples were provided if available and, irrespective of subsequent pt randomization, DNA was analyzed using a gene panel from Foundation Medicine Inc. (FMI) or exome sequencing by Human Longevity Inc. (HLI). Results were compared with cohorts from FMI (mPaC; FoundationOne CDx panel) and The Cancer Genome Atlas (TCGA; primary and mPaC; exome sequencing).
Tumor samples from 187/3315 (5.6%) pts screened for entry into POLO were available and sequenced. Prevalence of tumor HRRm in the POLO, FMI and TCGA cohorts are presented in the Table. The higher BRCAm prevalence observed in the POLO and FMI cohorts compared with TCGA may be due to sample size or differences in ethnicity or tumor sample location (primary vs metastatic). Mutations in BRCA2, BRCA1 and ATM were most common and were generally mutually exclusive. The prevalence of somatic (s) BRCAm in POLO was consistent with the FMI dataset (~2%); g and s BRCAm were mutually exclusive. Of the HRRm observed in non-BRCA genes, mutations in ATM were most prevalent. Prevalence of mutations in non-HRR genes (CDKN2A, SMAD4, KRAS, TP53) in POLO was consistent with that seen in other pancreatic cancer cohorts.
TablePrevalence, %*POLO (N=187)FMI (N=1046)TCGA (N=146)BRCA24.84.32.1BRCA13.22.10ATM5.32.55.5PALB21.10.90.7CDK1200.50RAD51C00.10RAD51B00.20RAD54L00.20RAD51D00.20BRIP10.50.30.7FANCI00.30FANCL0.50.10BARD10.50.20.7CHEK100.20CHEK200.62.1Any HRR15.512.011.0Non-BRCA HRR7.55.68.9*Some tumors had a mutation in &gt;1 gene
In summary, based on the subgroup of pts with analyzed tumor tissue, the genetic profile of the screened POLO population is reflective of that seen in the overall pancreatic cancer population. ~8% of pts had tumors harboring a BRCAm, with mutations in BRCA2 more prevalent than BRCA1; ~7% of pts had tumors harboring a non-BRCA HRRm, most commonly in ATM (~5%).
Citation Format: Zhongwu Lai, Talia Golan, Hedy L. Kindler, Brian Dougherty, Athena Matakidou, Liqin Dong, Gershon Locker, Elizabeth A. Harrington. POLO: Homologous recombination repair gene mutations (HRRm) in metastatic pancreatic cancer (mPaC) 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 CT217.
Abstract CT274: Diagnosis based on signal : The first time break the routinely used circle of signal-to-image-to-diagnose
Authors: Dong Di , He Bingxi , Kong Boyu , Zhang Lei , Tong Lixia , Huang Feng , Han Dong , Huang Zhipei , Zhang Huimao , Tian Jie 
Published: September 2020

Abstract
Purpose: The routinely used diagnostic scheme of cancers follows the process of signal-to-image-to-diagnosis. It is essential to reconstruct the visible images from the signal of medical device so that the human doctor can perform diagnosis. However, the huge amount of information inside the signal is not optimally mined, which causes the current unsatisfactory performance of image based diagnosis. In this study, for the first time, we developed an AI based diagnostic scheme for lung nodules directly from the signal (rawdata) to diagnosis, skipping the reconstruction step. Experimental Design: In this study, we focused on the discrimination of malignant from benign lung nodules using CT rawdata. We collected a simulation dataset (n=606, from LUNA public dataset; rawdata was generated from CT images) and a prospective dataset (n=268, from the First Hospital of Ji Lin University, China; Clinical trials: NCT04241614). In the prospective dataset, all patients underwent preoperative CT scan (both rawdata and CT images were available) and had pathologically confirmed result of the nodules. We used 3D-CNN (Convolutional Neural Networks) to generate a model from rawdata (Model_rawdata) and another model from CT image (Model_image). The performances of the two models were compared with area under curve (AUC). In addition, we explored the additional value of rawdata to image-based diagnostic scheme. Results: The simulation study showed that rawdata could distinguish malignant lung nodules (AUCs for training and validation cohorts were 0.88 and 0.80, respectively). In the prospective study using only the lung area, both Model_rawdata and Model_image had good classification performance (both AUCs were greater than 0.65). In the prospective study using only the nodule area, the Model_rawdata performed similar with Model_image (both AUCs were greater than 0.7). The stratification analysis showed that the Model_rawdata was not affected by CT scanning parameters. Furthermore, the addition of rawdata to image (Model_combination) could improve the diagnostic performance. Conclusions: Without reconstruction, the rawdata from CT system had comparative performance to image-based diagnosis. The rawdata could provide additional diagnostic value to images. This research breaks the routinely used circle of imaged based diagnosis, which may open up a new field for AI based diagnosis.
Citation Format: Di Dong, Bingxi He, Boyu Kong, Lei Zhang, Lixia Tong, Feng Huang, Dong Han, Zhipei Huang, Huimao Zhang, Jie Tian. Diagnosis based on signal : The first time break the routinely used circle of signal-to-image-to-diagnose [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 CT274.
Abstract LB-015: Yap reprograms de novo lipogenesis to fuel liver cancer
Authors: Salmi Talhah M. , Vaidyanathan Srimayee , McConville Malcolm J. , Brown Kristin K. , Cox Andrew G. 
Published: September 2020

Abstract
Hepatocellular carcinoma (HCC) is the most common form of liver cancer, originating from liver cells known as hepatocytes. At the molecular level, HCC is driven by transcription factors which are able to reprogram metabolism to support tumorigenesis that are still poorly understood. The Yes-associated protein (Yap) is the nuclear effector of the Hippo pathway, responsible in regulating organ size control and metabolism. Metabolic reprogramming has recently emerged as a fundamental hallmark of cancer. In our previous studies, we found that Yap integrates the anabolic demands of tumour growth by reprogramming glutamine and glucose metabolism to support nucleotide biosynthesis. The central aim of this study was to determine the role that Yap plays in regulating lipid metabolism in the context of liver cancer. We took advantage of a larval zebrafish model in which a hyperactivated form of Yap is specifically expressed in hepatocytes (lf:YapS87A;lf:NLS-mcherry). We found that the expression of Yap was sufficient to stimulate de novo lipogenesis (DNL) and induce lipid droplet formation in hepatocytes (steatosis). To determine whether the stimulation of DNL was required for oncogenic growth, we exposed larvae to pharmacological inhibitors of DNL and examined the impact on growth at the cellular level by multiphoton microscopy. Strikingly, we identified that fatty acid synthase (FAS) and stearoyl-CoA desaturase (SCD) inhibitors suppressed Yap-driven growth. To complement these studies, we took a genetic approach using CRISPR to generate FAS and SCD KO zebrafish larvae and we found that Yap-driven growth required both FAS and SCD. Importantly both chemical and genetic suppression of FAS and SCD activity had no effect on normal liver growth. Together, these findings suggest that oncogenic Yap-driven growth is conditionally dependent upon the stimulation of DNL. Consequently, these studies provide a rationale for examining the clinical efficacy of DNL inhibitors to combat liver cancer.
Citation Format: Talhah M. Salmi, Srimayee Vaidyanathan, Malcolm J. McConville, Kristin K. Brown, Andrew G. Cox. Yap reprograms de novo lipogenesis to fuel liver cancer [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 LB-015.
Abstract LB-052: Photochemistry mediated tumor priming potentiates cytoreduction of distant metastases to enable potential surgical cure in a late stage model of pancreas cancer
Authors: Anbil Sriram , Mai Zhiming , Pigula Michael , Hasan Tayyaba 
Published: September 2020

Abstract
Pancreatic cancer is a devastating disease for which the 5 year survival rate remains &lt; 10% despite years of concerted research efforts. Potentially curative surgical resection cannot even be offered to most patients due to the presence of distant metastases at the time of diagnosis. Here, we present a neoadjuvant strategy comprised of photochemistry mediated tumor modulation combined with systemic therapy to significantly cytoreduce, and in 50% of cases completely eliminate, distant metastases to create a window of potential resectability. In a late stage model of pancreas cancer in which distant metastases are present at the time of treatment, combined photodynamic therapy (PDT) and gemcitabine/abraxane led to a 10,000 fold decrease in the number of distant metastases compared to untreated controls. In comparison, gemcitabine + abraxane, the current standard of care for pancreas cancer, only led to a 100 fold cytoreduction. 50% of animals treated with PDT + gem/abraxane harbored no detectable metastases 51 days after treatment compared to 0% of gem/abraxane treated animals, suggesting that PDT plus cytoreduction could enable potentially curative surgery in a sizeable percentage of animals. The strategy presented here is rapidly translatable and holds significant promise to dramatically increase the percentage of patients that are currently eligible for curative therapy for this devastating disease.
Citation Format: Sriram Anbil, Zhiming Mai, Michael Pigula, Tayyaba Hasan. Photochemistry mediated tumor priming potentiates cytoreduction of distant metastases to enable potential surgical cure in a late stage model of pancreas cancer [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 LB-052.
Abstract LB-056: A novel cyclic peptide inhibitor targeting the YAP-TEAD protein-protein interaction shows potent anti-tumor effect in a variety of human malignancies including mesothelioma
Authors: HU YI P. , Wang Yinghua M. , Lee Daniel , Ren Yi 
Published: September 2020

Abstract
The Hippo signaling pathway plays an important role in organ size control. Dysregulations of this pathway have been implicated in human cancer. Oncoprotein YAP is a major downstream effector molecule for Hippo pathway and has no intrinsic DNA binding domain. The functionality of YAP depends on the interaction of YAP with transcription factor TEAD in cell nucleus. Inhibitors targeting YAP-TEAD PPI could rectify abnormal Hippo pathway, leading to tumor remission. Screening through a carefully designed peptide library derived from the YAP protein, we have successfully identified potent YAP inhibiting peptides (YIP). Surface plasmon resonance (SPR) showed that the YIP bind to TEAD with high affinity in the nM-pM (KD) range. Subsequently, the binding interaction was confirmed by Pull-down experiments. In cell-based assays, YIP inhibited cell proliferation in various cancer cell lines at low µM (IC50) range. Furthermore, cellular nuclear tests indicated that YIP could penetrate into the nucleus and inhibited YAP-TEAD interaction by TEAD-luciferase assay in a dose dependent manner. In several s.c. xenograft animal models, a lead YIP strongly suppressed the tumour growth including NF-2 mutant mesothelioma cells. The lead YIP has good drug-like pharmacological properties and represents a promising candidate targeting the Hippo pathway as an effective treatment for cancers.
Citation Format: YI P. HU, Yinghua M. Wang, Daniel Lee, Yi Ren. A novel cyclic peptide inhibitor targeting the YAP-TEAD protein-protein interaction shows potent anti-tumor effect in a variety of human malignancies including mesothelioma [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 LB-056.
Abstract LB-062: A live-cell, protein-protein interaction assay identified inhibitors of KRAS4b-G12D interaction with full-length RAF1
Authors: Columbus John , Turbyville Thomas J. , Wall Vanessa , Esposito Dominic , Barda David A. , Peng Sheng-Bin 
Published: September 2020

Abstract
KRAS4b is a major driver of cancers of the pancreas, lung, and colon, and until recently was considered undruggable. However, recent discoveries have revealed that molecules can target KRAS directly, and that our understanding of KRAS is incomplete. To exploit this new appreciation of KRAS druggability and biology, we have developed several protein-protein interaction (PPI) assays to target KRAS activity in live cells. Here we report on a campaign where we screened a 20,000-compound library against full length KRAS4b-G12D and RAF1 interactions in live HEK293 cells using the NanoBRET platform. From the list of screening hits, we identified several structurally related active compounds with dose-dependent, albeit weak, inhibition of the PPI signal. We expanded these active compounds to a more complete list of structural analogs which we tested in a full dose response. From this expanded group of compounds, we identified several with low µM IC50s. Follow up with these compounds in secondary assays revealed promising biological readouts, including inhibition of downstream pERK levels in G12D mutant PANC1 cells. In summary, by using well-designed live cell assays, we have identified promising leads, which we are pursuing with mechanism of action studies.
Citation Format: John Columbus, Thomas J. Turbyville, Vanessa Wall, Dominic Esposito, David A. Barda, Sheng-Bin Peng. A live-cell, protein-protein interaction assay identified inhibitors of KRAS4b-G12D interaction with full-length RAF1 [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 LB-062.
Abstract LB-087: Blockade of β-catenin-induced CCL28 suppresses gastric cancer progression via inhibition of Treg cell infiltration
Authors: Ji Lu , Zhu Helen He , Ma Bin , Gao Wei-Qiang 
Published: September 2020

Abstract
Dysregulation of Wnt/β-catenin signaling is frequently observed in human gastric cancer. Elucidation of tumor immune microenvironment is essential for the understanding of tumorigenesis and the development of immunotherapeutic strategies. However, it remains unclear how β-catenin signaling regulates stomach tumor immune microenvironment. Our in vitro study unraveled CCL28 as a direct transcriptional target gene of β-catenin/T cell factor (TCF). Protein levels of β-catenin and CCL28 were positively correlated in human gastric adenocarcinoma. β-Catenin-activated CCL28 was able to recruit Regulatory T (Treg) cells in transwell migration assay. In a clinically relevant mouse gastric cancer model established by Helicobacter (H.) felis infection and MNU treatment, inhibition of β-catenin/TCF activity by a pharmacological inhibitor iCRT14 suppressed CCL28 expression and Treg cell infiltration in the stomach. Moreover, anti-CCL28 antibody attenuated Treg cell infiltration and tumor progression in H. felis/MNU mouse models. Diphtheria toxin (DT)-induced Treg cell ablation restrained gastric cancer progression in H. felis/MNU-treated DEREG (Foxp3-DTR) mice, clarifying the tumor-promoting role of Treg cells. Thus, the β-catenin-CCL28-Treg cell axis may serve as an important mechanism for immunosuppression of the stomach tumor microenvironment. Our findings highlighted an immunoregulatory role of β-catenin signaling in stomach tumors and the therapeutic potentials of CCL28 blockade for the treatment of gastric cancer.
Citation Format: Lu Ji, Helen He Zhu, Bin Ma, Wei-Qiang Gao. Blockade of β-catenin-induced CCL28 suppresses gastric cancer progression via inhibition of Treg cell infiltration [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 LB-087.
Abstract LB-171: Assessing the impact of PIK3CA mutation on the three-dimensional organization of chromatin
Authors: Miranda Adam X. , Park Ben H. , Hodges Emily 
Published: September 2020

Abstract
Background: Three-dimensional organization of chromatin within the nucleus is an important and dynamic regulator of cellular transcription. Changes in chromatin topology are implicated in processes like cell differentiation and cell fate decisions, but have been largely unstudied with regards to mutations and cancer cell transformation. Our goal is to assess the changes in chromatin topology that occur in response to a single oncogenic mutation and how these changes may influence cancer cell transformation.
Methods: Using AAV-mediated homologous recombination, a E545K “hotspot” PIK3CA mutation was incorporated into MCF10A breast epithelial cells and conversely, corrected back to wild-type in MCF7 breast cancer cells that natively harbor a E545K PIK3CA mutation. To interrogate the chromatin topology of these cell lines and the unmodified versions we will use a technique called tethered chromosome conformation capture (TCC). TCC maps chromatin topology by combining the proximity ligation of interacting DNA segments with next generation sequencing to create a matrix of interacting DNA elements. We can analyze and overlay these matrices to look for significant differences in topologically associating domains (TADs).
Results: Preliminary results comparing MCF7 parental cells and MCF7 cells with the PIK3CA exon 9 mutation corrected suggest rearrangement of TADs at many key cancer-associated genes. One of these rearrangements is the formation of a de novo TAD on chromosome 10 near PTEN, a tumor suppressor gene that acts antagonistically to PIK3CA. Rearrangement of chromatin topology at this locus could lead to downregulation of a negative actor on this pathway further stimulating downstream elements of the PIK3CA pathway.
Conclusions: Oncogenic mutations can cause changes that can have a drastic impact on transcription. Rearrangement of chromatin topology is a key mechanism by which the transcriptional program of a cell can be modified. Our experiments reveal key sites of chromatin rearrangement caused by a single oncogenic mutation that may promote a cancer phenotype in our cells. We plan to investigate the degree to which the expression of PTEN is altered by chromosomal rearrangements as well as perform CRISPR-KO of the interacting loci to determine the transcriptional effect of removing the loop. These assays will also be conducted for other sites of chromatin rearrangement. Results from these experiments will reveal the influence oncogenic mutations may have on chromatin topology and expression.
Citation Format: Adam X. Miranda, Ben H. Park, Emily Hodges. Assessing the impact of PIK3CA mutation on the three-dimensional organization of chromatin [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 LB-171.
Abstract LB-180: A human breast cancer 3D spheroid platform for microscopy based high throughput screening
Authors: Rines Christine Gjerdrum , Gordon Kara , Basa Ranor , Smith Alyson , Oshima Robert , Farhy Chen , Terskikh Alexey , McDonough Patrick , Price Jeffrey 
Published: September 2020

Abstract
Breast cancer (BC) tumors originate in epithelial cells and rank second as a cause of cancer-related death in women (in 2020, ~270,000 women will be diagnosed, and 42,000 women will die from this disease in the USA). While important progress has been made on new treatments there is an urgent need to discover new therapeutics. We aim to discover therapeutics that elicits differentiation of BC tumor cells towards a phenotype that ceases proliferation and/or becomes more sensitive to therapeutic drugs. Also, since current high-throughput breast cancer drug discovery screens use conventional 2D cell cultures that do not fully represent the complex microenvironments of tumors in patients and often fail to predict clinical efficacy we are using 3D spheroids to better represent patient tumors. To identify potential therapeutic agents, we will quantify effects of test compounds on epigenetic markers (histone methylation/acetylation) within the nuclei of the tumor cells utilizing the Microscopic Imaging of Epigenetic Landscape (MIEL) assay developed by Alexey Terskikh's laboratory at SBP. The changes in epigenetics occur more rapidly than phenotypic changes resulting from differentiation which enables more rapid screening to identify potential therapeutic agents. Here we show that treating 2D cell cultures of the breast cancer cell line MCF7 with Tamoxifen, DPPE or E2 elicit changes in the epigenetic landscape. These epigenetic changes concur with increase in lipid droplet formation (a feature that is linked to milk-producing breast epithelium), and demonstrates that MIEL can be used as a readout of differentiation status. We are developing protocols to image breast cancer 3D spheroids on Vala Sciences' IC200 Structured Illumination Microscopy (IC200-SIM™ workstation). The SIM™ uses a multi-million array of micro-mirrors to achieve confocal resolution with rapid image acquisition, suitable for high throughput screening of spheroids cultured in the 96- or 384-well format. We envision that when developed, the MIEL-Breast Cancer Differentiation (MIEL-BCD) assay will be used to screen large chemical libraries (e.g., libraries with 100,000 different chemical entities) to identify compounds that promote differentiation of breast cancer cells to non-tumorigenic cells.
Citation Format: Christine Gjerdrum Rines, Kara Gordon, Ranor Basa, Alyson Smith, Robert Oshima, Chen Farhy, Alexey Terskikh, Patrick McDonough, Jeffrey Price. A human breast cancer 3D spheroid platform for microscopy based high throughput screening [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 LB-180.