bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PL03-02: Exploiting DNA replication stress for cancer therapies
Authors: Halazonetis Thanos 
Published: March 2020

Abstract
A feature of most cancers is genomic instability. We and others have proposed a model to explain the presence of such genomic instability. Briefly, we proposed that oncogenes, which are activated in practically all cancers and drive cell proliferation, induce DNA replication stress. The presence of DNA replication stress leads to the formation of DNA double-strand breaks, which, when incorrectly repaired, lead to genomic instability. DNA replication stress is a somewhat non-specific term used to indicate that cells have difficulties to replicate their DNA. Inhibitors of DNA polymerases slow down DNA replication and induce DNA replication stress. However, in this case, the replisome, i.e. the proteins that replicate the DNA, remains intact and DNA double-strand breaks are not formed. Oncogenes induce a different type of DNA replication stress, as select replisomes are disrupted, leaving the DNA “naked” and susceptible to DNA double-strand break formation. Recent results from a number of laboratories have provided great insights on how oncogenes induce DNA replication stress. Specifically, it has been found that oncogenes induce the firing of novel DNA replication origins. These oncogene-induced origins are present within transcribed genes. When these origins fire and DNA replication begins, the replisomes collide with the transcription machinery. These aberrant collisions lead to disruption of the replisome. Disrupted, aka as collapsed, replisomes need to be repaired for DNA replication to restart. Errors in this repair lead to DNA double-strand breaks and genomic instability. The main pathway for repair of collapsed DNA replication forks appears to be break-induced replication. This pathway is used very infrequently by normal cells and, as such, certain proteins that function in this pathway are not essential for normal development. However, their inactivation suppresses cancer development, because cancer cells rely on break-induced replication to repair their collapsed DNA replication forks. It follows that proteins that function in break-induced replication may be good targets for the development of effective, non-toxic cancer therapies.
Citation Format: Thanos Halazonetis. Exploiting DNA replication stress for cancer therapies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PL03-02. doi:10.1158/1535-7163.TARG-19-PL03-02
Abstract PL04-02: Extracellular vesicles as opportunities for integrative or focused liquid biopsy studies
Authors: Welsh Joshua , Aldape Kenneth , Jones Jennifer 
Published: March 2020

Abstract
Background: For patients who present with or develop progressive, metastatic cancer, new immunotherapies offer significant hope of remission or cure. However, many of the most effective immunotherapies and cancer vaccines are often effective in fewer than 50% of patients treated, and assessment of treatment responses is only feasible after multiple weeks or months of treatment, a period of time during which other more effective treatment options or combinations might have been selected instead for the non-responding patients. Therefore, improved methods for monitoring treatment responses, especially early during treatment, are needed. Extracellular Vesicles (EVs), are continuously released and carry surface receptors and RNA/DNA cargo related to the state of their cell of origin. Thus, EVs may enable near-real-time clinical blood and/or urine tests for early screening, risk stratification, and monitoring of cancer immunotherapies. Methods: To extract the information that is carried by EVs, our lab has developed a first-in-class pipeline to characterize EV heterogeneity and provide high-sensitivity quantification of informative EV subsets by combining multiplex assays with high-resolution, single EV flow cytometric methods together into a Multiplex-to-Single EV Analysis (Mt-SEA) pipeline. Results: In preliminary data from ongoing clinical trials, we have identified EV subset changes that correspond to responses to treatment. Moreover, as with other complex biological systems, we find that it is possible to interrogate several dimensions of EV cargo to further improve the utility and impact of this approach. The methods and tools that we have developed are being made available for use in the wider research community. Conclusions: We hypothesize that identification of sensitive and specific EV-associated biomarkers for responses to immunotherapies would significantly advance efforts to improve treatment outcomes and quality of life for advanced cancer patients. The Mt-SEA Pipeline of methods developed by the NCI Translational Nanobiology lab establishes a foundation for interrogating different genetic and molecular profiles in tumor-derived and immune cell-derived EVs in urine and/or blood within 1-2 weeks of the start of treatment.
Citation Format: Joshua Welsh, Kenneth Aldape, Jennifer Jones. Extracellular vesicles as opportunities for integrative or focused liquid biopsy studies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PL04-02. doi:10.1158/1535-7163.TARG-19-PL04-02
Abstract A19: The role of metaplastic tuft cell chemosensory signaling in pancreatic cancer
Authors: Hoffman Megan T. , The Stephanie , Salas-Escabillas Daniel J. , DelGiorno Kathleen E. , Bednar Filip , Margolskee Robert F. , Rao Arvind , Crawford Howard C. 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDA) is the third most common cause of cancer death in the US with a 9% 5-year survival rate. PDA is characterized by a robust stromal reaction, a large portion of which is composed of infiltrating immune cells and supported by fibroblasts. This fibroinflammatory response promotes both the initiation and progression of PDA. Key to this progression is the crosstalk between the tumor epithelium and immune compartment. Metaplastic tuft cells (MTCs) are a subset of the neoplastic epithelium derived by the transdifferentiation of acinar cells. Tuft cells have been characterized to have a “sense-and-respond” role in luminal surfaces throughout the body, using the taste chemosensory system to promote an inflammatory response in infected and damaged tissues. Among the pancreatic epithelium, MTCs uniquely express components of the gustation sensory system including taste receptors, TRPM5 and αGustducin, as well as an array of inflammatory cytokines, suggesting they are capable of promoting an immune response to extracellular challenges. To explore this hypothesis, we ablated αGustducin, a key protein in the chemosensory cascade, in a model of pancreatitis-associated tumorigenesis. We found that neoplasia in the GNAT3-/-; KrasG12D; PTF1aCreERT mice initiates and progresses more rapidly, a difference associated with alteration in immune cell subtypes. To further quantitate changes in the immune response, we performed mass cytometry (CyTOF), as a way to explore changes in cell number and type, and single-cell sequencing, to more deeply probe the unique gene signatures of cells within the tumor stroma. These large-scale analyses suggest substantial changes in the number of T-cell and myeloid cell populations, as well as alterations of fibroblasts and myeloid cell polarity. We conclude that MTCs use chemosensory signaling to promote the formation of a tumor-suppressive microenvironment.
Citation Format: Megan T. Hoffman, Stephanie The, Daniel J. Salas-Escabillas, Kathleen E. DelGiorno, Filip Bednar, Robert F. Margolskee, Arvind Rao, Howard C. Crawford. The role of metaplastic tuft cell chemosensory signaling in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A19.
Abstract C25: Aspiration liquid biopsy (ALB) of pancreatic cancer (PC)
Authors: Kashintsev Aleksei , Kokhanenko Nikolai , Imyanitov Evgeniy , Proutski Vitaliy , Granstrem Oleg , Solovieva Lyudmila , Medvedev Konstantin , Pavelets Konstantin , Anisimov Sergey 
Published: March 2020

Abstract
Introduction: Early detection of PC is the main clue for improving results of treatment. Liquid biopsy (LqB) is the most promising method of detection of disease in a screening context, but selection of biologic material for that is not a resolved problem. Pancreatic juice is the highly specific substance for that aim. However, its collection and analysis are associated with many technical difficulties.
Materials and Methods: For pancreatic juice collection we developed a method of ALB using a proprietory pancreatodigestive stent. This stent allows for active aspiration of pancreatic juice. We had recruited 15 patients with verified PC before treatment. Placement of the stent was performed by endoscopy and followed by collecting of pancreatic juice in sterile container at 4o C. After collecting sufficiently large volume of the material, we centrifugated it and made cell-block for cytologic examination.
Results: ALB was performed in all 15 cases without any complications. Placement and removal of the stent was atraumatic and without technical problems. However, only in 1 sample out of 15 did we detect atypical cells using standard cytologic examination.
Conclusion: We present new methodology for collecting biomaterial potentially useful for the early diagnosis of pancreatic cancer. This method is simple and can be easily replicated. Its application does not require high-quality specialized medical centers and personnel and can be performed in standard gastroenterologic clinics. Collected samples can be easily stored. Furthermore, in addition to cells it allows to obtain the liquid fraction of pancreatic juice that could be used for the detection of tumor DNA.
Citation Format: Aleksei Kashintsev, Nikolai Kokhanenko, Evgeniy Imyanitov, Vitaliy Proutski, Oleg Granstrem, Lyudmila Solovieva, Konstantin Medvedev, Konstantin Pavelets, Sergey Anisimov. Aspiration liquid biopsy (ALB) of pancreatic cancer (PC) [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C25.
Abstract C31: The glycosaminoglycan syndecan-4 facilitates pancreatic cancer progression and biologic aggressiveness
Authors: McElyea Samantha , Korc Murray 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a treatment-recalcitrant malignancy that harbors several key driver mutations at a high frequency (e.g., KRAS, TP53, CDKN2A, and SMAD4&lt;), as well numerous driver mutations that occur at a relatively low and variable frequency among patients with PDAC. Heparan-sulfate proteoglycans (HSPGs) constitute a large family of glycanated proteins that modulate numerous cellular processes and interact with components of the extracellular matrix (ECM) and with heparin-binding growth factors such as heparin binding EGF-like growth factor (HBEGF) that activates the EGF receptor (EGFR) and transforming growth factor beta (TGF-beta) moieties. Syndecan-4 (SDC4) is a transmembrane HSPG that has critical roles in focal adhesion formation, cytoskeletal attachment, cell contractility and motility, and cell signaling, especially in relation to pathways activated by heparin-binding growth factors. To date, the role of SDC4 in PDAC has not been clearly elucidated. Yet, data from 1,034 PDAC samples in The Cancer Genome Atlas (TCGA) revealed that 19% of these samples exhibited altered SDC4 expression, a majority of which were either gain-of-function or amplification alterations often co-occurring with enhanced TGF-beta1 expression, thus underscoring the potential importance of SDC4 in PDAC. Given that TGF-beta1 increases SDC4 expression whereas SDC4 modulates TGF-beta1 actions and interacts with EGFR, we sought to test the hypothesis that SDC4 contributes to PDAC’s progression. Accordingly, we established a novel genetically engineered mouse model (GEMM) of PDAC in which pancreas-specific Cre-mediated expression of oncogenic Kras was combined with deletion of a conditional Ink4a/Arf allele in the presence or absence of SDC4: Pdx1-Cre;LSL-KrasG12D;Ink4a/Arflox/lox;Sdc4-/-, termed KIS4-/-C mice. By comparison with control KIS4 animals, KIS4-/-C mice exhibited attenuated pancreatic tumor growth and markedly prolonged survival. There was attenuation of cancer cell proliferation in the tumors, as determined by Ki67 staining, as well as decreased desmoplasia as evidenced by Mason trichrome staining. By contrast, KIS4+/-C animals with heterozygous loss of SDC4 only exhibited a modest survival advantage by comparison with control KIS4 animals. Taken together, these findings suggest that strategies based on suppressing SDC4 expression and/or function may yield new therapeutic approaches in PDAC. (Supported in part by National Cancer Institute grant CA-075059 to M.K.)
Citation Format: Samantha McElyea, Murray Korc. The glycosaminoglycan syndecan-4 facilitates pancreatic cancer progression and biologic aggressiveness [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C31.
Abstract C52: The radioprotector GC4419 enhances the response of PDAC tumors to high dose per fraction radiation exposure
Authors: Story Michael D. , Sishc Brock J. 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States, with an estimated 5-year overall survival rate of ~6%. While surgery followed by adjuvant therapy is the standard of care, most patients present with advanced disease. Recent clinical trials have demonstrated that the traditional radiation dose limit of 50.4 Gy to tumors located at the head of the pancreas is not sufficient to generate tumor control at doses tolerable to the jejunum; however, doses exceeding 60 Gy, particularly when delivered as stereotactic body radiation therapy (SBRT), drastically enhance progression free-survival at 2 years. Here, we present evidence that the radioprotector GC4419 (Galera Therapeutics, St. Louis, MO) whose enantiomer, GC4403, has demonstrated radioprotective properties against GI toxicity, sensitizes PDAC cells and xenografts to radiation exposure. Furthermore, combination therapy with immune oncology agents targeting the PD-L1 pathway enhanced the response of Panc02 tumors (syngeneic to C57.BL/6 mice) to combined radiation and immune therapy. These results present the foundation for a newly initiated dose-escalation clinical trial for treating PDAC tumors with GC4419 and SBRT.
Citation Format: Michael D. Story, Brock J. Sishc. The radioprotector GC4419 enhances the response of PDAC tumors to high dose per fraction radiation exposure [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C52.
Abstract C57: Organoid profiling identifies common responders to chemotherapy in pancreatic cancer
Authors: Tiriac Herve , Belleau Pascal , Engle Dannielle , Plenker Dennis , Deschenes Astrid , Somerville Tim , Froeling Fieke , Moffitt Richard , Knox Jennifer , Krasnitz Alexander , Gallinger Steven , Tuveson David 
Published: March 2020

Abstract
Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we find that PDO therapeutic profiles paralleled patient outcomes and that PDOs enable longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.
Citation Format: Herve Tiriac, Pascal Belleau, Dannielle Engle, Dennis Plenker, Astrid Deschenes, Tim Somerville, Fieke Froeling, Richard Moffitt, Jennifer Knox, Alexander Krasnitz, Steven Gallinger, David Tuveson. Organoid profiling identifies common responders to chemotherapy in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C57.
Abstract PR12: The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice
Authors: Engle Dannielle , Tiriac Herve , Rivera Keith , Pommier Arnaud , Whalen Sean , Oni Tobiloba , Alagesan Brinda , Lee Eun , Yao Melissa , Lucito Matthew , Spielman Benjamin , Yu Kenneth , Grutzmann Robert , Aust Daniela , Gimotty Phyllis , Pollard Katherine , Hruban Ralph , Goggins Michael , Pilarsky Christian , Park Young , Pappin Darryl , Hollingsworth Michael A. , Tuveson David 
Published: March 2020

Abstract
Glycosylation alterations are indicative of tissue inflammation and neoplasia, but whether these alterations contribute to disease pathogenesis is largely unknown. To study the role of glycan changes in pancreatic disease, we inducibly expressed human fucosyltransferase 3 and b1,3-galactosyltransferase 5 in mice, reconstituting the glycan sialyl-Lewis a, also known as carbohydrate antigen 19-9 (CA19-9). Notably, CA19-9 expression in mice resulted in rapid and severe pancreatitis with hyperactivation of epidermal growth factor receptor (EGFR) signaling. Mechanistically, CA19-9 modification of the matricellular protein fibulin-3 increased its interaction with EGFR, and blockade of fibulin-3, EGFR, or CA19-9 prevented EGFR hyperactivation in organoids. CA19-9–mediated pancreatitis was reversible and could be suppressed with CA19-9 antibodies. CA19-9 also cooperated with the KrasG12D oncogene to produce aggressive pancreatic cancer. These findings implicate CA19-9 in the etiology of pancreatitis and pancreatic cancer and nominate CA19-9 as a therapeutic target.
This abstract is also being presented as Poster C16.
Citation Format: Dannielle Engle, Herve Tiriac, Keith Rivera, Arnaud Pommier, Sean Whalen, Tobiloba Oni, Brinda Alagesan, Eun Lee, Melissa Yao, Matthew Lucito, Benjamin Spielman, Kenneth Yu, Robert Grutzmann, Daniela Aust, Phyllis Gimotty, Katherine Pollard, Ralph Hruban, Michael Goggins, Christian Pilarsky, Young Park, Darryl Pappin, Michael A. Hollingsworth, David Tuveson. The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR12.
Abstract BS1-2: Genome regulation by long noncoding RNA genes
Authors: Chang HY 
Published: March 2020

Abstract
The discovery of extensive transcription of long noncoding RNAs (lncRNAs) provide an important new perspective on the centrality of RNA in gene regulation. I will discuss genome-scale strategies to discover and characterize lncRNAs, including RNA chemical modifications and RNA structures. LncRNAs form extensive networks of ribonucleoprotein (RNP) complexes with numerous chromatin regulators, and target these enzymatic activities to appropriate locations in the genome. Long noncoding RNAs can function as modular scaffolds to specify higher order organization in RNP complexes and in chromatin states. A new emerging theme is that DNA elements that mediate lncRNA expression can also have powerful effects in controlling chromatin neighborhoods, which alter oncogene expression and activity. The importance of these modes of regulation is underscored by the newly recognized roles of long RNAs in human diseases.
Citation Format: HY Chang. Genome regulation by long noncoding RNA genes [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr BS1-2.
Abstract CS1-2: Emerging Therapies for HER2 Positive Breast Cancer
Authors: Modi S 
Published: March 2020

Abstract
HER2 targeted therapies have had a significant impact in improving clinical outcomes and survival for patients with HER2 positive breast cancer. However, new therapies for patients with refractory disease are still needed. Based on a greater understanding of the biology and mechanisms of resistance, a new generation of HER2 agents is evolving. Here we provide an overview of promising novel therapies, both proven and in development, for the treatment of refractory HER2 positive breast cancer. This will include a review of antibody drug conjugates, tyrosine kinase inhibitors, immune strategies as well as future combination therapies.
Citation Format: S Modi. Emerging Therapies for HER2 Positive Breast Cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr CS1-2.