bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract I14: Polymerase theta synthetic lethal interaction in homologous recombination-deficient pancreatic ductal adenocarcinoma
Authors: Wang Annie , Zamperone Andrea , Sohail Mohammad , Wang Lidong , Balogun Fiyinfolu , Li Jiufeng , Zhao Ende , Diolaiti Daniel , Sfeir Agnel , Simeone Diane M. 
Published: March 2020

Abstract
Recent genomic characterization of PDA reveals that between 20-25 % of PDA harbor recurrent mutations in genes, including BRCA1/2, PALB2, and ATM, which are critical for homologous recombination (HR), an important form of DNA repair. In many patients, these may be germline mutations. This subgroup of PDAs, termed HR-deficient PDA, has emerged as a defined biological entity associated with increased chemoresistance and a more aggressive disease course. The defects in HR observed in these tumors impart cells with a specific vulnerability to PARP inhibitors and platinum-containing therapy. Still, as observed in the case of many other targeted therapies, only a fraction of HR-defective patient tumors respond to PARP inhibition. More so, many patients that initially respond eventually often develop resistance and progress. Therefore, novel therapies which can be effective against HR-defective PDA, alone or in combination with PARP inhibitors or other combinatorial regimens, are urgently needed. We have recently determined that inactivation of the HR pathway is associated with overexpression of polymerase theta (PolO–, also known as POLQ) in PDA. POLQ is a key enzyme that regulates an alternative pathway of DNA repair, known as the alternative non-homologous end-joining (Alt-NHEJ) pathway. In the setting of defective HR, Alt-NHEJ becomes a critical pathway responsible for the repair of DNA breaks and POLQ inhibition in HR-defective tumor cells demonstrates a synthetic lethality phenotype, not observed in cells with intact HR. Furthermore, POLQ knockdown significantly upregulated the cGAS-STING pathway in HR-deficient PDAs linking the DNA damage response to the immune response. Overall, targeting POLQ may represent a novel and in a valuable therapeutic strategy in HR-defective pancreatic cancer, as POLQ inhibitors are currently in development for clinical use.
Citation Format: Annie Wang, Andrea Zamperone, Mohammad Sohail, Lidong Wang, Fiyinfolu Balogun, Jiufeng Li, Ende Zhao, Daniel Diolaiti, Agnel Sfeir, Diane M. Simeone. Polymerase theta synthetic lethal interaction in homologous recombination-deficient pancreatic ductal adenocarcinoma [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 I14.
Abstract I18: Retooling a blood-based biomarker into a theranostic agent
Authors: Lewis Jason S. 
Published: March 2020

Abstract
Over the past 30 years, our ability to noninvasively diagnose, localize, and treat many forms of cancer has grown significantly. However, the biomolecular basis of many malignancies—most notably pancreatic cancer—remains convoluted, and technical advances have not translated to significantly improved survival rates. This is reflected in 1- and 5-year survival rates of 27% and 6%, respectively, for pancreatic cancer diagnoses. Given the tremendous current focus on the creation of new therapeutics for treating pancreatic cancer, the development of companion technologies that can safely, accurately, and unambiguously aid in the early diagnosis, staging, and treatment monitoring of pancreatic cancer is a vitally important—yet unmet—clinical need. The remarkable specificity and selectivity of antibodies for cancer biomarkers have made immunoglobulins some of the most flexible and adaptable tools in modern medicine. For therapeutic purposes, a wide range of nonlabeled antibodies has now entered the clinic. Antibody-based PET and SPECT imaging agents are not far behind. For example, an array of 89Zr-labeled radioimmunoconjugates has shown significant promise in both preclinical and clinical studies. CA19-9 levels in the serum are routinely used for diagnosis, risk stratification, and follow-up of PDAC. While CA19-9 is a shed antigen entering the circulation, the concentration is much higher in the tumor tissue, making it a potential target for in vivo imaging with radiolabeled antibodies. Our studies show that a tumor antigen secreted to the circulation can be used for sensitive detection of primary tumors and metastatic disease by immuno-PET. For example, in proof-of-concept preclinical studies, we were able to visualize pancreatic cancer xenograft and orthotopic models of early- and late-stage disease with excellent tumoral uptake and target-to-non-target ratios using the 89Zr-labeled human monoclonal antibody [89Zr]Zr-DFO-HuMab-5B1 (MVT-2163, NCT02687230). This 5B1 radioimmunoconjugate scaffold has also been deployed with therapeutic beta- and alpha-emitting radionuclides, creating an effective radiotherapeutic paradigm for the imaging and therapy of PDAC. In conclusion, our study shows that a tumor antigen secreted by PDAC to the circulation can be used for sensitive detection of primary tumors and metastatic disease by immuno-PET. This significantly broadens the number of molecular targets that can be used for PET imaging and provides new opportunities for noninvasive characterization of tumors in pancreatic cancer patients.
Citation Format: Jason S. Lewis. Retooling a blood-based biomarker into a theranostic agent [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 I18.
Abstract I22: New players and unique features of cancer lysosomes
Authors: Perera Rushika M 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDA) cells and tumors constitutively activate nutrient scavenging pathways, namely, autophagy (cellular self-catabolism) and macropinocytosis (bulk uptake of extracellular material) in order to maintain metabolic homeostasis. Importantly, both of these pathways converge on the lysosome, an acidic organelle that harbors within its lumen a complex series of enzymatic reactions that enable degradation of incoming cargo material. Our prior work has shown that the lysosome is greatly expanded and qualitatively different in PDA cells compared to normal tissue. PDA tumors are effectively “addicted” to enhanced catabolic activity as blocking lysosome function specifically inhibits in vitro and in vivo growth of PDA cell lines and tumor xenografts with minimal effects on normal cells. How key changes in lysosome composition and content contribute to the aggressive nature of PDA remains an open question. We have optimized methodologies to isolate and purify lysosomes from normal human pancreatic epithelial cells and several established patient-derived PDA cancer cell lines, using affinity-based capture techniques that isolate 50-80% intact lysosomes free of cytoplasm and other contaminating organelles. By systematically implementing lysosome purification from normal, primary, and metastatic PDA tumors combined with mass spectrometry-based proteomics, we have identified both resident and substrate proteins that are uniquely associated with PDA lysosomes. Several cancer-specific lysosomal membrane proteins emerged from this analysis that may endow cancer lysosomes with enhanced functionality, including rapid membrane repair in the face of sustained mechanical and chemical insults. Similarly, we find that PDA lysosomes degrade select cellular proteins to enable dynamic remodeling of the cellular proteome in a manner that favors tumor growth and progression. Collectively, our data provide strong evidence in support of the lysosome as a central mediator of cellular adaptation to stress and promoter of tumorigenesis.
Citation Format: Rushika M Perera. New players and unique features of cancer lysosomes [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 I22.
Abstract I25: Understanding and exploiting natural barriers to pancreatic tumorigenesis
Authors: Lowe Scott W. 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an extraordinarily aggressive cancer that arises in the context of a unique tumor microenvironment. Molecularly, PDAC involves a combination of undruggable cancer drivers, including activating mutations in the KRAS oncogene and disruption of tumor suppressors such a TP53, SMAD4, and CDKN2A together with poorly characterized epigenetic changes that correlate with metastatic progression. Histologically, PDAC arises within a heterogeneous tissue microenviroment characterized by dense fibroinflammatory stroma that influences disease progression and limits therapy response. Our laboratory has developed genetically engineered mouse models based on ES cells (GEMMESCs) of pancreas cancer, where chimeric mice are produced directly from multiallelic ES cells harboring a latent KrasG12D oncogene together with all the genetic elements needed for Kras activation in the together with those needed for tetracycline-inducible (and reversible) regulation of short hairpin RNAs targeting capable of suppressing any gene of interest at any time after pancreas cancer initiation. Using this system, we have probed the epigenetic requirements for pancreas cancer initiation and compare them to those required for pancreatic regeneration following tissue damage; in addition, we have explored the metabolic programs needed for p53 to suppress tumorigenesis. Our studies have identified elements of cellular plasticity that act at multiple points that suppress pancreas cancer progression and identify actionable intervention points required for these transitions.
Citation Format: Scott W. Lowe. Understanding and exploiting natural barriers to pancreatic tumorigenesis [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 I25.
Abstract PR05: Autophagy facilitates immune evasion of pancreatic cancer through downregulation of MHC class I molecules
Authors: Yamamoto Keisuke , Venida Anthony , Biancur Doug E. , Yamamoto-Kakiuchi Miwako , Sohn Albert P. , Perera Rushika M. , Kimmelman Alec C 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy refractory to most therapies, including immune checkpoint blockade (ICB). Autophagy is a highly conserved self-degradation process that recycles cellular components. PDAC requires high levels of autophagy/lysosome function to meet their metabolic demand under nutrient-deprived conditions; however, little is known about substrates that are preferentially targeted and subsequent biologic impacts of their loss on PDAC pathogenesis. Here we found that cell surface expression of major histocompatibility complex class I (MHC-I) molecules, a critical component of antigen-presentation to CD8+ cytotoxic T lymphocytes (CTLs), is downregulated in PDAC cells though an autophagy-dependent pathway. Autophagy inhibition in PDAC cells restored surface MHC-I levels and improved antigen presentation, leading to enhanced antitumor T-cell response in syngeneic mouse models of PDAC, which was further enhanced by combination with ICB. Our findings indicate that elevated autophagy/lysosome function facilitates immune evasion of PDAC cells through selective targeting of MHC-I molecules and provide a rationale for the combination of autophagy inhibition and ICB as a therapeutic strategy against PDAC.
This abstract is also being presented as Poster B61.
Citation Format: Keisuke Yamamoto, Anthony Venida, Doug E. Biancur, Miwako Yamamoto-Kakiuchi, Albert P. Sohn, Rushika M. Perera, Alec C Kimmelman. Autophagy facilitates immune evasion of pancreatic cancer through downregulation of MHC class I molecules [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 PR05.
Abstract PR10: Enhancing the effect of autophagy inhibition for pancreatic cancer treatment
Authors: Bryant Kirsten L. , Klomp Jennifer E. , Lee Ye S. , Stalnecker Clint A. , Grover Kajal R. , Edwards A. Cole , Peng Sen , Pierobon Mariaelena , Petricoin Emanuel F. , Tran Nhan , Kimmelman Alec C. , Cox Adrienne D. , Der Channing J. 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth. We determined the role of mutationally activated KRAS, found in ~95% of PDAC, in supporting autophagy. Surprisingly, acute KRAS suppression, which blocks proliferation, was associated with increased rather than decreased autophagic flux. Pharmacologic inhibition of ERK MAPK phenocopied the genetic silencing of KRAS and also increased autophagic flux. We speculated that the loss of ERK-driven metabolic processes may induce compensatory mechanisms to increase autophagy. Addressing a mechanism for ERK suppression-increased autophagy, we describe three mechanisms: 1) ERK inhibition-mediated increased transcription of autophagy and lysosomal genes, 2) ERK inhibitor-induced AMPK activation and suppression of mTOR signaling, and 3) ERK inhibition-facilitated decreased glycolytic flux. We then addressed whether ERK inhibition increased PDAC dependence on autophagy. Supporting this possibility, we found that cotreatment with the autophagy inhibitor chloroquine (CQ) synergistically enhanced ERK inhibitor-mediated antiproliferative activity. Similarly, genetic or pharmacologic inhibition of specific regulators of autophagy also enhanced ERK inhibitor activity. Encouraged by the synergistic relationship between ERK and autophagy inhibition, we performed a CRISPR/Cas-9 mediated genetic loss of function screen in the presence of CQ to determine additional sensitizers as well as mediators of resistance to autophagy inhibition. Top sensitizers included multiple mediators of the DNA damage response. One such sensitizing gene was CHEK1, which encodes the CHK1 serine/threonine kinase, required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to DNA damage. Accordingly, we showed that treatment with prexasertib, a clinical candidate CHK1 inhibitor, increased autophagic flux in PDAC cells and synergized with CQ to decrease PDAC cell proliferation and increase apoptosis. We conclude that concurrent suppression of multiple metabolic processes, to block compensatory rebound activities, will be needed for effective PDAC treatment.
This abstract is also being presented as Poster B07.
Citation Format: Kirsten L. Bryant, Jennifer E. Klomp, Ye S. Lee, Clint A. Stalnecker, Kajal R. Grover, A. Cole Edwards, Sen Peng, Mariaelena Pierobon, Emanuel F. Petricoin III, Nhan Tran, Alec C. Kimmelman, Adrienne D. Cox, Channing J. Der. Enhancing the effect of autophagy inhibition for pancreatic cancer treatment [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 PR10.
Abstract ES10-1: Cellular Plasticity, Fate, Potential and Lineage Commitment of Mammary Gland Stem Cells
Authors: Blanpain C 
Published: March 2020

Abstract
Stem cells ensure tissue development, homeostasis and repair. We have recently developed new methods to study by lineage tracing the cellular hierarchy and clonal dynamics that govern the development and homeostasis of the mammary gland. I will present new studies combining lineage tracing, clonal analysis, lineage ablation, single cell RNA sequencing, chromatin profiling, and functional experiments in vivo to investigate the cellular and molecular mechanisms regulating multipotency and lineage restriction during mammary gland development and the cellular reprograming occurring after oncogene expression. Defining the mechanisms regulating tissue expansion and cell fate during development and adult regeneration and understanding how these mechanisms are corrupted during tumorigenesis will have important implications for regenerative medicine and cancer therapy.
This work is supported by the ERC, WELBIO, FNRS, TELEVIE, and the Fondation Baillet-Latour.
Citation Format: C Blanpain. Cellular Plasticity, Fate, Potential and Lineage Commitment of Mammary Gland Stem Cells [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 ES10-1.
Abstract ES12-2: Targeted DNA repair in cancer and new NUDT5 inhibitors to block hormone signalling to target breast cancer
Authors: Helleday T 
Published: March 2020

Abstract
DNA damaging agents, i.e., radio- and chemotherapy, constitute the backbone for treatment of a wide variety of cancers and may result in complete cure from the disease. Our strategy is to exploit endogenous DNA damage caused by cancer vulnerabilities, by DNA repair inhibitors using a synthetic lethal strategy. Our early work on PARP inhibitors in BRCA mutated cancers is establishing in breast cancer and here I will describe novel DNA repair targets and how these can be integrated into treatment of breast cancer. Here, I will also describe a novel link between PARP and hormone dependent cancers. Interestingly, we show that the PARP related protein NUDT5 activity is critical to elicit nuclear ATP production following hormone stimulation and a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. The NUDT5 protein is critical for 3D organoid growth of breast cancer cells. Here, we confirm the involvement of NUDT5 in ADP-ribose metabolism and identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can effectively block growth of 3D breast cancer organoids.
Citation Format: T Helleday. Targeted DNA repair in cancer and new NUDT5 inhibitors to block hormone signalling to target 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 ES12-2.
Abstract ES4-2: Single cell transcriptomics reveals multi-step adaptations to endocrine therapy
Authors: Magnani L , Barozzi I , Hong S 
Published: March 2020

Abstract
Resistant tumours are thought to arise from the action of Darwinian selection on genetically heterogenous cancer cell populations. However, simple clonal selection is inadequate to describe the late relapses often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. During this talk, I will briefly introduce a series of molecular tools that can be used to study transcriptional changes at the single cell level in relevant models. I will then show how used these tools to dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNA-sequencing and imaging we could disentangle the transcriptional variability of plastic cells and define a rare subpopulation of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. We find evidence for sub-clonal expression of a PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. I will then update the audience on how it is possible to integrate these technologies directly into clinical studies and what developments are happening in the field of single cell technologies. I will finally propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers.
Citation Format: L Magnani, I Barozzi, S Hong. Single cell transcriptomics reveals multi-step adaptations to endocrine therapy [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 ES4-2.
Abstract ES5-3: Surgical considerations after preoperative therapy for hormone receptor positive breast cancer
Authors: King TA 
Published: March 2020

Abstract
Session Title: Multidisciplinary approaches to optimize surgical therapy in hormone receptor positive breast cancer
Talk Title: Surgical considerations after preoperative therapy in hormone receptor positive breast cancer
Abstract:
Preoperative therapy increases rates of breast conservation and decreases the need for axillary lymph node dissection (ALND) in select patients. In hormone receptor positive (HR+) HER2 negative breast cancer patients the choice between neoadjuvant chemotherapy (NAC) and neoadjuvant endocrine therapy (NET) to achieve breast conservation can be challenging and the low rates of axillary pCR with either approach have been associated with higher rates of ALND. For HR+ HER2- patients receiving NAC, available literature supports performing sentinel lymph node biopsy (SLNB) after receipt of therapy with the decision to perform axillary lymph node dissection dictated by the status of the sentinel lymph nodes. For patients receiving NET, there is little data to guide surgical management of the axilla. In a recent review of the NCDB, we assessed axillary management by initial treatment strategy (NET, NAC, or upfront surgery) among a large population of Stage II-III HR+ HER2- breast cancer patients and found that SLNB use after NET in both clinically node negative and clinically node positive patients was similar to SLNB use with upfront surgery. However, among those with pN1 disease, patients who received NET were less likely to undergo ALND. While failure to achieve a nodal pCR after NAC is associated with inferior DFS and OS outcomes; whether or not the same is true after NET remains uncertain. Further, the impact of residual nodal disease after NET on LRR remains an area of ongoing investigation. Understanding the differences in and implications of residual nodal disease after neoadjuvant therapy (NAC vs NET) in HR+ HER2- breast cancer provides the opportunity to develop subtype specific strategies for optimal surgical management of the axilla.
Citation Format: TA King. Surgical considerations after preoperative therapy for hormone receptor 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 ES5-3.