bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract I17: Genomic loss of the wild-type KRAS allele in pancreatic tumor progression and metastasis
Authors: Yan Han , Yu Chih-Chieh , Fine Stuart , Lee Ayman , Yang Ye-Ran , Yan Juan , Garcia-Carracedo Dario , Karg Dillon , Cheung Edwin , Friedman Richard , Chen Emily , Luo Ji , Miao Yi , Qiu Wanglong , Su Gloria 
Published: March 2020

Abstract
KRAS is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). Intriguingly, human tumors with RAS mutations often display loss of the remaining wild-type (WT) allele, including PDAC. We previously reported that selective loss of WT Kras allele is associated with PDAC progression to metastasis in both mice and humans. These data suggest that WT KRAS functions as a tumor suppressor in the context of mutant KRAS and loss of WT KRAS offers growth advantage in clonal evolution and tumor progression to metastasis. To investigate the underlying mechanism, we have examined the impact of inducible WT KRAS expression on human PDAC cell lines that had spontaneously lost the WT allele. We observed re-expression of WT KRAS significantly attenuated the malignancy of pancreatic cancer cells in vitro and in vivo. RNA-Seq and proteomic analyses identified HIPPO signaling, specifically YAP1 activation, is inhibited by WT KRAS restoration. We observed a marked reduction of YAP1 nuclear localization and a consequent inhibition of YAP1 transcriptional activity upon restoration of WT KRAS. Expression of constitutively activated YAP1 mitigated the growth-inhibitory effects of WT KRAS, confirming that YAP1 is a downstream effector of the pathway. Furthermore, YAP1 nuclear localization was found to be associated with poor prognosis in PDAC patients. Together, these results offer a novel mechanism that WT KRAS suppresses tumor metastasis via inhibition of YAP1 activation and further demonstrate that genomic loss of the WT KRAS allele is not a mere consequence of genomic instability but rather a selective event that promotes pancreatic tumor progression to metastasis.
Citation Format: Han Yan, Chih-Chieh Yu, Stuart Fine, Ayman Lee, Ye-Ran Yang, Juan Yan, Dario Garcia-Carracedo, Dillon Karg, Edwin Cheung, Richard Friedman, Emily Chen, Ji Luo, Yi Miao, Wanglong Qiu, Gloria Su. Genomic loss of the wild-type KRAS allele in pancreatic tumor progression and metastasis [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 I17.
Abstract I21: Understanding metabolic limitations in pancreatic cancer
Authors: Heiden Matthew G. Vander 
Published: March 2020

Abstract
Complex regulatory mechanisms enable cell metabolism to match physiologic state. The major pathways cells use to turn nutrients into energy and to synthesize macromolecules have been elucidated; however, there remain many unanswered questions regarding how metabolism supports cancer cell proliferation and thus how best to target metabolism for pancreatic cancer treatment. Of note, some therapies for pancreas cancer target metabolic processes that are thought to be essential in all cells. This raises a key question of how drugs that target otherwise essential processes like nucleotide metabolism show differential effectiveness to treat cancers. We have characterized the factors that drive sensitivity to disruption of specific metabolic processes, including nucleotide metabolism, and find that both cancer cell extrinsic and intrinsic factors dictate metabolic vulnerabilities. Further, this leads to different cells being more reliant on limiting nutrients for different metabolic processes, creating a framework to understand how specific cancer cells becomes sensitive to agents that target otherwise essential pathways.
Citation Format: Matthew G. Vander Heiden. Understanding metabolic limitations 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 I21.
Abstract I26: Investigating the immune microenvironment in mouse models of pancreatic cancer
Authors: Pickering Karen , Lapienyte Laura , Karim Saadia , Strathdee Douglas , Sansom Owen , Morton Jen 
Published: March 2020

Abstract
Pancreatic cancer is predicted to become the second most common cause of cancer death in the Western world by ~2025. The focus of our research has been to better understand the disease and identify more effective and targeted therapies, in particular, using genetically engineered mouse models, which develop pancreatic tumors reminiscent of the human disease including development of a complex microenvironment. The pancreatic cancer microenvironment is characterized by significant infiltration of immune cells, but a distinct lack of T cells. Thus, immunotherapies have had little efficacy in PC despite promise in other cancers. Recent data have suggested that genomic instability and increased mutation burden may predict the efficacy of immune checkpoint inhibitors. To investigate this, we have generated a model of APOBEC mutagenesis in pancreatic cancer. The APOBEC family of cytidine deaminase enzymes, whose normal function is to protect from viral infections, have been revealed as drivers of mutation in a variety of human tumors, including pancreatic cancer. We have engineered mice to express Cre-inducible APOBEC3B and crossed these with the KPC genetically engineered mouse model of pancreatic cancer. We find that overexpressing APOBEC3B results in a poorer prognosis in these animals and some changes in the immune microenvironment. We are currently performing genomic and transcriptomic analyses to determine mutational burden and tumor subtype in an effort to identify therapeutic opportunities in patients bearing this signature. In contrast with T cells, recent studies have suggested that B cells may be tumor promoting in pancreatic cancer. However, clinical trials targeting B cells have been conducted recently and the results have been very disappointing. We have now generated an autochthonous model of B-cell depletion and find that B cells are not tumor promoting in this setting. We are now investigating the mechanisms behind this and the microenvironmental differences that are observed in spontaneous versus allograft models.
Citation Format: Karen Pickering, Laura Lapienyte, Saadia Karim, Douglas Strathdee, Owen Sansom, Jen Morton. Investigating the immune microenvironment in mouse models of 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 I26.
Abstract I27: Pancreatic cancer immunotherapy: Moving forward
Authors: Le Dung T. 
Published: March 2020

Abstract
As immunotherapy becomes a pillar of therapy for some of our patients with solid tumors, the role in pancreatic cancer remains limited despite a multitude of studies testing combinations of novel agents. The landscape of effective systemic therapies to date is limited to combination chemotherapy and PARP inhibitors in a small subset of patients with germline BRCA mutations. We also currently await the phase 3 data testing PEGPH20, a recombinant hyaluronidase, in combination with gemcitabine and nab-paclitaxel. These more recent studies were developed from studying and targeting the unique characteristics of pancreatic cancer based on the genomics, chemotherapy sensitivity, and tumor microenvironment characterization. Research in combination strategies that include immunotherapy agents is continuing to build on what we are actively learning about the genomics, epigenetics, RNA expression, and tumor microenvironment characterization specific to pancreatic cancer biology. Historically, studies involving single-agent immunotherapy approaches to pancreatic cancer have yielded responses in 0 or 1 patient. More recent studies with combination immunotherapy approaches with and without chemotherapy have increased the number of responders, but responses still occur in only a handful of patients except in studies where the agents are combined with chemotherapy, which may be the driver of the responses. Further characterization of the responders may help us to identify predictive biomarkers, and further understanding of the nonresponders can help drive future directions. This lecture will review the current strategies that have made it into clinical trials or strategies being proposed for further study and preliminary data that are available to support continued development. Advances in increasing T-cell delivery such as cell-based or neoantigen vaccines, modified T cells, viral and bacterial vectors, or bispecific antibodies may increase immune cell infiltration into tumors while new agonist agents promoting immune cell activation or antagonist targeting negative checkpoints or immune cell populations can increase the probability of success. The combination of increasing the number of responders and better understanding those subsets will eventually lead to additional treatment options for our patients.
Citation Format: Dung T. Le. Pancreatic cancer immunotherapy: Moving forward [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 I27.
Abstract PR04: STING and TLR-independent activation of T-cell responses against pancreatic cancer using agonistic CD40 antibody
Authors: Byrne Katelyn T. , Morrison Alexander H. , Vonderheide Robert H. 
Published: March 2020

Abstract
Immunotherapy is increasingly used in combination with current standard-of-care treatments such as chemotherapy that likely provides danger signals via immunogenic tumor cell death and activation of STING or TLR pathways. However, both the toxicity and immunosuppressive effects of chemotherapy risks hindering clinical benefit. Agonistic CD40 antibody is a potent activator of immune responses, acting upstream of immune checkpoint blockade (ICB) by driving T-cell priming. Here, we show that anti-CD40 is sufficient to drive potent T-cell responses against murine KPC (KrasG12D;Trp53R172H;Pdx-Cre) pancreatic tumors if combined with ICB. CD40/ICB was more effective than CD40/ICB/chemotherapy (median overall survival 76 days vs. 44 days in CD40/ICB vs. CD40/ICB/chemotherapy-treated mice, p&lt;0.01). Therapeutic efficacy of CD40/ICB was fully independent of the STING, MyD88, and IFNAR pathways, requiring instead host expression of CD40, cross-presenting dendritic cells, and an intact T-cell compartment. Therapy-induced CD4 and CD8 T cell responses displayed enhanced polyfunctional cytokine secretion (48.9% vs. 29.5% of CD8+ T cells in vehicle control treated mice), cleared established primary tumors (43% vs. 0% in vehicle control or single-treatment cohorts p&lt;0.0001), and formed protective memory responses in 57% of CD40/ICB cured mice. Immunosuppressive regulatory T cells were noticeably absent from the tumor site after CD40 treatment (7% of CD4+ T cells vs. 33% in mice treated with ICB alone, p&lt;0.01), concomitant with improved T-cell activation and proliferation, whereas ICB was needed to potentiate the full activation and reinvigoration of the T-cell response both locally and systemically. The efficacy of CD40/ICB in in this ICB-resistant KPC model opens the possibility of optimized immunotherapy regimens free of the toxicity and immunosuppressive effects of cytotoxic therapy.
This abstract is also being presented as Poster B08.
Citation Format: Katelyn T. Byrne, Alexander H. Morrison, Robert H. Vonderheide. STING and TLR-independent activation of T-cell responses against pancreatic cancer using agonistic CD40 antibody [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 PR04.
Abstract PR07: Phase I/II study of mesothelin-targeted immunotoxin LMB-100 with nab-paclitaxel for patients with advanced pancreatic adenocarcinoma
Authors: Alewine Christine C. , Ahmad Mehwish , Peer Cody J. , Hu Zishuo , Lee Min-jung , Yuno Akiro , Kindrick Jessica , Thomas Anish , Steinberg Seth , Trepel Jane B. , Figg William D. , Hassan Raffit , Pastan Ira 
Published: March 2020

Abstract
Purpose: LMB-100 recombinant immunotoxin (iTox) consists of a mesothelin-binding Fab for targeting and a modified Pseudomonas exotoxin A payload. Preclinical studies showed that combining taxanes with iTox results in synergistic antitumor activity. The primary objectives of this phase I/II study were to determine the maximum tolerated dose (MTD) of LMB-100 when given with nanoalbumin bound (nab)-paclitaxel to participants with previously treated advanced pancreatic adenocarcinoma and to assess the objective response rate.
Patients and Methods: Patients (n = 20) received fixed-dose nab-paclitaxel (125 mg/m2 on Days 1 and 8) with LMB-100 (65 or 100 mcg/kg on Days 1, 3, and 5) in 21-day cycles. Treatment was limited to 2-3 cycles by protocol. Safety and tolerability, pharmacokinetics, immunogenicity, and relationship of activity to tumor mesothelin expression were assessed.
Results: Dose-limiting toxicity (DLT) of Grade 3 myalgia was observed in 2 of 5 patients treated with 100 mcg/kg. DLT of Grade 3 edema from capillary leak syndrome (CLS) was observed in 1 of 6 patients at MTD of 65 mcg/kg. Severe toxicities of Grade 4 left ventricular dysfunction and hypotension from CLS were observed in 1 patient in the phase II expansion, resulting in study closure. LMB-100 anti-drug antibody formation limited LMB-100 exposure in 5 of 13 patients during cycle 2. Seven of 17 patients with evaluable CA19-9 experienced &gt;50% decrease of this tumor marker, and one patient developed a partial response. Response was associated with higher tumor mesothelin expression and Cycle 2 LMB-100 exposure.
Conclusions: The combination caused serious toxicity. Despite some observed clinical activity, further testing of this combination will not be pursued.
This abstract is also being presented as Poster B01.
Citation Format: Christine C. Alewine, Mehwish Ahmad, Cody J. Peer, Zishuo Hu, Min-jung Lee, Akiro Yuno, Jessica Kindrick, Anish Thomas, Seth Steinberg, Jane B. Trepel, William D. Figg, Raffit Hassan, Ira Pastan. Phase I/II study of mesothelin-targeted immunotoxin LMB-100 with nab-paclitaxel for patients with advanced pancreatic 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 PR07.
Abstract PR08: Intratumoral T-cell distribution in murine and patient pancreatic cancer correlates with tissue heterogeneity and survival
Authors: Carstens Julienne L. , Sampaio Pedro Correa de , Barua Soutik , Wang Huamin , Burks Jared K. , Rao Arvind , LeBleu Valerie S. , Kalluri Raghu 
Published: March 2020

Abstract
The complex microenvironment characteristic of pancreatic ductal adenocarcinoma (PDAC) has been implicated as a critical mediator of tumor progression and therapeutic response. Spatial relationships of individual cellular and acellular components within tumors may offer novel insights into the dynamic and complex functions of PDAC. Using eight-color multiplex immunohistochemistry and novel spatial analysis algorithms, we report a heterogeneous and increased population of infiltrating T lymphocytes in the tumors compared to uninvolved pancreatic tissues of treatment-naïve PDAC patients. Spatial distribution of cytotoxic T cells in proximity to cancer cells independently correlates with increased overall patient survival. Collagen-I and aSMA-positive fibroblasts do not correlate with a paucity of T-cell accumulation around cancer cells, suggesting that PDAC desmoplasia may not be a simple physical barrier. However, T-cell infiltration was reduced in proximity to specific cancer cell subpopulations, supporting cancer-cell intrinsic mechanisms for immune avoidance. Further expansion of this technology using early and late primary tumors and metastatic tissue of genetically engineered mouse models (KrasLSL-G12D; p53R172H; PDX1-Cre; EYFPLSL) demonstrates similar T-cell heterogeneity and spatial associations. These data support the validity of multiplex and spatial analysis platforms for exploring the structure-function relationships in the PDAC microenvironment and suggest differential spatial relationships between cancer subtypes and the surrounding microenvironment may be a determining factor in PDAC progression.
This abstract is also being presented as Poster A04.
Citation Format: Julienne L. Carstens, Pedro Correa de Sampaio, Soutik Barua, Huamin Wang, Jared K. Burks, Arvind Rao, Valerie S. LeBleu, Raghu Kalluri. Intratumoral T-cell distribution in murine and patient pancreatic cancer correlates with tissue heterogeneity and survival [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 PR08.
Abstract PR13: Macrophage metabolism inhibits pancreatic cancer therapy
Authors: Halbrook Christopher J. , Menjivar Rosa , Thurston Galloway , Magliano Marina Pasca di , Lyssiotis Costas 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDA) is projected to become the 3rd most prevalent cancer-related death in the United States in 2016, contrasting a relatively low incidence rate. The lethality of PDA is largely due to a lack of effective treatment options. A principal barrier in PDA treatment is the physiology of the tumors, characterized by a densely fibrotic stroma, rich with immune cell infiltration. The majority of these immune cells are immunosuppressive myeloid cells, including macrophages. These macrophages within the tumor, termed tumor-associated macrophages (TAMs), are strongly immunosuppressive, inhibiting both infiltration and activation of cytotoxic T cells. While immunotherapy has emerged as a promising strategy to treat other solid tumors, immune suppression has rendered PDA refractory to such approaches. Accordingly, much effort has been made to understand the role of TAMs in pancreatic tumorigenesis and tumor maintenance. Several studies have identified pathways by which PDA cells recruit and polarize macrophages into TAMs and the effects that TAMs have on the tumor microenvironment. Depletion of TAMs leads to the inhibition or regression of tumor growth, mediated largely by increased infiltration of cytotoxic T cells into the tumor. In addition to signaling proteins, metabolic byproducts can also influence cellular crosstalk in the tumor microenvironment; however, this has not been described in the context of PDA. Utilizing reciprocal conditioned media approaches combined with LC/MS metabolomics, we have profiled the metabolic crosstalk between cancer cells and macrophage cultures and found TAMs release metabolites that can regulate the response of PDA cells to chemotherapy. We further noted several additional metabolic pathways by which TAMs can deplete important nutrients in the microenvironment to directly inhibit T-cell activity. Taken together, these data provide mechanistic insight into previous reports that macrophages can drive immune and chemoresistance in PDA. Furthermore, these results also suggest that further development of interventions that target either PDA-mediated polarization of TAMs or TAM-mediated inhibition of therapy represent opportunities to improve the efficacy of currently available treatment options.
This abstract is also being presented as Poster A36.
Citation Format: Christopher J. Halbrook, Rosa Menjivar, Galloway Thurston, Marina Pasca di Magliano, Costas Lyssiotis. Macrophage metabolism inhibits pancreatic cancer therapy [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 PR13.
Abstract BS1-1: RNA Methylation in human cancer
Authors: He C 
Published: March 2020

Abstract
Over 150 types of post-transcriptional RNA modifications have been identified in all kingdoms of life. We have discovered the first two RNA demethylases, FTO and ALKBH5, which catalyze oxidative demethylation of the most prevalent modifications of mammalian messenger RNA (mRNA) and other nuclear RNA, N6-methyladenosine (m6A). These findings indicate that reversible RNA modification could impact biological regulation analogous to the well-known reversible DNA and histone chemical modifications. We have also characterized proteins that selectively recognize m6A-modified mRNA and affect the translation status and lifetime of the target mRNA, as well as molecular machines that deposit the m6A methylation on mRNA. Functional studies reveal m6A methylation as a critical mechanism to synchronize groups of transcripts for coordinated metabolism, translation, and decay, allowing timely and coordinated protein synthesis and transcriptome switching during cell differentiation and development. Misregulations of these processes lead to embryo lethality and human diseases such as cancer. I will focus on our discoveries of how aberrant expressions of m6A regulators could contribute to human cancer. I will also present effects of m6A regulation on immune response related to cancer progression.
Citation Format: C He. RNA Methylation in human 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 BS1-1.
Abstract CS1-1: Origins and Clinical Implications of HER2 Heterogeneity
Authors: Richardson A 
Published: March 2020

Abstract
The presentation will describe the types of HER2 heterogeneity and how it is identified pathologically including case examples and molecular studies. The implications for treatment decisions and for its possible role in patient outcomes will also be discussed.
Citation Format: A Richardson. Origins and Clinical Implications of HER2 Heterogeneity [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 CS1-1.
Abstract ES1-3: Assessment of PD-L1 in Breast Cancer to Predict Response to Immunotherapy
Authors: Rimm DL 
Published: March 2020

Abstract
Many tumors showed promise in phase one trials of immunotherapy, but breast cancer was not high on the list. Since then, focus in breast cancer has shifted to Triple Negative Breast Cancer (TNBC) which has shown promise in both the metastatic and neo-adjuvant setting. This presentation will provide a history of the PD-L1 assay to select response to therapy in lung cancer where it was most successful and then discuss its transition to breast cancer. In TNBC, there are successful trials and even FDA approval, but there is also deep concerns related to the IHC-based patient selection assay. This presentation will discuss the breast cancer PD-L1 assay(s) and the controversy surrounding its implementation.
Citation Format: DL Rimm. Assessment of PD-L1 in Breast Cancer to Predict Response to Immunotherapy [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 ES1-3.