bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-202: Role of the FOXA transcription factors in shaping distinct transcriptional programs in human pancreatic cancers
Authors: Milan Marta , Natoli Gioacchino 
Published: August 2018

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer and is characterized by a high intra-tumor heterogeneity, with the coexistence of well- and poorly-differentiated cells in virtually all the tumor cases. FOXA1/2 play a fundamental role in pancreas development and are believed to act as pioneer factors, namely to create accessible chromatin by displacing nucleosomes early in development and making genomic regulatory elements available to other transcriptional regulators. Therefore, we asked whether FOXA1/2 also control differentiation in human PDAC. Whereas FOXA1 showed a remarkable propensity to be expressed selectively by well-differentiated tumor areas and cell lines, FOXA2 showed a broad profile of expression throughout PDAC stages. Through the combination of genomic and functional assays we found that FOXA2 contributed to activate distinct transcriptional programs in tumor cells of different grades. Such complexity in FOXA2 activity specifically depended on its interaction with distinct transcription factors selectively expressed in high- or low-grade tumor cells. While in low-grade (well-differentiated) PDAC cells FOXA2 binding specificity relied on the interaction with the epithelial transcription factor HNF1beta, in high-grade cells it depended on the cooperation with HOXB8 and HOXB9. Knocking out these transcription factors was sufficient to abolish differential recruitment of FOXA2 to grade specific genomic sites. In summary, we found that FOXA2 is broadly express throughout PDAC stages and, through the interaction with different transcription factors, shapes the transcriptional program of the different tumor grades in pancreatic cancer. These findings help to shed light on the complexity of PDAC heterogeneity and on the circuitries that maintain PDAC differentiation and grading.
Citation Format: Marta Milan, Gioacchino Natoli. Role of the FOXA transcription factors in shaping distinct transcriptional programs in human pancreatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-202.
Abstract LB-207: A novel role for polycomb group protein BMI1 in prostate cancer
Authors: Zhu Sen , Zhang Dongyu , Yan Lin , Jiang Weihua , Liu Qipeng , Wang Rui , Xia Bo , Zhao Jonathan C. , Wang Rong-Fu , Shi Xiaobing , Lam Hung-ming , Dong Xuesen , Yu Jindan , Chen Kaifu , Cao Qi 
Published: August 2018

Abstract
BMI1, a Polycomb Group (PcG) protein, plays a critical role in epigenetic regulation of cancer stem cell self-renewal, cell differentiation and proliferation. BMI1 is upregulated in multiple types of cancer, including prostate cancer. As a key component of Polycomb Repressive Complex 1 (PRC1), BMI1 can exert its oncogenic functions by enhancing the enzymatic activities of RING1B to ubiquitinate histone H2A at lysine 119 and repress gene transcription. Here we report a PRC1-independent role of BMI1 that is critical for castrate-resistant prostate cancer (CRPC) progression. BMI1 binds the androgen receptor (AR) and prevents MDM2-mediated AR protein degradation, resulting in sustained AR signaling in prostate cancer cells. More importantly, we demonstrate that targeting BMI1 effectively inhibits tumor growth of xenografts that have developed resistance to surgical castration and enzalutamide treatment. These results suggest that blocking BMI1 alone or in combination with anti-AR therapy can be more efficient to suppress prostate tumor growth.
Citation Format: Sen Zhu, Dongyu Zhang, Lin Yan, Weihua Jiang, Qipeng Liu, Rui Wang, Bo Xia, Jonathan C. Zhao, Rong-Fu Wang, Xiaobing Shi, Hung-ming Lam, Xuesen Dong, Jindan Yu, Kaifu Chen, Qi Cao. A novel role for polycomb group protein BMI1 in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-207.
Abstract LB-218: Pathologist reproducibility of combined positive score (CPS) for the evaluation of PD-L1 in gastric or gastroesophageal junction adenocarcinoma tumors
Authors: Guerrero Lindsay , Kulangara Karina , Truong Yen , Schwefel Sue , Hanks Debra 
Published: August 2018

Abstract
Background: The clinically relevant and highly reproducible combined positive score (CPS) algorithm is used in conjunction with PD-L1 IHC 22C3 pharmDx for evaluation of programmed death ligand 1 (PD-L1) expression in gastric or gastroesophageal junction (GEJ) adenocarcinoma specimens. PD-L1 IHC 22C3 pharmDx and the CPS algorithm were approved by the United States Food and Drug Administration (FDA) on September 22, 2017 to aid in identifying patients likely to respond to pembrolizumab.
Objective: Assessment of pathologist reproducibility in the gastric and GEJ adenocarcinoma Early Validation Program (EVP).
Methods: Immunohistochemical (IHC) staining for PD-L1 was performed on thirty gastric or GEJ adenocarcinoma surgical resection specimens with PD-L1 IHC 22C3 pharmDx. All specimens were evaluated by in-house pathologists and assigned a reference CPS. Inter-pathologist and intra-pathologist reproducibility was assessed in ten pathologists from five clinical labs. Acceptance criteria was based on a minimum of 85% agreement with the reference CPS.
Results: Nine pathologists met acceptance criteria for inter-observer reproducibility (87-100% agreement) and intra-observer reproducibility (87-100% agreement). One pathologist had 90% inter-pathologist agreement and 80% intra-pathologist agreement. This pathologist received additional training and achieved 87% intra-pathologist agreement upon re-testing. Upon completion of EVP, all ten participating pathologists were certified to score gastric or GEJ adenocarcinoma specimens stained with PD-L1 IHC 22C3 pharmDx. Inter-pathologist (87.6% overall agreement) and intra-pathologist (93% overall agreement) studies performed in analytical validation demonstrate similar reproducibility.
Conclusion: The CPS algorithm is highly reproducible within and among pathologists for gastric or GEJ adenocarcinoma specimens stained with PD-L1 IHC 22C3 pharmDx, as demonstrated in analytical validation.
Citation Format: Lindsay Guerrero, Karina Kulangara, Yen Truong, Sue Schwefel, Debra Hanks. Pathologist reproducibility of combined positive score (CPS) for the evaluation of PD-L1 in gastric or gastroesophageal junction adenocarcinoma tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-218.
Abstract LB-254: Combined inhibition of MEK and autophagy promotes regression of pancreatic cancer
Authors: Kinsey Conan , Guillen Katrin , Camolotto Soledad , Boespflug Amelie , Shea Jill , Seipp Michael , Scaife Courtney , McMahon Martin 
Published: August 2018

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a recalcitrant disease responsible for ~43,000 deaths in the USA in 2017. Despite an advanced understanding of the genetics, biochemistry and biology of pancreatic cancer, there is no effective pathway-targeted therapy for PDAC such that the standard of care treatment for most patients remains conventional cytotoxic chemotherapy. Although the clinical picture remains grim, progress has been made in understanding how alterations in tumor suppressors and proto-oncogenes contribute to PDAC initiation and progression. Whereas initiating mutations in KRAS promote the growth of premalignant pancreatic intra-epithelial neoplasia, progression to cancer malignancy requires cooperating alterations of tumor suppressors such as TP53, CDKN2A, and/or SMAD4. Downstream of KRAS oncoproteins, the RAF→MEK→ERK MAP kinase signaling pathway plays a central role in the genesis and maintenance of PDAC. However, to date, pharmacological inhibition of this pathway has demonstrated little clinical benefit in PDAC patients. Here we show that inhibition of KRAS→RAF→MEK→ERK signaling in PDAC cell lines elicits autophagy, a process of cellular self-consumption, which protects pancreatic cancer cells from the potentially cytotoxic effects of pathway inhibition. Mechanistically, inhibition of MEK1/2 leads to activation of ULK1 through the LKB1-AMPK-ULK1 axis. Combined inhibition of MEK1/2 and autophagy (with chloroquine) displays synergistic anti-proliferative effects against PDAC cell lines in vitro. Most strikingly, whereas single agent therapy had modest effects, combined treatment of xenografted patient-derived PDAC tumors with trametinib plus chloroquine/hydroxychloroquine elicited striking tumor regression. Finally, the observed anti-tumor effects of combination trametinib plus chloroquine were observed against a NRAS mutated melanoma and a BRAF mutated colorectal patient-derived xenografts. These data may warrant testing this combination therapy in patients with KRAS mutated pancreatic cancers, a disease for which new pathway-targeted therapies are urgently required.
Citation Format: Conan Kinsey, Katrin Guillen, Soledad Camolotto, Amelie Boespflug, Jill Shea, Michael Seipp, Courtney Scaife, Martin McMahon. Combined inhibition of MEK and autophagy promotes regression of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-254.
Abstract LB-276: Application of a CRISPR/Cas9 screen to identify novel therapeutic strategies with CDK4/6 inhibitors in pancreatic cancer
Authors: Goodwin Craig , Javaid Sehrish , Cox Adrienne D. , Wood Kris , Der Channing 
Published: August 2018

Abstract
While mutational activation of KRAS occurs in nearly all pancreatic ductal adenocarcinomas (PDAC), clinically relevant agents directly targeting KRAS remain elusive. The second most frequent aberration in PDAC is loss of the tumor suppressor CDKN2A, which encodes INK4A, an endogenous inhibitor of the CDK4 and CDK6 cell cycle regulatory proteins that promote G1 cell cycle progression. KRAS and INK4A mutations cooperate to accelerate PDAC metastatic development, in part, by converging to block RB tumor suppressor activity. While no anti-KRAS targeted therapies have reached the clinic, pharmacologic restoration of CDKN2A function by inhibition of CDK4/6 may be an effective anti-KRAS therapeutic strategy. We found that CDK4/6 inhibitors (e.g., palbociclib) elicited single-agent activity in a subset of tested PDAC cell lines. Furthermore, concurrent treatment with the ERK inhibitor SCH772984 caused a potent synergistic reduction in anchorage-dependent and -independent cell growth, induced apoptosis, and increased senescence and G1 arrest. We next sought to identify novel genes that regulate sensitivity to palbociclib. Using a CRISPR/Cas9 loss-of-function screen, we individually silenced expression of 2500 genes from the “druggable genome” in combination with palbociclib. We identified genes that caused synergistic growth suppression in combination, suggesting small molecule combinations to overcome de novo or acquired CDK4/6 inhibitor resistance in the clinic. We also identified genes whose loss imparts a survival advantage, suggesting possible resistance mechanisms to single-agent CDK4/6 inhibition. In total, these data suggest that CDK4/6 inhibitors alone, or in combination, may benefit patients clinically.
Citation Format: Craig Goodwin, Sehrish Javaid, Adrienne D. Cox, Kris Wood, Channing Der. Application of a CRISPR/Cas9 screen to identify novel therapeutic strategies with CDK4/6 inhibitors in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-276.
Abstract LB-278: In vivo evaluation model of human T cell activation by immune checkpoint inhibitors using human PBMC-transferred NOG mouse
Authors: Nishime Chiyoko , Katano Ikumi , Nishinaka Eiko , Kawai Kenji , Ito Ryoji , Hata Jun-ichi , Yamamoto Taichi 
Published: August 2018

Abstract
Within the past decade, immune checkpoint inhibitors, such as anti-programmed death (PD)-1 antibodies (e.g. pembrolizumab; Keytruda and Nivolumab: OPDIVO), treatment has become one of the most advancing therapeutic options in oncology. The PD-1/PD-L1 pathway plays a crucial role in mediating self tolerance and controlling self damage to suppress effector/self-reactive T cells and protects against autoimmune reactions. Therapeutic treatment of anti-PD-1 antibodies clearly suppresses tumor growth and induces T cell activation in cancer patients by blockade of the PD-1/PD-L1 pathway, but over activation of T cells exhibits immune-related adverse effects with exacerbation of autoimmune reactions. A human peripheral blood mononuclear cells (hPBMC) transferred humanized NOG mouse has been used to evaluate the efficacy and safety of therapeutic antibodies due to the efficient engraftment of human T cells in the mice. The human T cells were spontaneously activated in the mice because of xenogenic-reaction and the mice frequently died of graft-versus-host disease (GVHD) (Ito R et al., Transplantation, 2009). In the present study, we evaluate the potential adverse effects of 2 therapeutic antibodies, Keytruda and OPDIVO by using conventional NOG mice transferred with hPBMC. These mice showed a weight loss, wasting, rough fur, and skin thickening suggesting of GVHD symptoms. These changes exacerbated in either antibody treated hPBMC-NOG mice with increase of activation marker for T cells, and they died earlier than saline-treated group. By immune-cytoloical analysis, human T cells was significantly decreased in number in hPBMC-NOG mice even though the antibodies
were treated. These results demonstrated the hPBMC-NOG mice might become powerful preclinical tools to analyze human T cells activated by therapeutic immune checkpoint inhibitors.
Citation Format: Chiyoko Nishime, Ikumi Katano, Eiko Nishinaka, Kenji Kawai, Ryoji Ito, Jun-ichi Hata, Taichi Yamamoto. In vivo evaluation model of human T cell activation by immune checkpoint inhibitors using human PBMC-transferred NOG mouse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-278.
Abstract LB-279: Efficacy of fractionated injections of CLR 131 in a OPM-2 SCID nude mouse model
Authors: Longcor Jarrod , Banach Maria , Friend John 
Published: August 2018

Abstract
Background: Multiple myeloma remains an incurable disease. Treatment with immunomodulators and proteasome inhibitors have provided significant benefits to patients but they still relapse. The introduction of new treatments like daratumumab have provided further benefit. However, patients continue to experience issues and relapse. CLR 131 is a novel radioiodinated therapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells to provide targeted delivery of iodine-131 directly to tumor cells. This study evaluates the effect of fractionated injections of CLR 131 in OPM-2 tumor bearing mice in comparison to equivalent doses of CLR 131 and the standard dosing of bortezomid.
Methods: The OPM-2 cell line (human multiple myeloma) was purchased from American Type Culture Collection (ATCC, Rockville, MD) and maintained in McCoy's 5a media supplemented with 10% fetal bovine serum. Female CB17 SCID mice approximately 5-7 weeks of age were injected subcutaneously with 1x107 viable cells (in ~100 µL Dulbecco's PBS) into the right flank. The study was initiated when tumor size had reached a pre-determined size (approximately 150-200 mm3). The mice were given potassium iodide at a concentration of 0.1% in their drinking water to block possible free iodide in the drug formulation three days prior to injection and continuing through two weeks post-injection.
Results: All treatment groups showed a reduction in tumor growth with the fractionated dose of CLR 131 producing the greatest inhibition. The control group showed exponential growth throughout the study, increasing in volume by an average 11 fold from baseline. This compared with a 3.5 fold increase from baseline in the fractionated dose group and 7.5 fold for the bortezomid group.
Conclusions: The results of the study indicated that a fractioned injection of CLR 131 (2 injections of ~50 µCi) on human multiple myeloma (OPM-2) tumor bearing model showed a significant inhibition of tumor growth as well as a survival benefit. While a single injection of CLR 131 at either ~50 uCi and ~100 uCi were effective, there was an important improvement with by using fractionated dosing. The implication is that in this clinically predictive in vivo model CLR 131, which is currently in a Phase 2 clinical trial for multiple myeloma, might show improved clinical efficacy in patients if a fractionated dose is utilized.
Citation Format: Jarrod Longcor, Maria Banach, John Friend. Efficacy of fractionated injections of CLR 131 in a OPM-2 SCID nude mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-279.
Abstract LB-282: Dynamic regulation of CD73 expression in cancer associated fibroblasts enforces immunosuppression via a feedforward adenosinergic pathway
Authors: Yu Miao , Guo Gang , Huang Lei , Deng Libin , Bollag Roni , Mellor Andrew , Shi Huidong , Cui Yan 
Published: August 2018

Abstract
CD73 is the major extracellular adenosine-generating ecto-5'-nucleotidase (Nt5e) that metabolizes extracellular (e) AMP and generates immunosuppressive adenosine (eADO). Elevated CD73 expression is often exploited by tumors and other cellular constituents of the tumor microenvironment (TME) as a mechanism of immune evasion. Clinically, a high level of CD73 expression in the tumor microenvironment (TME) is linked to poor prognosis. Experimental evidence also demonstrates that host CD73 activity in both hematopoietic and non-hematopoietic compartments augments the suppressive milieu of the TME. Nevertheless, the identities of CD73-expressing non-hematopoietic cells and factors that regulate CD73 activity of these cells have yet to be clearly defined. Our recent results unravel that cancer associated fibroblasts (CAFs) constitute a crucial non-hematopoietic CD73hi compartment in the TME of human colorectal cancer (CRC) and murine MC38 CRC and EG7 lymphoma ectopic models. Strikingly, the CD73 expression profile among cohorts of published human CRC and breast cancer patient data sets confirmed its significant positive association with that of CAF-related markers, both of which are negatively correlated with poor survival. Cellular and transcriptomic analyses of CAFs in the EG7 TME reveal that CD73 expression in CAFs increases progressively during tumor progression, associated with elevated tissue hypoxia. Mechanistically, we demonstrate that the progressive elevation of CD73 expression in CAFs during tumor progression is caused by elevated eADO in the TME, which is resulted by the hypoxia/necrosis-associated eATP release. Furthermore, this eADO/adenosingeric pathway-induced CD73 upregulation in CAFs is mostly mediated by activation of A2BR and downstream MAPK signaling, which exacerbates eADO accumulation and serves as a feedforward loop of re-enforcing the immunosuppressive TME. Our study demonstrated that clinically and experimentally, high level of CD73 expression in CAFs represents another crucial immune checkpoint in the TME. Targeted inactivation or blockade of A2BR signaling may serve as a new strategy to prevent or alleviate the initiation of the eADO-CD73-associated amplification of immunosuppression in the TME, thereby improving the outcome of immunotherapy.
Citation Format: Miao Yu, Gang Guo, Lei Huang, Libin Deng, Roni Bollag, Andrew Mellor, Huidong Shi, Yan Cui. Dynamic regulation of CD73 expression in cancer associated fibroblasts enforces immunosuppression via a feedforward adenosinergic pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-282.
Abstract LB-284: Engineering a hypermutant mouse model of NSCLC to modulate immune response
Authors: Smith Olivia C. , Westcott Peter M. , Canner David A. , Rideout William M. , Bhutkar Arjun , Beytagh Mary C. , Tammela Tuomas , Jacks Tyler E. 
Published: August 2018

Abstract
Immune checkpoint inhibitors are an exciting new class of cancer therapy with unprecedented response rates, and have shed light on the importance of understanding the immune context of tumors. Despite achieving durable clinical responses for a subset of patients, immune checkpoint therapies produce variable response rates, even within tumor type, suggesting a need for improved understanding of the tumor-immune cell axis. Recent clinical trials using checkpoint blockade against CTLA-4 and PD-1 have underscored the relevance of tumor mutational landscapes in predicting these response rates. For example, non-small cell lung cancer (NSCLC) patients with high mutational burden and PD-L1 expression respond better to anti-PD-1 treatment than those with high PD-L1 expression alone. While genetically engineered mouse models (GEMMs) of cancer are powerful platforms for testing new therapies, existing models fail to recapitulate the mutational burden and signatures of human cancers, limiting their ability to model relevant immune responses. We have therefore used CRISPR-Cas9 to knockout the DNA mismatch repair (MMR) gene Msh2 in the widely-used Kras and P53 mutant (KP) GEMM of NSCLC. Specifically, lentivirus expressing a short guide RNA (sgRNA) targeting Msh2, and Cre-recombinase, is delivered intra-tracheally into KP mice carrying a Cas9 allele. Whole-exome sequencing reveals elevated mutational burdens in Msh2KO tumors, as compared to non-targeted controls, and mutational signatures characteristic of MMR deficient human tumors. Histological characterization indicates elevated T cell infiltration of Msh2KO tumors at early time points, while tumors at later stages show minimal infiltration and appear like immune “cold” human tumors. Our future efforts will test checkpoint blockade therapies combined with immunogenic chemotherapy to facilitate neo-antigen presentation in late stage tumors. Development and characterization of this “hypermutant” model should prove valuable for future preclinical development of immunotherapies in NSCLC.
Citation Format: Olivia C. Smith, Peter M. Westcott, David A. Canner, William M. Rideout, Arjun Bhutkar, Mary C. Beytagh, Tuomas Tammela, Tyler E. Jacks. Engineering a hypermutant mouse model of NSCLC to modulate immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-284.