bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4708: Imprime (beta-1,3/1,6 glucan) synergizes with a CD40 agonist to stimulate T cell-dependent antitumor activity in a poorly immunogenic model of pancreatic carcinoma
Authors: Liu Mingen , Graham Kathleen , Chan Anissa S. , Ottoson Nadine R. , Bose Nandita , Beatty Gregory L. 
Published: August 2018

Abstract
Introduction: While some solid tumors show remarkable sensitivity to immunotherapy, pancreatic ductal adenocarcinoma (PDAC) has demonstrated impressive resistance. This poor responsiveness to immunotherapy may reflect multiple mechanisms necessary for generating productive T-cell immunosurveillance, including ineffective tumor antigen presentation by myeloid cells. Here, we hypothesized that combining two immune agonists capable of “licensing” myeloid cells with enhanced T-cell stimulatory properties would synergize to reverse the poorly immunogenic state of pancreatic cancer and, in doing so, drive productive T cell-dependent antitumor immunity.
Methods: C57BL/6 mice were challenged subcutaneously with a syngeneic PDAC cell line (7940B.PDA) derived from a tumor arising spontaneously in the KrasG12D/+; Trp53R172H/+; Pdx-1 Cre (KPC) mouse model. Mice with tumors measuring approximately 5 mm3 in diameter were treated with defined combinations of gemcitabine chemotherapy, a CD40 agonist (FGK45), and Imprime (a yeast β-1,3/1,6 glucan that coordinately activates innate and adaptive immune responses through pattern recognition receptors). CD4 and CD8 T cells were depleted in vivo using GK1.5 and 2.43 antibodies, respectively. Tumor growth curves and overall survival were determined.
Results: Monotherapy with Imprime or a CD40 agonist only modestly delayed tumor outgrowth compared to chemotherapy alone. Delivering chemotherapy 48 hours prior to Imprime administration produced a two-fold increase in the median overall survival, but responses were not durable and all mice relapsed. In contrast, concurrent single administration of Imprime and a CD40 agonist induced complete and durable regressions in 60% of mice. Tumor-free mice resisted tumor rechallenge and therapeutic efficacy was completely abrogated with CD4/CD8 cell depletion.
Conclusions: The combination of two myeloid-directed immune agonists (Imprime and a CD40 agonist) shows promising activity for stimulating T cell-dependent antitumor immunity against PDAC, a poorly immunogenic cancer.
Citation Format: Mingen Liu, Kathleen Graham, Anissa S. Chan, Nadine R. Ottoson, Nandita Bose, Gregory L. Beatty. Imprime (beta-1,3/1,6 glucan) synergizes with a CD40 agonist to stimulate T cell-dependent antitumor activity in a poorly immunogenic model of pancreatic carcinoma [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 4708.
Abstract 4709: Cell-specific gene program-based small-molecule immunomodulators targeting solid-tumor microenvironments
Authors: Kischuk Erin , Majumder Joydeb , Fine Jonathan A. , Lantz Travis C. , Dhawan Deepika , Knapp Deborah W. , Ratliff Timothy L. , Chopra Gaurav 
Published: August 2018

Abstract
Cancer immunotherapy includes promising strategies based on immune checkpoint blockade (e.g., anti-PD-1/PD-L1, anti-CTLA-4). A limitation of such therapies for solid tumors stems from other immune-suppressive mechanisms mediated by myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages. We hypothesize that molecules that target specific suppressive immune cells in the tumor microenvironment can reprogram the pro-tumor microenvironment towards antitumor immunity. Using our proteome-scale target/antitarget network-based lead optimization method (CANDESIGN), we designed and synthesized cell-specific nontoxic chemical libraries with modular functions for anticancer potency and immunomodulation. We used machine learning iteratively on experimental data to identify cell-specific target/anti-target networks (gene programs) as well as designed and synthesized compound libraries targeting cell-specific programs for desired cancer and immune cell function ex vivo. Specifically, we altered suppressive function of MDSCs by targeting upregulated genes in activated monocytic MDSCs in the tumor microenvironment compared to cells in spleen. We synthesized a potent nontoxic compound that specifically modulates activated MDSC function and corresponding changes in CD4+ and CD8+ T-cell activity in a mouse bladder cancer model. We observed a significant reduction in tumor mass following treatment by oral gavage. Interestingly, the bladder cancer cells used in our mouse model (as well as human and dog bladder cancer cells) are insensitive to our lead compound in vitro, suggesting in vivo antitumor activity via immunomodulation. Our lead decreased frequency of monocytic and granulocytic MDSCs in the ascites and the tumor. Moreover, a decreased frequency of MDSC expressing suppressive functional markers (e.g., Arg1, iNOS, PD-L1) and increased IFNγ+CD8+ T cells were observed in the tumor microenvironment after compound treatment. Finally, we performed a small clinical trial on pet dogs with bladder tumors treated with our compound tablets for 4-5 weeks that resulted in ~50% reduction in tumor volume. We conclude that designing cell-specific compounds perturbing the tumor microenvironment to combat immune suppression gives a selective advantage to the immune system to combat solid tumors via single and combination drug/cell therapies.
Citation Format: Erin Kischuk, Joydeb Majumder, Jonathan A. Fine, Travis C. Lantz, Deepika Dhawan, Deborah W. Knapp, Timothy L. Ratliff, Gaurav Chopra. Cell-specific gene program-based small-molecule immunomodulators targeting solid-tumor microenvironments [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 4709.
Abstract 4725: Blockade of cyclin D-CDK4/6 sensitizes immune-refractory tumor cells to tumor antigen-specific T cell-mediated cytotoxicity by repressing SCP3-NANOG axis
Authors: Oh Se Jin , Kim Tae Woo 
Published: August 2018

Abstract
Antitumor immune drives tumor cell to acquire immune-refractory phenotypes. Previously, we demonstrated tumor antigen-specific T cells edited them resistant to CTL killing and enriched NANOGhigh cancer stem cell-like (CSC-like) cells. In this study, in an effort to elucidate targetable pathways of immune-edited tumor cells with the multiaggressiveness, we show synaptonemal complex protein 3 (SCP3), a member of Cor1 family, which is overexpressed in the immune-edited cells, upregulates NANOG by hyperactivating cyclin D1-CDK4/6 axis. The SCP3-cyclin D1-CDK4/6 axis was preserved across various types of human cancer and, notably, negatively correlated with the progression-free survival of cervical cancer patients. Moreover, targeting CDK4/6 with its inhibitor, palbociclib, succeeded in reversing the multiaggressive phenotypes of immune-edited tumor cells, and led to long-term control of the disease. Collectively, our findings establish a firm molecular link of multiaggressiveness among SCP3, NANOG, cyclin D1, and CDK4/6, and identify CDK4/6 inhibitors as an actionable drug for controlling SCP3high immune-refractory cancer.
Citation Format: Se Jin Oh, Tae Woo Kim. Blockade of cyclin D-CDK4/6 sensitizes immune-refractory tumor cells to tumor antigen-specific T cell-mediated cytotoxicity by repressing SCP3-NANOG axis [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 4725.
Abstract 477: Targeting of ErbB3 with functional cooperative miRNAs enhances efficacy of trastuzumab in ErbB2-overexpressing breast cancer cells
Authors: Lyu Hui , Huang Jingcao , Wang Bolun , Han Amy , Liu Bolin 
Published: August 2018

Abstract
Introduction: ErbB3 serves as a critical co-receptor of erbB2 and plays a vital role in the development of erbB2-overexpressing (erbB2+) breast cancer. It is thought to be an important compensatory target for combinatorial strategy to improve the treatments for erbB2+ breast cancer patients. MiRNAs regulate gene expression by the sequence-specific targeting of mRNAs, leading to translational repression or mRNA degradation. ErbB3 is a direct target of both miR-125a and miR-205. Here, we study the potential activity of miRNA based erbB3-targeted therapy in erbB2+ breast cancer cells.
Methods: Cell growth assays were used to determine cell viability. Western blot analyses were performed to assess the expression and activation of proteins. Flow cytometry analysis was carried out to examine cell cycle progression. Lentiviral vector containing one or two miRNAs was used to ectopically express miR-125a and/or miR-205.
Results: Co-expression of miR-125a and miR-205 showed a potent activity to downregulate erbB3 while single miRNA had no or little effect on erbB3 when miR-125a or miR-205 was only increased below 10-fold in BT474 cells. Combination of the two miRNAs not only resulted in a dramatic reduction of phosphorylated erbB3 (P-erbB3) and the downstream signaling kinases Akt (P-Akt) and Src (P-Scr), it also inhibited cell proliferation and increased the cells at G1 phase. More importantly, concomitant expression of the two miRNAs significantly enhanced trastuzumab-mediated growth inhibition and cell cycle G1 arrest in BT474 cells. Interestingly, the expression levels of miR-125a, but not miR-205 in the trastuzumab-resistant BT474-HR20 cells were much lower than that in the parental BT474 cells. Ectopic expression of miR-125a alone profoundly inhibited proliferation of BT474-HR20 cells. These data suggested that reduced miR-125a might be a novel mechanism leading to trastuzumab resistance; and upregulation of miR-125a could be a useful tool to abrogate the resistance.
Conclusions: Co-expression of miR-125a and miR-205 is a new approach to inhibit erbB3. Specific targeting of erbB3 via the functional cooperative miRNAs enhances efficacy of trastuzumab against erbB2+ breast cancer cells. Our data support further exploration of the possible role of miR-125a in the development of trastuzumab resistance.
Keywords: ErbB3, ErbB2, miRNA, Trastuzumab, Breast Cancer
Citation Format: Hui Lyu, Jingcao Huang, Bolun Wang, Amy Han, Bolin Liu. Targeting of ErbB3 with functional cooperative miRNAs enhances efficacy of trastuzumab in ErbB2-overexpressing breast cancer cells [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 477.
Abstract 4803: CXCR6-directed therapeutic approach potentiates efficacy of docetaxel in prostate cancer
Authors: Kapur Neeraj , Mir Hina , Sonpavde Guru , Lillard James W. , Singh Shailesh 
Published: August 2018

Abstract
Development of chemo-resistance negatively impacts therapeutic outcome of advanced prostate cancer (PCa). Molecular mechanism used by cancer cells to overcome therapeutic effect is still undefined. Here, we demonstrate the influence of CXCR6/CXCL16 mediated molecular signals on the efficacy of docetaxel (DTX). Out data showed poor DTX efficacy on PCa cells (LNCaP, PC3, and DU145) after stimulating CXCR6 with soluble CXCL16, while significant improvement in cytotoxic effect of DTX was observed after CXCR6 blockade using anti-CXCR6 monoclonal antibody. Interestingly, CXCR6, CXCL16, and ADAM-10, a metalloproteinase involved in CXCL16 cleavage from PCa cell membranes, were significantly elevated in response to DTX treatment. This was further confirmed on xenograft tumor by immunohistochemistry. Further, phospho-proteomic profiling and western blot analysis showed activation of pro-survival molecules: GSK-3β, NFκB, ERK/1/2, and survivin following soluble CXCL16 treatment. Activation of CXCR6-CXCL16 axis also inhibited expression of the epithelial marker (E-cadherin) while increased expression of mesenchymal markers (β-catenin, α-SMA, vimentin, snail), which highlights the role of CXCR6 in promoting mesenchymal phenotype that is known to have a significant impact on cancer progression and therapeutic outcome. Thus, our study shows that CXCR6-CXCL16 signaling instigates chemotherapeutic resistance by increasing pro-survival signaling and promoting mesenchymal phenotype. Hence, combining CXCR6 blockade with DTX would be a better treatment option for advanced, drug-resistant PCa.
Citation Format: Neeraj Kapur, Hina Mir, Guru Sonpavde, James W. Lillard, Shailesh Singh. CXCR6-directed therapeutic approach potentiates efficacy of docetaxel 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 4803.
Abstract 4844: Evidence of PARP-1 dependent cytotoxic agents with low target affinity
Authors: Puentes Laura , Reilly Sean 
Published: August 2018

Abstract
Introduction: Inhibition of nuclear protein poly (ADP-ribose) polymerase-1 (PARP1) is synthetically lethal in BRCA mutated cancers. However, the mechanism by which PARPi exert cytotoxic effects is not fully understood. In this study, we compare 16 olaparib analogs and measured their potency in a radioligand binding assay to measure their affinity for PARP1, and in a cytotoxicity assay to measure their ability to serve as a chemotherapeutic.
Methods: Compounds were prepared by replacing the piperazine core on olaparib with a series of diazaspiro ring systems. PARP1 affinity was assessed using radioligand binding competition assays. In vitro cytotoxicity was performed on BRCA1 methylated and PARP1-/- ovarian cancer cell lines to evaluate the relative potency of the analog compounds.
Results: The 16 analogs displayed lower affinity to PARP1 but comparable or higher potency in cell kill assays when compared to olaparib. Of the 16 compounds, those that contained the diazaspiro core with an N-Boc-functional group displayed the highest degree of potency. Cytotoxicity assays were performed for each compound using PARP1 -/- and PARP2 -/- cells to assess off-target effects. Dose response curves for PARP1-/- cells resulted in a rightward shift; no changes in the dose-response curves were detected for PARP2 -/- cells.
Conclusion: Radioligand binding assays demonstrated that these compounds have low PARP1 affinity. Evaluation of the relative potency of these compounds revealed that compounds having a lower PARP1 affinity relative to olaparib still retained a high potency in cell kill assays. In vitro cytotoxicity assays on PARP1 -/- and PARP2 -/- cells confirmed that these compounds are PARP1 but not PARP2 dependent. Future studies will focus on assessing catalytic inhibition of PARP1 and PARP1 trapping in order to better elucidate the antiproliferative effects of these compounds.
Citation Format: Laura Puentes, Sean Reilly. Evidence of PARP-1 dependent cytotoxic agents with low target affinity [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 4844.
Abstract 485: Modulation of microRNA expression in EGFR-tyrosine kinase inhibitor-resistant non-small cell lung cancer cell lines
Authors: Haque Inamul , Motes Hannah , Sharma Mukut , Reyes Emma Borrego-Diaz , Godwin Andrew K. , Huang Chao H. 
Published: August 2018

Abstract
Objectives: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are now standard of care in lung cancer patients with EGFR mutation. Invariably, these patients develop resistance and require treatment with another EGFR-TKI or chemotherapy. The gatekeeper mutation T790M is responsible for about 50% of resistance. Other mechanisms may also confer resistance in these patients. High expression of microRNA-10b (miRNA-10b) is associated with worse prognosis in resected lung cancer patients with EGFR mutation. Both miRNA-27a and -27b are associated with increased expression of c-met, which is a potential mechanism of resistance to EGFR-TKI. The goal of this study is to determine the optimal treatment and miRNA characteristic of EGFR mutation lung cancer cells resistant to EGFR-TKI. We hypothesized that miRNA-10b, -27a and -27b modulated Erlotinib (ERL) resistance by different EGFR-TKIs and chemotherapeutic agents in EGFR mutant NSCLC cell lines.
Materials and Methods: Lung cancer cell lines with EGFR mutation HCC827 and HCC4006 resistant to ERL were generated. ERL-resistant cells were then treated with 10 nM afatinib (Afa), 0.5 mg/mL pemetrexed (Pem), and combination of 10 nM Afa/0.5mg/mL Pem for 72h. The cells were harvested and microRNA assay was performed by real-time PCR. NCI-H460 cell line without EGFR mutation was used as control.
Results: We observed increased expression of miRNA-10b, miRNA-27a and miRNA-27b in ERL-resistant HCC4006 compared to control cells NCI-H460. There was an upregulation of miRNA-27a and -27b but not of miRNA-10b in ERL-resistant HCC827. Treatment of ERL-resistant cells with Afa, Pem, and combined treatment changed the expression of miRNA-10b, miRNA-27a and miRNA-27b. These miRNAs were downregulated by 2nd-generation EGFR-TKI therapy alone or in combination with Pem. Different treatments had different effects on these miRNAs. There might be differences in miRNA regulation in different cell lines when treated with EGFR-TKI or chemotherapy. Our results suggest that microRNA may be used as targets for developing novel approach to treating patients with EGFR-TKI resistance.
Conclusion: This study may have implications in the management of patients resistant to EGFR TKI. MicroRNA analysis showed upregulation of several microRNAs that should be confirmed in clinical setting.
Citation Format: Inamul Haque, Hannah Motes, Mukut Sharma, Emma Borrego-Diaz Reyes, Andrew K. Godwin, Chao H. Huang. Modulation of microRNA expression in EGFR-tyrosine kinase inhibitor-resistant non-small cell lung cancer cell lines [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 485.
Abstract 4862: Protein arginine methyltransferase 5 as a tumor promoter and therapeutic target in gastrointestinal cancers
Authors: Prabhu Lakshmi , Chen Lan , Safa Ahmad , Korc Murray , Zhang Zhong-Yin , Lu Tao 
Published: August 2018

Abstract
Colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) are among the most commonly diagnosed forms of cancer in the United States. Due to their widespread prevalence and high mortality rate, it is vital to develop effective therapeutic drugs to combat these deadly diseases. In both CRC and PDAC, the multifunctional factor nuclear factor kappa B (NF-kB), a central coordinator of immune responses, is activated abnormally, leading to tumorigenesis and cancer progression. Therefore, controlling NF-kB activity is critical in the treatment of these cancers. Previously, we discovered a novel mechanism by which NF-kB is activated through methylation by an epigenetic enzyme known as protein arginine methyltransferase 5 (PRMT5). We showed that overexpression of PRMT5 significantly promoted several characteristics associated with cancer, including increased cell proliferation, migration, and anchorage-independent growth in both CRC and PDAC cells, thus, putting forward PRMT5 as a novel therapeutic target in these cancers. In this study, we successfully adapted AlphaLISA technique into a high-throughput screen platform, and further employed this approach to successfully identify PR5-LL-FDA1 as a potent PRMT5 inhibitor from commercially-available screening libraries. Furthermore, we confirmed that treatment of PDAC and CRC cells with PR5-LL-FDA1 led to decreased NF-kB activation, and reduced cancer associated properties in PDAC and CRC cells. Importantly, we show that PR5-LL-FDA1 is more efficacious than the commercial PRMT5 inhibitor, EPZ015666 in both PDAC and CRC. Our work clearly highlights the significant potential of PRMT5 as a therapeutic target in PDAC and CRC and hold the promise to establish PR5-LL-FDA1 as a promising basis for new drug development in the future.
Citation Format: Lakshmi Prabhu, Lan Chen, Ahmad Safa, Murray Korc, Zhong-Yin Zhang, Tao Lu. Protein arginine methyltransferase 5 as a tumor promoter and therapeutic target in gastrointestinal 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 4862.
Abstract 4866: BI 907828: A novel, potent MDM2 inhibitor that induces antitumor immunologic memory and acts synergistically with an anti-PD-1 antibody in syngeneic mouse models of cancer
Authors: Rudolph Dorothea , Reschke Markus , Blake Sophia , Rinnenthal Jörg , Wernitznig Andreas , Weyer-Czernilofsky Ulrike , Gollner Andreas , Haslinger Christian , Garin-Chesa Pilar , Quant Jens , McConnell Darryl B. , Norbert Kraut , Moll Jürgen 
Published: August 2018

Abstract
MDM2 inhibitors block the interaction between the Tumor Protein p53 (TP53) and MDM2, its key negative regulator, and represent a new therapeutic concept in cancer therapy. MDM2 inhibitors are designed to restore p53 activity in TP53 wild-type tumors. Several MDM2 inhibitors are currently being evaluated in early clinical development. While the tumor targeting activity of MDM2 inhibitors has been well documented, recent preclinical data with the tool compound Nutlin-3 have shown that p53 activation by local, intra-tumoral injections induces anti-tumor immunity (Cancer Res 2017, 77(9) 2292-2305). Here we present data on BI 907828, a novel and potent MDM2 inhibitor with optimized drug-like properties that is suitable for intermittent dose schedules in syngeneic mouse models of cancer. Our data show that immune modulation contributes to efficacy of BI 907828 after oral administration in a Colon-26 syngeneic mouse model. Responding mice develop anti-tumor immunity that can control the tumor growth of a secondary tumor without any further treatment in a re-challenge study. A T cell depletion study shows a contribution of CD8+ T cells but not of CD4+ T cells to single-agent efficacy with BI 907828. Moreover, preclinical data in a Colon-26 syngeneic mouse model of cancer show synergistic efficacy for the combination of a PD-1 checkpoint inhibitor with BI 907828. In summary, BI 907828 is a novel, potent, orally bioavailable MDM2 inhibitor that shows synergistic efficacy in combination with a PD-1 checkpoint inhibitor in syngeneic mouse models of cancer.
Citation Format: Dorothea Rudolph, Markus Reschke, Sophia Blake, Jörg Rinnenthal, Andreas Wernitznig, Ulrike Weyer-Czernilofsky, Andreas Gollner, Christian Haslinger, Pilar Garin-Chesa, Jens Quant, Darryl B. McConnell, Kraut Norbert, Jürgen Moll. BI 907828: A novel, potent MDM2 inhibitor that induces antitumor immunologic memory and acts synergistically with an anti-PD-1 antibody in syngeneic mouse models of 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 4866.