bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3772: Preclinical study of a novel TLR8 selective agonist for cancer immunotherapy
Authors: Wang Yuxun , Yang Heping , Zhang Xingzhong , Ren Shuwen , Li Huanping , Zhao Shuda , Gu Longjun , Zhang Yin , Zeng Yikun , Wang Longsheng , Fu Guangliang , Bao Fang , Liu Fang , Wu Zhiheng , Zhu Panhu , Xu Hui , Gao Yaqiao , Zhang Jian , Wang Pei , Chen Shoujun , Gao Daxin 
Published: August 2018

Abstract
The innate immune system has emerged as one of the major pathways for drug discovery focusing on cancer immunotherapy. TLR8 plays a crucial role in activating innate immunity and facilitates adaptive immunity thereby exerting potent immune-mediated anticancer activity. We previously presented preliminary characterization of a novel TLR8 agonist DN-A1 (Abstract 2995, AACR Annual Meeting 2017). In the present study, we carried out further comprehensive comparative preclinical study of DN-A1 and motolimod, the only TLR8 selective drug candidate in clinical trials. The result indicated that DN-A1 clearly differentiated from motolimod. DN-A1 was highly selective for TLR8 while motolimod exhibited moderate activity over TLR7 in addition to its primary agonistic activity over TLR8. DN-A1 had superior in vitro ADMET and in vivo PK profiles. Moreover, DN-A1 displayed more potent in vitro and in vivo biological activity and produced stronger anticancer efficacy than motolimod. These findings were further supported by DN-A1's stronger effect than motolimod in activating innate immunity in both monkey in vivo and human PBMC ex vivo systems. Furthermore, DN-A1 significantly suppressed tumor growth as a single agent and combination with the chemotherapeutic agent enhanced efficacy of either agent alone in leukemia tumor model. GLP toxicity study in rats and preliminary toxicity study in monkeys revealed acceptable safety profile of DN-A1. Importantly, DN-A1 consistently caused skin injection site reaction (ISR) when administered subcutaneously in both rats and monkeys. In contrast, motolimod failed to induce ISR under the same condition where DN-A1 caused ISR. Recent reports of motolimod's clinical data indicated that ISR was strongly correlated with substantial survival benefit in cancer patients whereas there was no survival benefit when motolimod failed to induce ISR. Therefore, DN-A1 holds great potential as the best-in-class TLR8 selective immunotherapeutic drug candidate poised for human clinical trials.
Citation Format: Yuxun Wang, Heping Yang, Xingzhong Zhang, Shuwen Ren, Huanping Li, Shuda Zhao, Longjun Gu, Yin Zhang, Yikun Zeng, Longsheng Wang, Guangliang Fu, Fang Bao, Fang Liu, Zhiheng Wu, Panhu Zhu, Hui Xu, Yaqiao Gao, Jian Zhang, Pei Wang, Shoujun Chen, Daxin Gao. Preclinical study of a novel TLR8 selective agonist for cancer immunotherapy [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 3772.
Abstract 3775: Use of RLI-15 a clinical grade fusion protein with IL-15 superagonistic activity for the activation of anti-tumor immune response
Authors: Adkins Irena , Sadilkova Lenka , Hradilova Nada , Tomala Jakub , Tomalova Barbora , Kovar Marek , Mikyskova Romana , Reinis Milan , Martynoff Guy de , Bechard David , Moebius Ulrich , Spisek Radek 
Published: August 2018

Abstract
RLI-15, a superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi+ domain represents a promising candidate for the induction of anti-tumor immunity. RLI-15 was designed to bypass the need of endogenous IL-15Rα, thereby leveraging the activity of IL-15 in vivo on target immune cells. RLI-15 stimulates the proliferation and the cytotoxic activity of natural killer (NK) cells and memory CD8+ T cells with no significant expansion and activation of regulatory T cell compartment. RLI-15 was previously shown to exhibit a potent anti-metastatic activity in B16F10 melanoma and Renca renal cell carcinoma mouse models. RLI-15 also significantly delayed tumor growth and prolonged survival when combined with anti-PD1 therapy in CT26 and MC38 colon carcinoma models. Here, we report that the combination treatment with clinical-grade RLI-15 and an anti-PD1 antibody leads to a significant anti-tumor efficacy in a TRAMP-C2 prostate cancer mouse model with 70 % of mice remaining tumor free after the treatment. We evaluated the optimal schedule of such combination therapy to set the basis for the design of upcoming clinical trials. We further tested how the administration schedule affects the pharmacodynamics properties of clinical-grade RLI-15 and translates into the anti-tumor efficacy in metastatic Renca and CT26 mouse models. In cynomolgous monkeys, various schedules of administration of RLI-15 showed a dose-dependent expansion of peripheral blood lymphocytes, predominantly of NK cell and memory CD8+ T cell compartments. The toxicity in mice and cynomolgous monkeys was evaluated to determine the maximal tolerated dose of RLI-15. Furthermore, the activity of clinical-grade RLI-15 was tested in vitro on human PBMCs and the superiority over IL-2 and IL-15 stimulatory capacity has been confirmed. The complex analysis of RLI-15 behavior and of the induced anti-tumor immune response will be explored in the design of a planned Phase I clinical study in patients with both solid tumors and hematological malignancies.
Citation Format: Irena Adkins, Lenka Sadilkova, Nada Hradilova, Jakub Tomala, Barbora Tomalova, Marek Kovar, Romana Mikyskova, Milan Reinis, Guy de Martynoff, David Bechard, Ulrich Moebius, Radek Spisek. Use of RLI-15 a clinical grade fusion protein with IL-15 superagonistic activity for the activation of anti-tumor 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 3775.
Abstract 3777: RORγ agonist enhances antitumor effects of immune checkpoint anti-PD1
Authors: Gaur Pankaj , Verma Vivek , Nandre Rahul , Vir Pooja , Wang Hua , Kang Baolin , Carter Laura , Hu Xiao , Liu Xikui , Gupta Seema , Khleif Samir 
Published: August 2018

Abstract
Anti-PD1/PDL1 therapies have demonstrated great clinical benefit in some cancers, albeit in a limited percentage of patients. RORγt is a master transcription factor, which promotes Type 17 T cell differentiation and is known to enhance the stemness and plasticity of effector cells and to modulate PD1 expression. Since one of the potential failure mechanism of anti-PD1 is the lack of sustained CD8 infiltration within the TME, we assessed whether combining a synthetic, small-molecule RORγ agonist could enhance the antitumor effects of anti-PD1 treatment. To assess this combination treatment, we tested the effects of anti-PD1 antibody (1 mg/kg twice weekly) combined with a RORγ-agonist (LYC-54143; 100 mg/kg PO, BID given continuously till the end of study) in tumor-bearing murine mode lthat utilizes a vaccine for proper priming. We found that RORγ agonist combined with PD1 antibody significantly enhanced the anti-PD1 antitumor effect. This result was manifested by further delaying the tumor growth and prolonging mice survival. At day 35 after tumor implantation, 66% of mice survived in the group treated with anti-PD1 and RORγ agonist and vaccine when compared to 0% survival following anti-PD1 + vaccine or vaccine- alone treatments. This enhanced antitumor activity was observed/confirmed in several tumor models with the combination of RORγ agonist + anti-PD1 treatment. These results show that RORγ agonists may enhance the effectiveness of anti-PD1 therapy and therefore this combination is a promising therapeutic strategy for cancer.
Citation Format: Pankaj Gaur, Vivek Verma, Rahul Nandre, Pooja Vir, Hua Wang, Baolin Kang, Laura Carter, Xiao Hu, Xikui Liu, Seema Gupta, Samir Khleif. RORγ agonist enhances antitumor effects of immune checkpoint anti-PD1 [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 3777.
Abstract 378: Stat3 promotes ovarian cancer by modulating the energy metabolism and develops drug resistance in patients
Authors: Raja Vaishnavi , Giri Shailendra , Sakr Sharif , Hijaz Miriana , Quiles Raymond , Munkarah Adnan R. , Rattan Ramandeep 
Published: August 2018

Abstract
Signal Transducers and Activators of Transcription (STAT) are a group of transcription factors that are known to play a major role in cancer progression. In ovarian cancer, increased STAT3 leads to cancer proliferation in response to cytokines and confers resistance to chemotherapy-induced apoptosis in epithelial malignancies. STAT3 is constitutively activated in patient derived ovarian cancer cells, and increased STAT3 expression is a predictor of poor prognosis. Apart from its function as a transcription factor, recently STAT3 has been shown to modulate mitochondrial function to promote carcinogenesis. The aim of our study was to investigate if STAT3 activation can modulate cellular metabolism of ovarian cancer cells. Stable clones expressing STAT3 were generated in A2780 ovarian cancer cells, along with empty vector clones. Ectopic expression of STAT3 in A2780 ovarian cancer cell line resulted in increased proliferation (p&lt;0.01) and colony formation ability (p&lt;0.001) in vitro and led to large ovarian tumors (p&lt;0.01) compared to parental and vector controls in xenograft mouse model. Bioenergetics profiling showed higher mitochondrial respiration (OCR) and glycolysis (ECAR) in STAT3 clones compared to parental and vector clones. Ratio of ECAR/OCR in the STAT3 overexpressing cells placed them in the ‘metabolically active' phenotype, while parental A2780 and vector clones were in ‘metabolically less active' phenotype. A selective inhibitor of STAT3, STATTIC, inhibited the STAT3 mediated growth of A2780 cells both in vitro (p&lt;0.01) and in vivo (p&lt;0.01). In addition, STATTIC treatments reversed the ‘metabolically active' state of STAT3 overexpressing clones to a ‘lower metabolic state', placing them in the same category as the control cells. In addition, STATTIC inhibited the cell proliferation and modulated bioenergetic phenotype of other ovarian cancer cells lines (PEO4, C200 and OVCAR3) that display a ‘metabolically active' phenotype. Overall, STAT3 can induce metabolic changes in ovarian cancer cells, maybe as survival mechanism and enhances the cellular fitness of the ovarian cancer cell resulting in increased oncogenic abilities.
Citation Format: Vaishnavi Raja, Shailendra Giri, Sharif Sakr, Miriana Hijaz, Raymond Quiles, Adnan R. Munkarah, Ramandeep Rattan. Stat3 promotes ovarian cancer by modulating the energy metabolism and develops drug resistance in patients [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 378.
Abstract 3782: Transcriptional regulation of MHC Class II in tumor associated plasmacytoid dendritic cells in glioblastoma
Authors: Chintala Sreenivasulu , Tewari Brij N. , Henriquez Mario , Fetcko Kaleigh , Filley Anna , Dey Mahua 
Published: August 2018

Abstract
Background: Glioblastoma (GBM), an aggressive grade IV astrocytoma, is the most common primary brain tumor in adults and carry very poor prognosis. One of the hallmark features of GBM is tumor induced dense immunosuppression that renders immunotherapeutic strategies against GBM ineffective. In order to develop successful immunotherapeutic strategies for GBM, it is critical to understand the mechanism of immunosuppression in the tumor microenvironment (TME). In our previous publication, we have shown that plasmacytoid dendritic cells (pDCs) accumulate in TME and preferentially up-regulate MHC-II expression in comparison to myeloid DCs (mDCs). GBM infiltrating pDCs are immunosuppressive in nature and lack the ability to secrete IFN-alpha, and MHC-II upregulation by immunosuppressive pDCs lead to development of tumor tolerance. MHC-II molecules are transcriptionally regulated by the multiprotein complex enhanceosome consisting of a catalytic Class II transactivator (C2ta) in a cell type-dependent mechanism. There are no studies clearly showing differential enhanceosome and C2ta regulation in GBM associated pDC and mDC. In the present study, we investigated the mechanism of differential expression of enhanceosome multiprotein complex in GBM associated pDC and mDC and identify the upstream regulators and downstream effectors. Methods: GL261 cells were intracranially injected (i.c.) in C57BL6 mice and allowed to establish tumors. Tumor and normal brain (n=5), along with cervical lymph nodes (cLN), were collected and processed for isolation of pDC and mDC using flow sorting. Quantitative RT-PCR analysis was used to determine the enhanceosome components. IHC/IF and Western blot analysis were performed to confirm differential expression of enhanceosome components in mouse and human GBM specimens. Cytokine/chemokine protein array and ELISA methods were used to determine the differential expression of cytokines/chemokines in pDC and mDC. Results: We found differential expression of enhanceosome components in tumor associated pDC compared to mDC. Additionally, we found that GBM derived cytokines regulate differential expression of enhanceosome in tumor associated pDC and mDCs. Conclusions: In conclusion results from our studies show that GBM microenvironment regulates differential expression of enhanceosome transcription factors in pDC compared to mDC in a cytokine dependent process. This in turn helps to maintain an immunosuppressive microenvironment for continued tumor growth.
Citation Format: Sreenivasulu Chintala, Brij N. Tewari, Mario Henriquez, Kaleigh Fetcko, Anna Filley, Mahua Dey. Transcriptional regulation of MHC Class II in tumor associated plasmacytoid dendritic cells in glioblastoma [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 3782.
Abstract 38: Mitophagy deficiency promotes osteolytic bone metastasis in breast cancer
Authors: Deng Rong , Zhang Hai-Liang , Cai Rui-Zhao , Tang Jun , Zhu Xiao-Feng 
Published: August 2018

Abstract
Introduction: Metastasis of breast cancer to the bone is a common complication and occurs in 65-80% of late-stage patients. Specifically, the development of osteolytic bone lesions increases patient morbidity and mortality with debilitating skeletal complications. Mitophagy is a selective form of autophagy that removes damaged or excessive mitochondria in response to various metabolic stresses. However, the role of mitophagy in development of cancer remains largely unclear. The Janus-faced role of mitophagy during tumorigenesis leads to a novel challenge when targeting it for cancer therapies. This study focuses on the role of mitophagy deficiency in breast cancer osteolytic bone metastasis, and explores the potential of rescuing mitophagy deficiency as possible therapeutic targets for metastatic disease.
Methods: Specific single-guide RNAs (sgRNAs) were used to deplete ULK1 expression in breast cancer cell lines. Mitophagy was monitored by detecting Tom20 and Hsp60. In addition, mitochondrial DNA (mtDNA) was used to further confirm the reduction of mitochondrial mass. For bone metastasis studies, luciferase-tagged tumor cells were injected into the left cardiac ventricle of anesthetized female nude mice. Metastatic progression was monitored by bioluminescence imaging (BLI). Micro-CT imaging was used to detect bone volume, cortical wall thickness, trabecular thickness and number in mice of tibia. TRAP assay was used to detect osteoclast differentiation assays.
Results: We found that the core Atg protein ULK1 was not only expressed at low level in breast cancer, but also required for hypoxia-induced mitophagy. ULK1-related mitophagy deficiency promoted the formation of metastatic osteolytic lesions in experimental bone metastasis mouse model with MDA-MB-231 cells. TRAP staining revealed that mature osteoclasts significantly increased in RAW264.7 cells treated with CM from ULK1-knockout breast cancer cells. In addition, MEK inhibitor trametinib was sufficient to upregulate the expression of ULK1 and reduced the release of cytokines, which is key to osteoclast differentiation via triggering mitophagy, thereby effectively blocking breast cancer osteolytic bone metastasis.
Conclusion: In conclusion, we demonstrate the functional importance of mitophagy defect in breast cancer for promoting osteolytic bone metastasis. We also provide strong preclinical evidence for using MEK-ERK pathway inhibitors to disrupt ERK kinase-involved ULK1 degradation and induce mitophagy as a breast cancer bone metastasis therapy.
Citation Format: Rong Deng, Hai-Liang Zhang, Rui-Zhao Cai, Jun Tang, Xiao-Feng Zhu. Mitophagy deficiency promotes osteolytic bone metastasis in breast 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 38.
Abstract 3809: T-cell activation through the inhibition of tumor-expressed IDO1 activity in tryptophan metabolism pathway
Authors: Dong Chunlan , Wang Ying , Gong Kefeng , Xing Frank , Shi Qian 
Published: August 2018

Abstract
Indoleamine 2,3-dioxygenase-1 (IDO1) has been described as a major mechanism of immunosuppression in tumors. Despite histologic evidence showing that most human tumor tissues have extensive infiltration by various pro-inflammatory and immune cells, expression of IDO1 by tumor cells results in aggressive tumor growth and resistance to T cell-targeting immunotherapies. To de-suppress T-cell function through inhibition of IDO1-mediated tryptophan metabolism pathway, we established an in vitro assay system allowing robust detection of production level of tryptophan metabolism product N-formyl-kynurenine (Kyn) in culture medium, plasma and tumor tissue through ELISA and LC-MS/MS. We screened a panel of human and murine tumor cell lines for IDO1 expression with and without INFg induction. Our data suggest that a few of these models constitutively express IDO1; about half of the tumor cell models in the panel express IDO1 in an IFNg-dependent manner while the others do not respond to the cytokine stimulation at all. The mechanism underlying the lack of response to cytokine induction on IDO1 production is under investigation. We next tested the reduction of kynurenine in culture medium through inhibition of IDO1 enzymatic activity. After 24h stimulation by IFNg, a murine cell model was treated by INCB024360 (Incyte) for 48h and 72h. Cell-free supernatants were then collected, followed by Kyn detection by LC-MS/MS. The results showed that longer compound treatment (72h) offered a more robust detection window (1,500 ng/mL Kyn down to 2,00 ng/mL), compared to 48h results (350 ng/mL Kyn down to 100 ng/mL). This reproducible assay offers a reliable platform for initial IDO compound screening. To correlate effective reduction of kynurenine production to reactivation of T-cell activity, a co-culture system was established in that T-cell proliferation and cytokine production (IL2) were examined upon IDO1 inhibition in a time course. To achieve maximal therapeutic effect, a combination of INCB024360 and aPD1 antibody was applied in a T cell-mediated tumor cell killing assay. Detailed data will be discussed.
Citation Format: Chunlan Dong, Ying Wang, Kefeng Gong, Frank Xing, Qian Shi. T-cell activation through the inhibition of tumor-expressed IDO1 activity in tryptophan metabolism 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 3809.
Abstract 3827: Bispecific antibodies with an anti-PD-1 backbone for cancer therapy generate enhanced immune activity
Authors: Li Baiyong , Huang Zhaoliang , Pang Xinghua , Zhong Tingting , Chen Na , Wang Max , Jin Xiaoping , Xia Dennis , Zhang Peng , Xia Michelle Yu 
Published: August 2018

Abstract
PD-1 antibody combination therapy shows great promise to further enhance clinical efficacy of PD-1 antibody. Bispecific antibody represents an emerging platform that allows simultaneous targeting of multiple pathways employing a single agent. Here we present a series of bispecific antibodies using anti-PD-1 antibody as backbone, including PD-1/CTLA-4 and PD-1/VEGF bispecific antibodies, which target additional immune suppressive pathways to further enhance cancer immunity. These include complementary check point pathway and suppression of dendritic cell maturation and antigen presentation. Clinical candidates for these projects have been selected demonstrating superior immune enhancing activity in preclinical study. These bispecific antibodes are designed based on Akeso Tetrabody platform, which has demonstrated robust developability properties. Akeso PD-1/CTLA-4 bispecific antibody AK104 has entered clinical trial for advanced solid tumors (ClinicalTrials.gov Identifier: NCT03261011).
Citation Format: Baiyong Li, Zhaoliang Huang, Xinghua Pang, Tingting Zhong, Na Chen, Max Wang, Xiaoping Jin, Dennis Xia, Peng Zhang, Michelle Yu Xia. Bispecific antibodies with an anti-PD-1 backbone for cancer therapy generate enhanced immune activity [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 3827.
Abstract 3839: A small-molecule inhibitor of the β-catenin-TCF4 interaction suppresses colorectal cancer growth in vitro and in vivo
Authors: Shin Seung Ho , Lim Do Young , Reddy Kanamata , Malakhova Margarita , Liu Fangfang , Wang Ting , Song Mengqiu , Chen Hanyong , Bae Ki Beom , Ryu Joohyun , Liu Kangdong , Lee Mee-Hyun , Bode Ann M. , Dong Zigang 
Published: August 2018

Abstract
Colorectal cancer is associated with aberrant activation of the Wnt pathway. β-Catenin plays essential roles in the Wnt pathway by interacting with T-cell factor 4 (TCF4) to transcribe oncogenes. We synthesized a small molecule, referred to as HI-B1, and evaluated signaling changes and biologic consequences induced by the compound. HI-B1 inhibited β-catenin/TCF4 luciferase activity and preferentially caused apoptosis of cancer cells in which the survival is dependent on β-catenin. The formation of the β-catenin/TCF4 complex was disrupted by HI-B1 due to the direct interaction of HI-B1 with β-catenin. Colon cancer patient-derived xenograft (PDX) studies showed that a tumor with higher levels of β-catenin expression was more sensitive to HI-B1 treatment, compared to a tumor with lower expression levels of β-catenin. The different sensitivities of PDX tumors to HI-B1 were dependent on the β-catenin expression level and potentially could be further exploited for biomarker development and therapeutic applications against colon cancer.
Citation Format: Seung Ho Shin, Do Young Lim, Kanamata Reddy, Margarita Malakhova, Fangfang Liu, Ting Wang, Mengqiu Song, Hanyong Chen, Ki Beom Bae, Joohyun Ryu, Kangdong Liu, Mee-Hyun Lee, Ann M. Bode, Zigang Dong. A small-molecule inhibitor of the β-catenin-TCF4 interaction suppresses colorectal cancer growth in vitro and in vivo [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 3839.