bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2731: Checkpoint inhibitor therapy in combination with the implantation of agarose encapsulated cancer cells inhibits tumor growth in a mouse model of osteosarcoma
Authors: Dumpala Pradeep R. , Martis Prithy C. , Bemrose Melissa A. , Dudley Atira , Smith Barry H. , Gazda Lawrence S. 
Published: August 2018

Abstract
We have previously shown that murine renal adenocarcinoma (RENCA) cells encapsulated in agarose macrobeads (MB) secrete factors that inhibit the proliferation of freely growing tumor cells outside the MB, both in vitro and in vivo. This effect is being investigated in ongoing clinical trials with colorectal patients who underwent laparoscopic intraperitoneal implantations of RENCA MBs (NCT01053013, NCT02046174). In the current study, we report the effect of immune checkpoint inhibitors (anti-PD-1 and anti-PD-L1 monoclonal antibodies) in combination with RENCA MBs on tumor burden in BALB/cJ mice induced with K7M2 murine osteosarcoma tumors. Mice that developed tumors (2-5 mm) on subcutaneous injection of K7M2 cells were randomly enrolled in the following study groups: sham, RENCA MBs only, anti-PD-1 only, RENCA MBs + anti-PD-1, anti-PD-L1 only, RENCA MBs + anti-PD-L1. Anti-PD-1 and anti-PD-L1 antibodies were administered ip bi-weekly for 3-6 weeks. RENCA MBs were implanted in the peritoneal cavity on the day of enrollment. Mean tumor volumes (mm3) throughout days 0-24 were: RENCA MB (199.17 ± 125.57), anti-PD-1 only (278.87 ± 180.34), anti-PD-L1 only (332.46 ± 185.13) and sham treated mice (512.61 ± 230.12). RENCA MB and anti-PD-L1 combination therapy did not inhibit tumor growth (375.00 ± 511.61). PD-L1 expression was absent in primary tumors as observed by immunostaining. Treatment with RENCA MBs plus anti-PD-1 treatment demonstrated an additive effect (116.94 ± 83.77) compared to RENCA MB only or anti-PD-1 alone. Moreover, tumors in 4 out of 16 mice from the RENCA MB plus anti-PD-1 group receded and were undetectable (3 in less than 1 week and 1 at 39 days) following treatment. Tumors also regressed and were not palpable in 1 mouse each in the anti-PD-1 and RENCA MB plus anti-PD-L1 groups at day 14 and 9, respectively. Discontinuation of anti-PD-1 and anti-PD-L1 treatment after 3 weeks of treatment resulted in loss of tumor growth regulation. Preliminary data suggests that continued treatment with these immune checkpoint inhibitors beyond 3 weeks prolongs the regulation of tumor growth in this model. These data support the use of anti-PD-1 in combination with the implantation of RENCA macrobeads in this mouse model of osteosarcoma, and the possibility of similar approaches in the clinic.
Citation Format: Pradeep R. Dumpala, Prithy C. Martis, Melissa A. Bemrose, Atira Dudley, Barry H. Smith, Lawrence S. Gazda. Checkpoint inhibitor therapy in combination with the implantation of agarose encapsulated cancer cells inhibits tumor growth in a mouse model of osteosarcoma [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 2731.
Abstract 2736: Preclinical pharmacologic and pharmacodynamic studies of a novel and potent IDO1 inhibitor D-0751
Authors: Wang Yaolin , Shi Zhe , Han Zixing , Wang Zhenwu , Jiang Yueheng , Dai Xing 
Published: August 2018

Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the degradation of the essential amino acid L-tryptophan to kynurenine. It plays an important role in the initial and rate-limiting step in the breakdown of tryptophan. It has been reported that IDO1, an enzyme induced by IFN-gamma, is one of the central regulators of immune responses in various physiologic and pathologic settings and the enzyme is frequently expressed in cancers. Kynurenine produced by IDO1 suppresses T-cell function in the tumor microenvironment, resulting in tumor cell evasion from immune cells. IDO1 inhibitors, such as epacadostat and BMS-986205, have shown preliminary clinical therapeutic response in melanoma and other solid tumors when combined with anti-PD-1 antibody. Here, we report the discovery of a novel and selective IDO1 inhibitor with potent activity in various cell-based assays. Our lead molecule D-0751 inhibits IDO1 activity in HeLa cell and human whole blood assay with IC50 of 0.6 nM and 13 nM, respectively. It activates the human T-cell activity in a HeLa co-culture study with EC50 at 9 nM. D-0751 is optimized to have good PK profile in rodent, dog and monkey as well as slow clearance when incubated with human hepatocyte. Pharmacodynamic (PD) effect has been observed in mouse models (blood and tumor samples) as well as in dog (blood samples) with efficient kynurenine reduction observed at optimal dose level. Taken together, these results support the advancement of D-0751 as a clinical candidate in combination with anti-PD-1/L1 antibody in various solid tumor indications.
Citation Format: Yaolin Wang, Zhe Shi, Zixing Han, Zhenwu Wang, Yueheng Jiang, Xing Dai. Preclinical pharmacologic and pharmacodynamic studies of a novel and potent IDO1 inhibitor D-0751 [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 2736.
Abstract 2739: The ketone body β-hydroxybutyrate alters expression of PD-L1 on malignant glioma cells but does not directly affect T cells in vitro
Authors: Woolf Eric C. , Manhas Kavita R. , Healey Deborah R. , Blattman Joseph N. , Scheck Adrienne C. 
Published: August 2018

Abstract
Patients with newly diagnosed glioblastoma multiforme (GBM), the most aggressive grade of glioma, have an average life expectancy of ~15 months, and less than 6% survive five years, despite the current standard of care, which consists of aggressive surgery followed by radiation and chemotherapy. Advances in the survival of GBM patients require the design of new therapeutic approaches. One novel strategy being explored in our laboratory and others involves using ketogenic therapy (KT). This approach involves shifting the body's metabolic physiology by increasing the production of ketone bodies such as β-hydroxybutyrate (BHB) and decreasing blood glucose. We have demonstrated that nutritionally-induced KT enhances survival and potentiates standard therapy in a mouse model of malignant glioma. Our previous study shows that KT works in part as an immune adjuvant, boosting tumor-reactive immune responses in the microenvironment by alleviating immune suppression in vivo. In particular we found that KT reduced expression of programmed cell death-1 (PD-1) on tumor-infiltrating T cells and its ligand PD-L1 on tumor cells. The PD-1/PD-L1 axis represents a crucial mechanism of glioma-mediated immunosuppression and is a major focus of immunotherapy in GBM and other cancers. The current study aims to determine the role of BHB in the anti-tumor and immune-enhancing effects of KT. We show that in vitro treatment with BHB induces a variety of molecular changes in glioma cells including reduced protein expression of PD-L1. Given that our in vivo data suggests that KT enhances T cell function against tumors we also sought to determine the impact of BHB on T cell function in vitro. Activated CD8+ and CD4+ T cells were cultured with varying doses of BHB prior to flow cytometric analysis. There were no significant changes in expression of immune checkpoint receptors (PD-1, CTLA-4 and LAG-3), production of anti-tumor promoting cytokines (IFN-y, TNF, IL-2) or viability in either T cell population following treatment with any dose of BHB. This suggests that BHB and KT may indirectly impact T cell function by influencing the way tumor cells manipulate the microenvironment. Taken together this data helps us better understand the anti-tumor mechanisms underlying KT and warrants further exploration of combinational treatment strategies using this approach and immunotherapies for GBM.
Citation Format: Eric C. Woolf, Kavita R. Manhas, Deborah R. Healey, Joseph N. Blattman, Adrienne C. Scheck. The ketone body β-hydroxybutyrate alters expression of PD-L1 on malignant glioma cells but does not directly affect T cells in vitro [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 2739.
Abstract 2746: Synergistic immunotherapeutic effects of TLR7/8 agonist on low-dose cyclophosphamide-treated C26 model
Authors: Yang Jing , Li Patrick Z. , Yin Xiangyun , Nie Xiaohua , Wang Jingshu , Lau Walter , Zhang Liguo , Li Lixin 
Published: August 2018

Abstract
In recent years, low dose cyclophosphamide has been used clinically either as a single agent or as combination therapy to treat lymphomas, and breast and ovarian cancers. The efficacy of low dose cyclophosphamide is primarily due to its ability to immune-modulate in addition to its direct anti-tumor effects. This ability highlights the potential for synergism between conventional chemotherapy and novel immunotherapy. Toll-like receptors (TLRs) are a crucial part of the innate immunity and present the first line of defense against pathogens. Resiquimod is the ligand for TLR7 and 8 and directly activate innate immune cells, including myeloid dendritic cells, plasmacytoid dendritic cells, and monocytes/macrophages. This activation may result in activation of co-stimulatory molecules, production of antiviral cytokines, and stimulation of cell-mediated NK and T cell immune responses. The aim of this study was to analyze whether immunopotentiating TLR7/8 agonist might synergize with low doses of cyclophosphamide in the treatment of colorectal carcinoma. The effect of combining a weekly dosing of cyclophosphamide intraperitoneally with systemic administration of Resiquimod was evaluated in an in vivo murine C26 synergistic model. Systemic administration of Resiquimod in mice induced significant systemic immune responses as evidenced by upregulating IFNα inducible gene clusters. The combined therapy with Resiquimod and cyclophosphamide was superior to each single treatment and increased efficacy of tumor inhibition and prolonged their survival significantly. Importantly, the combined treatment generated a significant numbers of tumor-specific T cell infiltration in tumor microenvironment. Our data suggest that systemic administration of TLR7/8 agonist enhances anti-tumor effect of low dose of cyclophosphamide. The data supports the use of a combination of TLR7/8 agonist and cyclophosphamide as a novel therapeutic strategy against colorectal carcinoma.
Citation Format: Jing Yang, Patrick Z. Li, Xiangyun Yin, Xiaohua Nie, Jingshu Wang, Walter Lau, Liguo Zhang, Lixin Li. Synergistic immunotherapeutic effects of TLR7/8 agonist on low-dose cyclophosphamide-treated C26 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 2746.
Abstract 275: Flavokawain B, a kava chalcone, acts synergistically with proteasome inhibitors (i.e., bortezomib and MG132) to reduce the growth of prostate cancer cells via downregulation of Skp2
Authors: Li Xuesen , Pham Victor , Tippin Matthew , Xu Shan , Fu Dongjun , Song Liankun , Hoang Bang H. , Zi Xiaolin 
Published: August 2018

Abstract
Flavokawain B, a chalcone isolated from kava root extracts, has been shown to inhibit the in vitro and in vivo growth of various cancer cell lines via induction of apoptosis. However, the mechanism of flavokawain B's action remains largely unknown. Here we have demonstrated that flavokawain B caused Skp2 degradation in an ubiquitin and proteasome dependent manner. In addition, flavokawain B inhibited NEDD8 conjugations to both Cullin1 and Ubc12 in PC3 cells and Ubc12 NEDDylation in an in vitro assay. Overexpression of dominant-negative cullin1 (1-452) or K720R mutant cullin1 rescued the effect of flavokawain B on Skp2 degradation, but further increased the expression of p27. However, siRNA knock-down of Skp1, CSN5, and UBC12 expression resulted in down-regulation of Skp2 expression and further enhanced the effect of flavokawain B on Skp2 degradation. siRNA knock-down of Cdh1, a known E3 ligase of Skp2 for targeted degradation, also didn't rescue the effect of flavokawain B on Skp2 degradation, but overexpression of F-box deleted Skp2 can reverse the effect of flavokawain B on Skp2 degradation. These results suggest that degradation of Skp2 by flavokawain B is involved in Cullin1. Furthermore, flavokawain B selectively inhibited the growth of pRb deficient cell lines and PC3 cells with Skp2 overexpression. Flavokawain B also acts synergistically with Bortezomib and MG132 to inhibit the growth of prostate cancer cell lines via down-regulation of Skp2 and up-regulation of p27 and p21 expression. These finding provide rationale for combination of flavokawain B and Bortezomib in treatment of prostate cancer.
Citation Format: Xuesen Li, Victor Pham, Matthew Tippin, Shan Xu, Dongjun Fu, Liankun Song, Bang H. Hoang, Xiaolin Zi. Flavokawain B, a kava chalcone, acts synergistically with proteasome inhibitors (i.e., bortezomib and MG132) to reduce the growth of prostate cancer cells via downregulation of Skp2 [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 275.
Abstract 276: Targeting cancer stem cells with chemopreventive agents for breast cancer prevention
Authors: Shan Naing Lin , Yang Jeffrey , Bak Min Ji , Wahler Joseph , Suh Nanjoo 
Published: August 2018

Abstract
Breast cancer accounts for one of the most common causes of cancer-related deaths in women. Despite the available treatment modalities to cure breast cancer, therapeutic resistance and recurrence remain major challenges, owing to the culminating evidence of the presence of cancer stem cell subpopulations in breast tumors. The purpose of the study is to identify chemopreventive and dietary compounds that effectively target cancer stem cells to inhibit breast cancer development and progression. The mammosphere culture system has been proven to enrich cancer stem-like cells, and cells from mammospheres are shown to be more tumorigenic in vivo. By culturing mammospheres from breast cancer cell lines, we have shown that 1,25 vitamin D3, a vitamin D3 analog, BXL0124, pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene), tocopherols and triterpenoids (CDDO-Im) decreased the mammosphere forming efficiency (MFE) in a dose-dependent manner. Vitamin D compounds (1,25D3 and BXL0124) decreased the MFE in SUM159, MCF10DCIS and MCF-7 breast cancer cell lines (dose range 1-100 nM). Pterostilbene, a bioactive component of blueberries, effectively decreased the MFE in the MCF-7 cell line. The size of the mammospheres was found to be smaller with increasing concentrations (10-100 μM). Tocopherols significantly decreased estrogen-stimulated MFE in MCF-7 cells (1-10 μM). CDDO-Im, a synthetic triterpenoid derived from natural oleanolic acid, has also been shown to decrease MFE and sphere size in MCF-7 cells (50-100 nM). The effect on the shape of the spheres was also observed, suggesting the differentiation-inducing properties of these compounds. Taken together, we demonstrate that naturally occurring compounds as well as synthetic analogs derived from natural and dietary compounds significantly inhibit sphere forming efficiency and cancer stemness in breast cancer cells. Our study suggests that chemopreventive compounds, 1,25D3, BXL0124, pterostilbene, tocopherols, and CDDO-Im, are agents with the potential to target cancer stem-like cells to prevent breast cancer.
Citation Format: Naing Lin Shan, Jeffrey Yang, Min Ji Bak, Joseph Wahler, Nanjoo Suh. Targeting cancer stem cells with chemopreventive agents for breast cancer prevention [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 276.
Abstract 278: Inhibition of skin tumor promotion by TPA using a combination of topically applied ursolic acid and curcumin
Authors: Tremmel Lisa , Rho Okkyung , DiGiovanni John 
Published: August 2018

Abstract
Despite the many advances that have been made in understanding cancer development and the discovery of new therapies, cancer still remains the second leading cause of death in the US. In addition, approximately two out of five people are expected to be diagnosed with an invasive cancer in their lifetime. Prevention remains an important strategy to reduce the burden of cancer. One approach to prevent cancer is the use of phytochemicals in various combinations as safe and effective cancer preventive agents. The purpose of this study was to examine the effects of the combination of ursolic acid (UA) and curcumin (Curc) for potential synergistic chemopreventive activity to inhibit tumor promotion using the mouse two-stage skin carcinogenesis model. UA and Curc alone have been shown to inhibit tumorigenesis in several mouse models, and both have been shown to inhibit mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). The anti-cancer activity of these phytochemicals is due primarily to their anti-inflammatory, anti-oxidant, and anti-proliferative effects. These effects are accomplished by acting on a broad spectrum of signaling pathways. In initial short-term experiments (mice treated twice weekly for two weeks with TPA), the combination of UA and Curc pretreated topically inhibited TPA-induced activation of epidermal NF-κB, Cox-2, epidermal growth factor receptor (EGFR) and Stat3 to a greater extent than either compound alone. Additionally, these compounds increased levels of programmed cell death protein 4 (Pdcd4). The alterations in these signaling pathways by the combination of UA and Curc were associated with decreased epidermal proliferation and skin inflammation as assessed by measuring BrdU incorporation and inflammatory gene expression, respectively. Furthermore, results from skin tumor experiments (mice initiated with DMBA and promoted twice weekly with TPA) indicate that the combination of UA and Curc given topically significantly inhibited mouse skin tumor promotion by TPA to a greater extent than the individual compounds given alone. The greatest effects were seen on tumor free survival and on tumor size. These results suggests the potential for the combination of UA and Curc to be used topically for chemopreventive strategies in non-melanoma skin cancer.
Citation Format: Lisa Tremmel, Okkyung Rho, John DiGiovanni. Inhibition of skin tumor promotion by TPA using a combination of topically applied ursolic acid and curcumin [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 278.
Abstract 2791: Physiologically based pharmacokinetic modeling and simulations to estimate the efficacious dose of the CEACAM6 function-blocking antibody BAY 1834942
Authors: Wittemer-Rump Sabine , Niederalt Christoph , Willuda Joerg , Trautwein Mark , Luetke-Eversloh Merlin , Doecke Wolf-Dietrich , Guenther Clemens , Scheerans Christian 
Published: August 2018

Abstract
BAY 1834942 is an immunostimulatory function-blocking (fb) antibody (Ab) against the target carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6) expressed on tumor cells in multiple cancer indications. The suggested mode of action of BAY 1834942 is the blockade of the immunosuppressive effect of CEACAM6 on activated T cells which restores the immune response against cancer cells.
Available preclinical pharmacokinetic (PK) and in vitro pharmacodynamic (PD) data, target receptor density information and tumor (patho-)physiology were used to create a model framework taking into account the three most essential ‘pillars' (target exposure, target binding and drug activity) to estimate the human efficacious dosing of BAY 1834942. For this purpose, a physiologically-based pharmacokinetic (PBPK) model considering target binding of BAY 1834942 in tumor tissue and on blood granulocytes has been developed. The aim of the PBPK model was to estimate the dose range and regimen for humans leading to exposure level at the tumor site that allows sufficient target binding. The PBPK simulations were based on 1) an analysis of PD in vitro data in order to estimate the degree of saturation needed for maximum drug activity, 2) the assessment of CEACAM6 receptor numbers on tumor cells and blood granulocytes and 3) in vivo PK data in order to develop and evaluate the PBPK model. For the latter, plasma PK data of BAY 1834942 in monkeys were used as well as known tumor concentration-time profiles of the antibodies MOPC21 (non-targeting Ab) and ZCE025 (anti-CEA Ab) in mice and humans. Uncertainty of parameters which are relevant for CEACAM6 target saturation was considered by stochastic in silico simulations to estimate the CEACAM6 saturation at the tumor vs. dosing. This analysis revealed that the predicted human efficacious dose strongly depends on CEACAM6 density. Thus, a low CEACAM6 density scenario (25,000 CEACAM6/tumor cell) and a high CEACAM6 density scenario (250,000 CEACAM6/tumor cell) were simulated and used to support dose selection for the first-in-man (FIM) study of BAY 1834942. The FIM study is currently under preparation.
Citation Format: Sabine Wittemer-Rump, Christoph Niederalt, Joerg Willuda, Mark Trautwein, Merlin Luetke-Eversloh, Wolf-Dietrich Doecke, Clemens Guenther, Christian Scheerans. Physiologically based pharmacokinetic modeling and simulations to estimate the efficacious dose of the CEACAM6 function-blocking antibody BAY 1834942 [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 2791.