bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1137: Unraveling spatially-dependent interactions of tumor-associated macrophage in the tumor microenvironment
Authors: Wang Victor , Martinek Jan , Brookes Hannah M. , Kim Kyung In , Palucka Karolina , Chuang Jeff 
Published: August 2019

Abstract
Tumor-infiltrating lymphocytes (TIL) are a strong prognostic factor in cancer patient outcomes. This includes immune checkpoint blockade (ICB) of the PD-1/PD-L1 axis, where patients with a higher abundance of pre-treatment TILs respond more frequently. However, tumors often elaborate mechanisms to exclude TILs and/or suppress their function. Identifying negative regulators of TILs is thus of great importance to improve patient outcomes and increase the patient population that may benefit from ICB. Tumor-associated macrophages (TAM) are a known modulator of TIL activity but the interaction between the two cell types is typically characterized with in vitro experiments and spatially-agnostic sequencing, ignoring location-specific factors contributing to the interaction’s net effects. Interrogating the TAM-TIL interactions in an intact tumor microenvironment (TME) will uncover novel mechanisms responsible for TAM function and may be key to reversing TIL immunosuppression. Here we leverage bulk RNA-sequencing with histocytometry, a multiplex quantitative tissue imaging method, to spatially-resolve the TAM-TIL interactions in intact human metastatic melanoma microenvironments. Bulk sequencing distinguishes tumor samples by high and low enrichment of lymphocyte gene sets, with additional sub-stratification by macrophage enrichment. Modular repertoire analysis implicates an interferon response in the differential lymphocyte enrichment, but does not address macrophage-dependent effects. Drawing from physical chemistry concepts, our spatial analyses of cell-cell interactions from histocytometry reveals distinct TAM populations potentially regulating TIL activity. Phagocytic TAMs in the tumor and non-phagocytic TAMs in the stroma physically contact T-cells, with the former interaction strongly correlated with lymphocyte enrichment and T-cell infiltration. Local and regional TAM phagocytosis affinities estimated by the Langmuir adsorption model further detail the nature of this interaction within the tumor, as well as the role of macrophage phagocytosis in regulating TILs. We demonstrate linear models integrating bulk sequencing and spatial metrics to quantify the relationships between genetics, cell-cell interactions, and T-cell invasiveness. Our work unravels important TAM interactions that shape the TME which have not been previously appreciated, providing novel insight into the forces driving T-cell exclusion and revealing new TAM biology to explore further.
Citation Format: Victor Wang, Jan Martinek, Hannah M. Brookes, Kyung In Kim, Karolina Palucka, Jeff Chuang. Unraveling spatially-dependent interactions of tumor-associated macrophage in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1137.
Abstract 1141: Preclinical analysis of biodistribution and PET imaging of a zirconium-89 labeled PSMA-targeted antibody-chelator conjugate
Authors: Hammer Stefanie , Zitzmann-Kolbe Sabine , Oden Felix , Jannsen Joerg , Bickel Eva , Mueller Andre , Everz Lothar , Hagemann Urs B. , Karlsson Jenny , Ryan Olav B. , Hennekes Hartwig , Cole Patricia E. , Mumberg Dominik 
Published: August 2019

Abstract
The PSMA targeted thorium-227 conjugate PSMA-TTC (BAY 2315497) is a targeted alpha therapy approach for metastatic castration resistant prostate cancer that has shown strong anti-tumor activity in PSMA-positive prostate cancer models (Hammer et al. AACR 2017/2018/2019). PSMA-TTC consists of a fully human IgG1 PSMA-targeted antibody covalently linked to a 3,2-HOPO chelator moiety, stably complexing the alpha emitter thorium-227. As this chelator can also complex zirconium-89, positron emission tomography (PET) imaging using the zirconium-89 labeled variant of the PSMA antibody-chelator conjugate could support clinical development of PSMA-TTC by enabling monitoring of organ distribution.
Herein, we describe radiolabeling of the PSMA antibody-chelator conjugate with zirconium-89 and its quality control using bioanalytical assays. In addition, the zirconium-89 labeled PSMA antibody-chelator conjugate was injected into mice bearing LNCaP xenograft tumors and biodistribution was assessed by measurement of radioactivity in tumor and organs as well as PET imaging at different time points after injection.
The PSMA antibody-chelator conjugate was successfully labeled with zirconium-89 at high yield, purity and specific activity. Target binding was confirmed by determination of the immunoreactive fraction. Biodistribution experiments revealed high, long lasting uptake of zirconium-89 in PSMA-positive LNCaP tumors after single injection of the zirconium-89 labeled conjugate. An uptake of 40-50% of the injected dose per gram of tumor was measured at 24, 48, 72, 168 and 240h after injection. The PET images showed that the zirconium-89 labeled PSMA antibody-chelator conjugate provided an excellent image contrast for the delineation of LNCaP xenografts between 48 and 168 h after administration. Other organs showed only very little background and tumor-to-heart ratio was greater than 10 when PET imaging was performed between 48 and 168 h after injection.
These results indicate that the zirconium-89 labeled PSMA antibody-chelator conjugate shows promise for PET imaging studies. These properties may allow its use to support clinical development of PSMA-TTC.
Citation Format: Stefanie Hammer, Sabine Zitzmann-Kolbe, Felix Oden, Joerg Jannsen, Eva Bickel, Andre Mueller, Lothar Everz, Urs B. Hagemann, Jenny Karlsson, Olav B. Ryan, Hartwig Hennekes, Patricia E. Cole, Dominik Mumberg. Preclinical analysis of biodistribution and PET imaging of a zirconium-89 labeled PSMA-targeted antibody-chelator conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1141.
Abstract 1160: Endoplasmic reticulum stress disrupts stemness-related transcriptional regulatory network: Implication for therapy response in cancer
Authors: Olou Appolinaire , Mehla Kamiya , Singh Pankaj 
Published: August 2019

Abstract
Pancreatic cancer is the third leading cause of cancer-associated deaths in the United States. We have recently demonstrated that endoplasmic reticulum (ER) stress correlates with improved survival in human pancreatic cancer patients on gemcitabine therapy. Cancer cell stemness is a significant contributor of poor response to therapy and disease recurrence. We also observed that inducing ER stress can diminish stemness in cancer cells. Hence, to investigate the mechanism of ER stress-mediated alterations in diminishing cancer stemness, we investigated the impact of ER stress on transcriptomic alterations by performing RNAseq studies. We subjected cancer cells to treatment with thapsigargin and the harvested mRNA was utilized for RNAseq analysis. We observed significant alterations in mRNA expression levels of the stemness-associated gene set, which also showed significant enrichment in Ingenuity pathway analysis. Hence, our studies demonstrate that ER stress regulates stemness at the transcriptional level. Our ongoing and future studies will target individual genes/pathways to identify their relative contributions to ER stress-mediated regulation of stemness. Considering the role of stemness in disease recurrence, our studies will provide novel mechanistic insights that may lead to novel therapies for targeting disease recurrence in pancreatic cancer.
Citation Format: Appolinaire Olou, Kamiya Mehla, Pankaj Singh. Endoplasmic reticulum stress disrupts stemness-related transcriptional regulatory network: Implication for therapy response in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1160.
Abstract 1162: CD24 regulates cancer stem cell like traits in bladder cancer
Authors: Oki Akira , Hoque Mohammad Obaidul 
Published: August 2019

Abstract
Tumors are hierarchically organized by a rare population of cancer stem cells (CSCs) that contributes to cancer initiation, progression, and treatment failure. A better understanding of the molecular mechanisms underlying urothelial CSC regulation and the identification of key molecules associated with CSC generation and maintenance are pivotal for the molecular-targeting therapy. CD24 is overexpressed and acts as a lynchpin of tumorigenesis and metastatic progression in urothelial carcinoma of the bladder (UCB). However, its contribution to cancer stem-like traits of CD24 have not been determined. The functional relevance of CD24 was evaluated using in vitro and in vivo approaches. The knockdown of CD24 attenuated cancer stemness properties including sphere formation, self-renewal, invasion, chemo-resistance, and tumor initiation. The high-CD24-expressing cells, isolated from patient-derived UCB xenograft tumors, exhibited their enhanced stemness properties. Biologically, CD24 was associated with the expression of several key CSC-related molecules, including CD133, ABCG2, and YAP1. In human UCB samples, CD24 was overexpressed not only in primary tumors, but also in urine from UCB subjects. Conclusion: CD24 plays a crucial role in maintaining the urothelial cancer stem-like traits.
Note: This abstract was not presented at the meeting.
Citation Format: Akira Oki, Mohammad Obaidul Hoque. CD24 regulates cancer stem cell like traits in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1162.
Abstract 1163: HR23A expression modulates drug resistance through regulation of autophagy and stem cell properties in cancer cells
Authors: Chuang Show-Mei , Yu Chung-Yun , Liu Bang-Hung , Lin Sheng-Chih , Tang Shao-Yi 
Published: August 2019

Abstract
DNA-damaging agents are commonly used as anticancer therapeutics. Unfortunately, drug resistance arises through a combination of mechanisms, with the sensitivity of cells to apoptosis depending on the balance between apoptotic and survival signals. Our previous studies show that knockdown of HR23A, an accessory protein involved in nucleotide-excision repair (NER) at an early lesion-recognition step, induces autophagy, increases the resistance to cisplatin, oxaliplatin, 5-FU and docetaxel. However, knockdown of HR23A contributed no effect to the sensitivity of tamoxifen or irinotecan. In present study, we found that knockdown of HR23A displayed more sensitivity to the treatment of doxorubicin in A549 cell line. Knockdown of HR23A enhanced cell death via increased ER stress-mediated apoptosis but not autophagy, suggesting a different role of HR23A in response to doxorubicin. Further investigation revealed that HR23A-knockdown cells appear to undergo epithelial-mesenchymal transition and take on certain attributes of cancer stemness. Our experiments show that depletion of HR23A enhances epithelial-mesenchymal transition, EMT regulator protein levels such as Twist1, Slug and Zeb1, cancer cell migration and various cancer stemness properties, including the expression of major pluripotency factors, the capacity for tumor-sphere formation in culture and the expression of cancer stem cell surface markers. The increases of these stemness properties are reversed by ectopic expression of HR23A or further knockdown of Twist1 in HR23A-depleted cells. Furthermore, HR23A directly targets the Twist1 protein and contributes to regulating Twist1 protein stability without changing its gene transcription. Together, our data suggest that knockdown of HR23A induces autophagy, undergoes epithelial-mesenchymal transition and promotes stemness properties, thus leading to the resistance to DNA-damaging agents.
Citation Format: Show-Mei Chuang, Chung-Yun Yu, Bang-Hung Liu, Sheng-Chih Lin, Shao-Yi Tang. HR23A expression modulates drug resistance through regulation of autophagy and stem cell properties in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1163.
Abstract 119: The influence of CD44/HA signaling on CML survival and resistance to tyrosine kinase inhibitor treatment
Authors: Humphries Kylie , Uchakina Olga , Hostetler Bryan , McKallip Robert 
Published: August 2019

Abstract
The development of tyrosine kinase inhibitors (TKIs) such as imatinib has greatly improved the prognosis and survival of patients diagnosed with chronic myeloid leukemia (CML). However, many CML patients relapse due to the presence of minimal residual disease and the development of TKI resistance. It is unknown exactly what causes the relapse, but based on research from our laboratory we hypothesize that hyaluronic acid (HA) produced by fibroblasts in the microenvironment of the bone marrow provide for a protective environment preventing the tumor cells from therapy-induced cell death or senescence. The purpose of this study is to determine the influence that HA and its binding to its receptor (CD44) has on CML survival and resistance development. Initially, we examined the effect that stromal cell derived and/or exogenously added HA has on CML resistance to imatinib. Cell survival, apoptosis, HA production, and signaling events elicited by the interactions of HA with CD44 was examined using methods such as ELISA, western blotting, and MTT analysis. Furthermore, we examined the potential therapeutic use of compounds known to alter HA production and/or signaling for the treatment of CML. Our study demonstrates increased cell survival when the tumor cells are co-cultured with fibroblasts or have exogenous HA added to them after imatinib treatment. Additionally, we show that knocking out hyaluronic acid synthases reduces this protective effect. This data supports our hypothesis and we believe it could help lead to improved therapeutic treatment for CML.
Note: This abstract was not presented at the meeting.
Citation Format: Kylie Humphries, Olga Uchakina, Bryan Hostetler, Robert McKallip. The influence of CD44/HA signaling on CML survival and resistance to tyrosine kinase inhibitor treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 119.
Abstract 12: A novel Hsp90 machine inhibitor combining chemotherapy and immunotherapy
Authors: Chadli Ahmed , Eisa Nada , Crowley Vincent , Lu Sumin , Jilani Yasmeen , Korkaya Hasan , Blagg Brian 
Published: August 2019

Abstract
Molecular chaperones are guardians of the proteome and of cellular homeostasis. Dysregulation in the function of the Hsp90 chaperoning machine in particular has been implicated in metabolic, oncological, neurodegenerative, and cardiovascular diseases. Targeting Hsp90 has been shown to have a combinatorial impact on dysfunctional circuitries that underlie human cancers. Thus, several inhibitors targeting the N-terminal ATP-binding pocket of Hsp90 are undergoing clinical trials as anticancer agents. They inactivate the ATPase activity of the chaperone, causing proteasomal degradation of its “client” oncogenic proteins. Although these inhibitors provided a proof-of-principal that Hsp90 is a valuable therapeutic target, they exhibit modest activity in the clinic, in part because they concomitantly induce a heat shock response (HSR), which turns on pro-survival pathways. Consequently, new mechanisms to inhibit the Hsp90 chaperone machine that do not induce the heat shock response are needed.
To address this, we have developed a unique high throughput screen (HTS) based on the progesterone receptor (PR) and the five purified chaperones required for folding steroid receptors, i.e., Hsp90, Hsp70, Hsp40, Hsp70/Hsp90 organizing protein (Hop), and p23. During our preliminary screening of natural products, we discovered that the compound AD07 kills cancer cells through inhibition of the Hsp90 machine without a significant induction of HSR. In addition, AD07 induces a powerful T cell-mediated immune response, resulting in highly efficient tumor killing in a syngeneic mouse model and long-term memory against the primary tumor. At the molecular level, AD07 reduces the protein levels of two key mediators of tumor-induced immune tolerance: programmed cell death ligand-1 (PDL-1) and indolamine 2,3 dioxygenase (IDO). We therefore propose that AD07 is a promising anti-tumor agent targeting the Hsp90 machine through a novel mechanism of action involving cancer cell toxicity, which increases its immunogenicity, and modulation of the tumor microenvironment to reduce immunotolerance.
Citation Format: Ahmed Chadli, Nada Eisa, Vincent Crowley, Sumin Lu, Yasmeen Jilani, Hasan Korkaya, Brian Blagg. A novel Hsp90 machine inhibitor combining chemotherapy and immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 12.
Abstract 1206: Inhibition of GPR4 attenuates intestinal inflammation in a mouse colitis model
Authors: Sanderlin Edward J. , Marie Mona , Velcicky Juraj , Loetscher Pius , Yang Li V. 
Published: August 2019

Abstract
Inflammatory bowel disease (IBD), a chronic inflammatory disorder of the digestive tract, is associated with a higher risk of colorectal cancer development. Current therapeutic approaches for IBD are limited and primarily include biologics and steroids such as anti-TNFα monoclonal antibodies and glucocorticoids. Chronic usage, however, can cause significant adverse drug effects such as increased risk of infection and lymphoma in some patients. GPR4, a pH-sensing G protein-coupled receptor, has recently emerged as a potential therapeutic target for intestinal inflammation. Previous studies demonstrate that GPR4 is a pro-inflammatory receptor expressed in vascular endothelial cells (EC) and stimulates leukocyte-EC adhesion and extravasation. Knockout of GPR4 alleviates intestinal inflammation in IBD mouse models. In this study, we have assessed the effects of a recently developed GPR4 antagonist, 2-(4-((2-Ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)phenyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (GPR4 antagonist 13, also known as NE 52-QQ57), in the dextran sulfate sodium (DSS)-induced acute colitis mouse model. The GPR4 antagonist 13 inhibited intestinal inflammation. All colitis parameters, such as body weight loss, fecal score, colon shortening, splenic expansion, and mesenteric lymph node enlargement, were reduced in the GPR4 antagonist 13 treatment group compared to the vehicle group. Histopathological features of active colitis and inflammatory gene expression of colon tissues were reduced in the GPR4 antagonist 13 treatment group compared to vehicle control. Our results indicate that the GPR4 antagonist 13 provides a protective effect in the DSS-induced colitis mouse model and inhibition of GPR4 can be explored as a novel anti-inflammatory approach.
Citation Format: Edward J. Sanderlin, Mona Marie, Juraj Velcicky, Pius Loetscher, Li V. Yang. Inhibition of GPR4 attenuates intestinal inflammation in a mouse colitis model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1206.
Abstract 1207: Reversing lactate-driven immunosuppression using the novel, potent and selective MCT4 inhibitor AZD0095
Authors: Critchlow Susan E. , Hughes Gareth , Staniszewska Anna , King Matt , Michopoulos Filippos , Hopcroft Lorna , Brown Martin R. , Bradley Jenna , Hammond Beverley , MorentinGutierrez Pablo , Carnevalli Larissa , Hardaker Elizabeth , Goldberg Frederick W. 
Published: August 2019

Abstract
Metabolic adaptation to a Warburg phenotype is a hallmark of cancer, where tumors rely on glucose to produce ATP and building blocks required to support rapid tumor growth. Glycolytic metabolism requires continuous export of lactate from cells by monocarboxylate transporters (MCTs) resulting in accumulation of lactic acid in the tumor microenvironment. Tumor-derived lactate is immune-suppressive and has been shown to modify immune cell function. Inhibition of the MCT4 lactate transporter has the potential to reduce lactate in the tumor microenvironment and reverse immune suppression. AZD0095 is a highly selective, potent inhibitor of MCT4 with a cellular activity of 1-3 nM with a &gt;1000-fold selectivity over MCT1. We confirm that lactic acid inhibits T cell proliferation and viability. AZD0095 does not inhibit T cell proliferation or survival (IC50 &gt; 10 μM). Oral administration of AZD0095 (10-100 mg/kg BID) modulates lactate transport in mouse syngeneic models which do not express the MCT1 lactate transporter. AZD0095 treatment causes an increase in tumor-infiltrating lymphocytes and an increase in cytotoxic T cells in combination with α-PD1. AZD0095 treatment suppresses myeloid infiltration as a monotherapy and in combination with checkpoint inhibitor. Consistent with the observed changes in immune cell infiltration, the combination of AZD0095 with checkpoint inhibitors α-PD1 or α-CTLA4 (10 mg/kg 3x week) enhances the anti-tumor activity of checkpoint inhibitor monotherapy in MC-38 and EMT6 (MCT1 knock-out) mouse syngeneic models. These data demonstrate that AZD0095 can reverse lactate-driven immunosuppression and enhance response to checkpoint inhibition in pre-clinical models.
Citation Format: Susan E. Critchlow, Gareth Hughes, Anna Staniszewska, Matt King, Filippos Michopoulos, Lorna Hopcroft, Martin R. Brown, Jenna Bradley, Beverley Hammond, Pablo MorentinGutierrez, Larissa Carnevalli, Elizabeth Hardaker, Frederick W. Goldberg. Reversing lactate-driven immunosuppression using the novel, potent and selective MCT4 inhibitor AZD0095 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1207.