bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1100: Genetic driver-mutations define composition and properties of tumor-associated myeloid cells in glioblastoma
Authors: Chen Zhihong , Hurting Cameron J. , Gabanic Ben , Murukuti Jyothi , Hambardzumyan Dolores 
Published: August 2019

Abstract
The GBM microenvironment is composed of numerous non-neoplastic cells, among which tumor-associated myeloid cells (TAMs) are the most abundant. TAMs are constituted of several different cell types, including brain microglia and bone-marrow-derived infiltrating cells, which can be further divided into inflammatory monocytes, monocyte-derived macrophages, and polymorphnuclear neutrophils. These myeloid cells are believed to promote tumor growth and immune evasion by expressing immune checkpoint proteins. Remarkable progress has been made in treating lung cancer and melanoma by using immune-checkpoint inhibitors; however, mixed results were obtained for its application in GBM. To examine how molecular-subtypes of GBM influence the composition and immunosuppression of tumor-associated myeloid cells, we used the RCAS_tv-a system, a somatic cell-specific gene transfer system, to generate de novo murine GBM (mGBM). By manipulating different known human oncogenic-driver mutations such as overexpressing PDGFB or EGFRVIII, or silencing NF1, we generated Proneural (PN), Classical (CL) and Mesenchymal (MES) GBMs respectively, which phenotypically resemble their human counterparts. We found that the majority (80%) of tumor-infiltrating myeloid cells in PN GBM are bone-marrow derived macrophages, whereas this number is significantly less in CL and MES mGBM. Interestingly, unique to MES, there is a significant presence (16%) of neutrophils in these tumors than in other subtypes (4%). Further characterization for subtype-specific expression of PD-L1, a druggable immune checkpoint molecule, by flow cytometry shows that MES has the highest expression of PD-L1), whereas the expression is lower in PN and CL subtypes. Treating GBM-bearing mice with anti-PDL1 antibodies did not prolong their survival. Concurrent treatment of irradiation and anti-PDL1 antibody did not confer significant survival advantage either compared to controls. These results reflect the unsuccessful trails of recent human clinical studies; however, it also emphasizes the importance of understanding the mechanism of resistance in GBM immunotherapy before effective immune treatment can be established. Our immunocompetent mouse models provide indispensable tools for these studies.
Note: This abstract was not presented at the meeting.
Citation Format: Zhihong Chen, Cameron J. Hurting, Ben Gabanic, Jyothi Murukuti, Dolores Hambardzumyan. Genetic driver-mutations define composition and properties of tumor-associated myeloid cells in glioblastoma [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 1100.
Abstract 1106: Co-administration of the iRGD tumor-penetrating peptide improves the tumor immunostimulatory effects of low-dose IL-2
Authors: Jarvelainen Harri , Botta Gregory P. , Mendoza Tatiana Hurtado De , Ruoslahti Erkki 
Published: August 2019

Abstract
Background: Recombinant IL-2 at high doses is an effective immunotherapy treatment for various types of solid tumors. However, its clinical utility has been limited by serious mechanism-based side-effects. The clinical-stage iRGD peptide specifically targets tumors and, via activation of the ‘CendR’ trans-tissue transport pathway, increases tumor penetration and accumulation of various types of co-administered drugs. By selectively increasing the drug delivery into tumors, but not to normal tissues, iRGD potentiates the pharmacological activity of various anti-cancer agents within tumor tissue, while reducing their toxicities. In this study we investigate whether co-administration of iRGD with low-dose IL-2 can improve the tumor immune microenvironment by increasing in the ratios of tumor-killing effector CD8 cells vs. the immunosuppressive T-regulatory cells.
Methods: Subcutaneous breast tumors (4T1) were generated in immunocompetent mice. Mice were treated with either vehicle control, iRGD, IL-2, or IL-2 + iRGD for 5 days. Tumors were preserved for immunohistochemistry (IHC) or enzymatically digested for fluorescence activated cell sorting (FACS) 16 hours after the last dosing. The FACS and IHC panels were designed to detect the percentage of total T cells, CD4 and CD8 T cells, and Treg cells.
Results: Low doses of IL-2 alone were found to increase Tregs within the tumor but had no effect in CD4 or CD8 effector T cells, compared to vehicle treatment. However, when Low dose IL-2 was co-administered with iRGD, we observed a significantly lower percentage of T regs and an increase in CD4 effector T cells. More importantly the ratio of CD8 / Treg cells was increased by at least 10-fold, compared to low dose IL-2 alone.
Conclusions: The combination treatment with iRGD and low doses of IL-2 is capable of favorably altering the tumor immune microenvironment such that immunosuppressive T reg cells were reduced, while there was an increase in the effector CD4 and CD8 T-cell populations. The tumor-selective IL-2 pharmacology benefit obtained with iRGD co-administration may provide new options for the use of the well-validated IL-2 in solid tumor patients, including a strategy to overcome the primary resistance to PD-1 blockade.
Citation Format: Harri Jarvelainen, Gregory P. Botta, Tatiana Hurtado De Mendoza, Erkki Ruoslahti. Co-administration of the iRGD tumor-penetrating peptide improves the tumor immunostimulatory effects of low-dose IL-2 [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 1106.
Abstract 113: c-Kit-dependent tissue resident macrophage progenitors drive cancer progression
Authors: Pathria Paulina , Takahashi Hideyuki , Kaneda Megan , Pu Minya , Messer Karen , Shepard Ryan M. , Louis Tiani L. , Shih Ann , Bertagnolli Mark , Wrasidlo Wolfgang , Cheresh David A. , Varner Judith A. 
Published: August 2019

Abstract
Macrophages play a key role in promoting tumor growth and resistance to therapy. Here we show that Tissue Resident Macrophages (TRM) as well as Bone Marrow-Derived Macrophages (BMDM) play critical but unique roles in promoting tumor growth. TRM were recently shown to originate in the yolk sac or fetal liver during embryogenesis; these cells self-maintain in post-natal tissues independent of hematopoietic stem cells. We found that BMDM are CD11b+Gr1+F4/80loCX3CR1loCCR2+and are recruited to tumors in a CCR2-dependent manner. In contrast, CD11b+Gr1-F4/80hiCX3CR1hiCCR2- TRMs accumulate in tumors independently of the trafficking receptor CCR2. Gene expression and functional studies indicate that tumor-derived TRM are highly proliferative, immune suppressive and distinct from BMDM. We show that TRM develop from c-Kit/c-KitL - dependent TRM progenitors that are abundant in tumors but not in normal tissues; purified progenitors form macrophages and potently stimulate tumor growth when adoptively transferred into mice. Tumor cells induce the expansion of TRM progenitors by secreting Stem Cell Factor (SCF/c-KitL). Notably, in vitro and in vivo proliferation of TRM progenitors and tumor growth are significantly inhibited by SCF and c-Kit inhibitors, including a novel, allosteric dual inhibitor of cKit and CDK8/19 that dramatically suppresses tumor growth by targeting both TRM and tumor cells. As cKit inhibitors synergize with other immune therapy regimens to suppress tumor growth, our studies identify cKit as a valuable target for immune therapy of solid tumors.
Citation Format: Paulina Pathria, Hideyuki Takahashi, Megan Kaneda, Minya Pu, Karen Messer, Ryan M. Shepard, Tiani L. Louis, Ann Shih, Mark Bertagnolli, Wolfgang Wrasidlo, David A. Cheresh, Judith A. Varner. c-Kit-dependent tissue resident macrophage progenitors drive cancer progression [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 113.
Abstract 1146: [18F]FPyGal: A novel ß-galactosidase specific PET tracer for in vivo imaging of tumor senescence
Authors: Krueger Marcel A. , Cotton Jonathan M. , Zhou Benyuan , Wolter Katharina , Schwenck Johannes , Kuehn Anna , Fuchs Kerstin , Maurer Andreas , Fougere Christian La , Zender Lars , Pichler Bernd J. 
Published: August 2019

Abstract
Senescence influences treatment outcome in cancer. Therefore it is of great interest to develop a diagnostic tool to detect senescent cells in cancer patients. Here we describe the evaluation of the PET tracer FPyGal for non-invasive imaging of ß-galactosidase as a surrogate marker for senescence. In vitro, we induced senescence in HCT116 cells by doxorubicin, in a liver progenitor cell line by p53-reactivation and in two liver carcinoma cell lines by a ribosomal checkpoint inhibitor (RCI). The cells were then incubated with FPyGal and tracer uptake was determined in a gamma-counter. For in vivo testing, the described cell lines were injected s.c. in mice. The tumor bearing mice were then treated appropriately to induce senescence. PET/MR scans were performed after i.v. injection of FPyGal for assessment of tracer uptake in the tumors. Ex vivo autoradiographies and X-Gal stainings were prepared to correlate intratumoral distribution of ⇓-galactosidase activity and tracer uptake. After toxicology studies, a pilot first-in-man study was performed in a cancer patient treated with Alisertib. Compared to the respective control cells, in vitro tracer uptake was significantly increased in all four cellular models tested. The strongest increase was observed in one of the liver carcinoma cell lines with a &gt;3-fold increase in senescent cells. FPyGal tracer uptake increased in control HCT116 tumors from 1.1 to 1.7%ID/cc in senescent cells in in vivo PET/MRI studies and in the HRas model from 0.9 to 1.5 %ID/cc. In one of the liver tumor models we could observe a 2-fold increase in treated mice. Ex vivo ⇓-galactosidase staining and IHC of tumor tissue confirmed induction of senescence. Autoradiography and X-Gal staining showed an intratumoral correlation of ⇓-gal activity and FPyGal uptake. The compound passed the toxicology tests. A first patient study revealed high and heterogeneous tracer uptake in a liver metastasis. FPyGal shows increased in vitro and in vivo uptake in senescent cells and tumors. No toxicity of the compound could be detected and a first-in-man study showed promising results. Clinical trials including histological cross-validation are currently being prepared.
Citation Format: Marcel A. Krueger, Jonathan M. Cotton, Benyuan Zhou, Katharina Wolter, Johannes Schwenck, Anna Kuehn, Kerstin Fuchs, Andreas Maurer, Christian La Fougere, Lars Zender, Bernd J. Pichler. [18F]FPyGal: A novel ß-galactosidase specific PET tracer for in vivo imaging of tumor senescence [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 1146.
Abstract 1147: A phage display identified peptide selectively binds to kidney injury molecule-1(KIM-1) and detects KIM-1-overexpressing tumors in vivo
Authors: Yoon Jae-Won , Lee Soo-woong , Haque Md. Enamul , Park Rang- Woon , Baek Moon-Chang , Kim Dong-Kyu , Kim Sang Kyoon , Lee Byungheon 
Published: August 2019

Abstract
Kidney injury molecule-1 (KIM-1), also known as hepatitis A virus cellular receptor-1 and T cell Ig mucin-1, is a transmembrane protein, which is not overexpressed in normal kidneys, but is significantly upregulated in damaged kidney tubular epithelial cells in toxic and ischemic acute kidney injury. Of interest, KIM-1 is overexpressed in most cases of renal cell carcinoma (RCC) and in other types of tumors including ovarian clear cell carcinoma and lung cancer. The extracellular domain of KIM-1 can be identified in the urine of patients with RCC and can thus be used as a biomarker for the detection of RCC. This study was carried out to identify a peptide that selectively binds to KIM-1 by screening a phage-displayed peptide library and to use the peptide for the detection of KIM-1-overexpressing tumors in vivo. Biopanning of a phage-displayed peptide library was performed on KIM-1-coated plates. Compared to other phage clones selected after biopanning, a phage clone displaying the CNWMINKEC peptide showed higher binding affinity to KIM-1 as examined by fluorometry and KIM-1-overexpressing 769-P renal tumor cells 1 as examined by ELISA. The CNWMINKEC peptide and a NeutrAvidin/biotin-CNWMINKEC multimer selectively bound to KIM-1 over albumin as examined by fluorometry and to KIM-1-overexpressing 769-P cells and A549 lung tumor cells compared to KIM-1-low expressing HEK293 normal cells when examined by flow cytometry. Co-localization and competition assays using an anti-KIM-1 antibody demonstrated that the binding of the CNWMINKEC peptide to 769-P cells was specifically mediated by KIM-1. Whole-body fluorescence imaging demonstrated selective homing of the CNWMINKEC peptide to KIM-1-overexpressing A498 renal tumor compared to KIM-1-low expressing HepG2 liver tumor in mice. The CNWMINKEC peptide was not cytotoxic to cells and was stable for up to 24 h in the presence of serum. These results suggest that the CNWMINKEC peptide is a promising probe for in vivo imaging and detection of KIM-1-overexpressing tumors.
Keywords In vivo imaging, kidney injury molecule-1, peptide, phage display, renal cell carcinoma
Note: This abstract was not presented at the meeting.
Citation Format: Jae-Won Yoon, Soo-woong Lee, Md. Enamul Haque, Rang- Woon Park, Moon-Chang Baek, Dong-Kyu Kim, Sang Kyoon Kim, Byungheon Lee. A phage display identified peptide selectively binds to kidney injury molecule-1(KIM-1) and detects KIM-1-overexpressing tumors in vivo [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 1147.
Abstract 1154: DCLK1 monoclonal antibody-based CAR-T cells as novel treatment strategy against multiple myeloma
Authors: Sureban Sripathi M. , Berahovich Robert , Zhou Hua , Xu Shirley , Wu Lijun , Golubovskaya Vita , Qu Dongfeng , May Randal , Bannerman-Menson Edwin , Houchen Courtney W. 
Published: August 2019

Abstract
Multiple Myeloma (MM) is characterized by the clonal expansion of malignant plasma cells in the bone marrow, and is the second most common hematological cancer. Cellular therapies including chimeric antigen T receptor cell (CAR-T) have emerged as a promising therapeutic strategy to combat this devastating disease. MM are derived from a rare population of cancer stem cells (CSC) that are responsible for initiation, progression, resistance to conventional therapy and recurrence. To date there have been no CAR-T therapies directed at CSC-specific antigens. In this report, we describe the effects of a novel CAR-T targeting the CSC marker DCLK1 on MM cells. Using mouse models, it has been demonstrated that DCLK1 marks the cell of origin of colon and pancreatic cancers. DCLK1 regulates epithelial to mesenchymal transition (EMT), and its upregulation is associated with poor overall survival in many cancer subtypes. Inhibition of DCLK1 activity following RNA silencing resulted in tumor xenograft growth arrest. These features lead us to explore the therapeutic potential of targeting DCLK1+ cells in MM. In order to create a novel DCLK1 CAR, we generated a new humanized DCLK1 monoclonal antibody, clone CBT-15 #8. This antibody recognizes a small extra cellular C-terminal epitope on human isoform 2 and 4 of DCLK1. Novel DCLK1 CAR-T cells containing the clone were generated and detected with anti-human FAB antibody by flow cytometry. Furthermore, we observed cell surface expression of DCLK1 on &gt;93 percent of MM Cells (RPMI8226) by flow cytometry. The CAR-T cells had significantly higher cytotoxicity in MM (RPMI8226 and MM1S) cells than in leukemia K562 cells. The CAR-T cells secreted significantly higher levels of IFN-γ in vitro than T cells (p=0.0036). Further studies are underway to determine its efficacy in inhibiting tumor xenografts in vivo. This report is the first to link the TSC marker DCLK1 to MM and may represent a novel therapeutic strategy for MM and other hematologic malignancies.
Citation Format: Sripathi M. Sureban, Robert Berahovich, Hua Zhou, Shirley Xu, Lijun Wu, Vita Golubovskaya, Dongfeng Qu, Randal May, Edwin Bannerman-Menson, Courtney W. Houchen. DCLK1 monoclonal antibody-based CAR-T cells as novel treatment strategy against multiple myeloma [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 1154.
Abstract 1156: Skeletal muscle progenitor cell-derived exosomes have therapeutic potential in inhibition of prostate cancer cell proliferation
Authors: Sinha Krishna M. , Yarmand Rozita , Kahraman Nermin , Duzagac Fahriye , Lopez Gabriel , Ozpolat Bulent , Huard Johnny 
Published: August 2019

Abstract
Adult stem cells have been used as regenerative medicine for treating human diseases through gene therapy approach. These stem cells secrete cytokines, growth factors and extracellular vesicles including exosomes, which may induce antitumor activities. We have demonstrated that muscle progenitor cells (MPCs) from adult (murine and human) skeletal muscle have a high regenerative potential to repair bone, skeletal muscle, and cartilage. However, to date, the potential therapeutic use of MPCs in cancers has not yet been investigated. The objectives of this study were to identify and examine the roles of secreted factors including exosomes from MPCs on the proliferation/survival, motility/migration and invasive potential of prostate cancer (PCa) cells. Here we showed that co-culture of PCa cell lines, PC3 and C42B, with MPCs in trans-well inserts strongly suppressed PCa cell proliferation and survival by activating CDK inhibitors (p16 and p27) and apoptotic BBC3 and NOXA genes. Mass spectrometry analysis of factors secreted by MPCs identified several proteins with known anti-proliferative functions, including IGFBP6/7, pigment epithelium-derived factor (PEDF), HPCAL1, NO, and SPARC. Conditioned media (CM) from MPCs significantly increased docetaxel-induced cytotoxicity of PCa cells by suppressing the expression of key genes including AR, MLL, FOXA1, TWF1, and TGIF. Next, we isolated exosomes from cultured mouse and human MPCs through step-wise ultracentrifugation methods and tested their effect in the proliferation of cancer cells. We observed that treatment of PCa cells with MPC-derived exosomes inhibited cell proliferation as assayed with MTT and down-regulated the expression of AR and its target NKX3.1 genes. We also observed that the migration ability of ovarian cancer cells (OVAC5) and pancreatic cancer (Panc1), was markedly reduced following MPC-derived exosome treatments compared to untreated cells. Taken together, our data suggest that MPCs can suppress the proliferation and survival of cancer cells through secreted factors including exosomes. Thus, adult stem cell-based therapy along with existing therapies may be a promising strategy in treating various solid cancers as well as regenerating cancer-induced bone and muscle tissue lesions.
Citation Format: Krishna M. Sinha, Rozita Yarmand, Nermin Kahraman, Fahriye Duzagac, Gabriel Lopez, Bulent Ozpolat, Johnny Huard. Skeletal muscle progenitor cell-derived exosomes have therapeutic potential in inhibition of prostate cancer cell proliferation [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 1156.
Abstract 1166: TDO2 overexpression is associated with cancer stem cells and poor prognosis in esophageal squamous cell carcinoma
Authors: Pham Thang Quoc , Oue Naohide , Sekino Yohei , Yamamoto Yuji , Sakamoto Naoya , Honma Ririno , Sentani Kazuhiro , Yasui Wataru 
Published: August 2019

Abstract
Objective: Esophageal cancer is one of the deadliest cancers in the world, and the main subtype is esophageal squamous cell carcinoma (ESCC), which comprises 90% of cases. We previously analyzed the gene expression profile of spheroid colonies and parental cells derived from gastric cancer (GC) cell lines by microarray analysis. Among the genes upregulated in spheroid colonies, tryptophan 2,3-dioxygenase (TDO2) is dramatically upregulated in MKN-1 cells (derived from adenosquamous cell carcinoma) compared with other GC cell lines. Expression of TDO2, an enzyme involved in tryptophan catabolism, has been linked with tumor survival and poor prognosis of brain and breast cancer. However, no studies have investigated the potential role of TDO2 in esophageal cancer. Here we explored the expression and biological significance of TDO2 in ESCC.
Methods: To explore the expression of TDO2 in cancer and normal samples, we used an online analytical tool, the Broad Institute TCGA Genome Data Analysis Center, http://firebrowse.org/. For quantitative reverse transcription-polymerase chain reaction (qRT-PCR), we used 10 ESCC samples (tumor tissues and the corresponding non-neoplastic tissue). TDO2 protein expression was evaluated in 90 ESCC tissue samples by immunohistochemistry. TDO2 function in ESCC cell lines and spheroid colony formation was evaluated by RNA interference (RNAi). Cell growth was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Modified Boyden chamber assays were performed to examine cell invasiveness.
Results: TDO2 expression was upregulated in most cancers except for liver cancer and pancreas cancer. The fold change expression of TDO2 between normal and cancer tissue was the highest in esophageal cancer. TDO2 overexpression was associated with tumor stage, recurrence status and the CD44 cancer stem cell marker in ESCC. TDO2 overexpression was correlated with poor outcome of ESCC patients. Inhibition of TDO2 expression by RNAi in TE-10 and TE-11 cell lines reduced both the number and the size of spheroid colonies as well as cell proliferation and invasive activity. Knockdown of TDO2 expression also induced inactivation of the EGFR signaling pathway.
Conclusion: Our results imply that TDO2 could play an important role in the progression of ESCC. Furthermore, TDO2 may be a potential therapeutic target in ESCC.
Citation Format: Thang Quoc Pham, Naohide Oue, Yohei Sekino, Yuji Yamamoto, Naoya Sakamoto, Ririno Honma, Kazuhiro Sentani, Wataru Yasui. TDO2 overexpression is associated with cancer stem cells and poor prognosis in esophageal squamous cell carcinoma [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 1166.