bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1150: Targeted immunoPET imaging of prostate cancer using a novel CD133 antibody
Authors: Glumac Paige , LeBeau Aaron 
Published: August 2019

Abstract
Prostate cancer is one of the most frequently diagnosed malignancies and the second leading cause of cancer related death among American men. Aggressive variant prostate cancer (AVPC) accounts for approximately 33% of all prostate cancer-related deaths and is characterized by visceral metastasis, minimal responses to current therapies, and poor overall prognosis. The current disease monitoring strategy for AVPC is positron emission tomography - computed tomography (PET/CT) with [18F]-fluorodeoxyglucose (FDG), which is not specific to prostate cancer cells and thus is inadequate in many cases. As such, novel targeted imaging agents are urgently needed for earlier detection and better monitoring of AVPC. The transmembrane glycoprotein, CD133, is overexpressed in AVPC and we have identified a single chain variable fragment, termed HA10, which preferentially recognizes a glycosylation-independent epitope on CD133. Further characterization of HA10 revealed that it was able to identify CD133 in cells, patient tissue samples, and in vivo xenograft models using fluorescent imaging. The purpose of this study was to investigate the performance of the radioimmunoconjugate, 89Zr-HA10, for µPET/CT imaging in preclinical models of prostate cancer. HA10 was conjugated to p-SCN-Deferoxamine (DFO) and then radiolabeled with [89Zr]Zr-oxalate at room temperature. Parental (CWR-R1) and CD133-transduced (CWR-R1CD133) prostate cancer cell lines were implanted subcutaneously into male athymic nu/nu mice. Mice were administered 180 µCi of 89Zr-HA10 via tail vein injection and µPET/CT imaging was conducted at 24, 48, 72, and 144 hours post-injection. The 89Zr-HA10 construct was successfully labeled with a radiochemical purity &gt;99% as determined by radio-thin layer chromatography. Specificity of 89Zr-HA10 was demonstrated for CD133-positive tumors with strong tumoral uptake detection from 24-72 hours. Furthermore, the margins of the CD133-positive tumors were clearly defined following 3D reconstruction of the µPET/CT images. These studies suggest that 89Zr-HA10 is a promising immunoPET imaging agent for AVPC and potentially other CD133-positive cancer subtypes. Moreover, the use of 89Zr-HA10 as a radiotracer will facilitate a more selective strategy for diagnosis and disease monitoring of these patients compared to the conventional FDG radiotracer. Further studies seek to evaluate the potential of 89Zr-HA10 to detect small metastatic lesions in vivo.
Citation Format: Paige Glumac, Aaron LeBeau. Targeted immunoPET imaging of prostate cancer using a novel CD133 antibody [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 1150.
Abstract 1152: Disulfiram targets both proliferating cancer cells and cancer stem-like population in ER-positive breast cancer
Authors: Jang Seojin , Oh Eunhye , Kim Yoon-Jae , Cho Tae-Min , Park Jung Min , Park Soeun , Park Minsu , Seo Jae Hong , Kim Ji Young 
Published: August 2019

Abstract
Drug repositioning can benefit from reduced development risk in terms of safety, toxicity and dosage, as it centers upon drugs that have already been tested in clinical trials. Disulfiram (DSF), a drug for the treatment of alcoholism, has potential anti-cancer activities in a copper (Cu)-dependent manner. In the present study, we investigated the effect of DSF on cell viability, apoptosis, breast cancer stem cells (BCSC)-like properties and p53 activation in ER-positive breast cancer MCF7 and T47D cells. DSF treatment caused a significant suppression of cell viability and marked induction of cell death in a Cu-dependent manner. This response was accompanied by caspase-3/-7 and p53 activation in ER-positive breast cancer cells. The latter phenomenon was associated with G1 phase arrest, coinciding with a significant increase in accumulation of nuclear p21 and downregulation of cyclin D1 and survivin. DSF treatment elicits a significant inhibitory effect on these BCSC-like properties including ALDH1 activity and CD44+/CD24- subpopulations. To examine the effect of DSF on mammosphere-forming ability, MCF7 and T47D cells were cultured in anchorage-independent serum-free culture conditions in the presence or absence of DSF and Cu. DSF considerably suppressed mammosphere formation, as evidenced by significant reduction in the number and volume of mammospheres. Our results demonstrate that DSF induces apoptosis and effectively targets cancer stem-like population, suggesting that disulfiram may be potentially effective for the treatment of ER-positive cancer.
Citation Format: Seojin Jang, Eunhye Oh, Yoon-Jae Kim, Tae-Min Cho, Jung Min Park, Soeun Park, Minsu Park, Jae Hong Seo, Ji Young Kim. Disulfiram targets both proliferating cancer cells and cancer stem-like population in ER-positive breast 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 1152.
Abstract 1153: Hypoxic microenvironments promote stemness and enhance the directed migration of glioma stem cells
Authors: Sharma Nitya V. , Chau Monica , Mukherjee Subhas , Ross James , Miller Brandon , Zhang Changming , Kong Jun , Tucker-Burden Carol , Kaissi Emily , Reitnauer John W. , Dundar Bilge , Olson Cheryl L. , Bix Gregory , Brat Daniel J. 
Published: August 2019

Abstract
Glioblastoma (GBM) is a highly malignant primary brain tumor and has a poor prognosis and is resistant to the most advanced therapies. The development of highly hypoxic centrally located necrotic regions is strongly associated with accelerated GBM progression, yet mechanistic explanations are not complete. Hypoxic regions within GBM are highly enriched for glioma stem cells (GSC), which are critical for tumor initiation, recurrence and therapeutic resistance due to their self-renewing capabilites. While most GBM cells migrate outward, away from hypoxia, GSCs accumulate there, forming a hypercellular border called pseudopalisades that promote their survival. Mechanisms that mediate GSC accumulation within pseudopalisades are unknown. We hypothesize that GSCs are enriched in the pseudopalisades due to the homing of a subpopulation towards the supportive hypoxic microenvironment. This in turn activates critical hypoxia-induced drivers to promote stemness, survival and migratory behavior encouraging the recruitment of more GSCs. Using two genetically distinct patient-derived GBM cell lines, we found that exposure to hypoxia in vitro led to enrichment of GSCs among a heterogeneous population of GSCs and non-GSCs. We found that hypoxia enhanced the expression of stem cell, pro-survival and pro-migratory factors in GSCs, such as the pro-migratory chemokine SDF-1α, and its cognate receptor CXCR4. Importantly, we found hypoxia also induced upregulation of OLIG2, one of four core transcription factors necessary and sufficient to induce stemness, in GSCs and non-GSCs exposed to hypoxia. We determined that OLIG2 was necessary for the expression of stem cell markers, and that its knockdown reduced cellular migration in hypoxia vs normoxia in GSCs. This suggests a critical role for OLIG2 in both hypoxia-induced stemness and homing behavior. We also generated a unique model of localized hypoxia in one brain hemisphere through vaso-cclusion and observed the homing of xenografted GBM cells towards hypoxia, regulated by OLIG2 in vivo. These data shed light on how hypoxic tumor microenvironments facilitate mechanisms vital to GBM progression and therapeutic resistance.
Citation Format: Nitya V. Sharma, Monica Chau, Subhas Mukherjee, James Ross, Brandon Miller, Changming Zhang, Jun Kong, Carol Tucker-Burden, Emily Kaissi, John W. Reitnauer, Bilge Dundar, Cheryl L. Olson, Gregory Bix, Daniel J. Brat. Hypoxic microenvironments promote stemness and enhance the directed migration of glioma stem 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 1153.
Abstract 1157: Single-cell transcriptmoics identifies rhamm positive proliferative cells within human colorectal cancer stem cells
Authors: Nakano Michitaka , Yoshikane Kikushige , Miyawaki Kohta , Mizuno Shinichi , Yamaguchi Kyoko , Yamauchi Takuji , Ariyama Hiroshi , Kusaba Hitoshi , Nakamura Masafumi , Maeda Takahiro , Baba Eishi , Akashi Koichi 
Published: August 2019

Abstract
Cancer stem cells (CSCs) can be prospectively isolated based on specific surface marker such as CD44, CD133, LGR5, and CD166, in human colorectal cancer. However, the employment of these CSCs' markers are still insufficient to prospectively isolate the colorectal CSCs. To overcome the cellular heterogeneity of previously reported CSCs fraction, we performed single-cell mRNA sequencing (scRNAseq) of 72 cells within organoid. By conducting scRNAseq, we identified CSCs-like sub-population with high expression of MKI67 and Cyclin families, which was generally expressed in proliferative state of the cells within the organoid. Remarkably, high expression of hyaluronan-mediated motility receptor (HMMR) encoding cell membranous and cytoplasmic molecule, receptor for hyaluronan mediated motility (RHAMM), which was reported to associate with CD44 in hyaluronan binding, was observed in the CSCs-like cells. Prospective isolation of RHAMM+ CD44+ cells, that were sub-population of conventional CSCs fraction, revealed higher organoid- and tumor-forming abilities. Furthermore, comprehensive gene expression analysis also demonstrated the proliferative gene expression within RHAMM+ CD44+ cells. Here, we report RHAMM+ proliferative cells that sub-fraction the conventional CSCs population. &lt;!–EndFragment–&gt;
Citation Format: Michitaka Nakano, Kikushige Yoshikane, Kohta Miyawaki, Shinichi Mizuno, Kyoko Yamaguchi, Takuji Yamauchi, Hiroshi Ariyama, Hitoshi Kusaba, Masafumi Nakamura, Takahiro Maeda, Eishi Baba, Koichi Akashi. Single-cell transcriptmoics identifies rhamm positive proliferative cells within human colorectal cancer stem 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 1157.
Abstract 1158: Seven genes were closely associated with ALDH1 in triple negative breast cancer
Authors: Ishikawa Takashi , Narui Kazutaka , Yamada Akimitsu , Kida Kumiko , Shima Hidetaka , Endo Chiho , Adachi Shoko , Sugae Sadatoshi , Miyagi Yohei , Ichikawa Yasushi , Endo Itaru 
Published: August 2019

Abstract
Background: Aldehyde dehydrogenase1 (ALDH1) is widely accepted as a marker of normal and malignant breast stem cells. We reported that ALDH1 expression was associated with aggressive phenotypes and poor clinical outcome of breast cancer patients. However, mechanics of how ALDH1 affects cancer stem cell features is not known.
Aim: To examine genes associated with ALDH1 and find novel druggable targets for the future cancer stem cell therapy.
Methods: ALDH1-positive and ALDH1-negative cells were dissected by a laser capture microdissection from 5 ALDH1 positive triple negative breast cancer samples. A differential analysis of mRNA expression was performed between ALDH1 positive and negative breast cancer cells in each sample by Affymetrix GeneChip microarrays. 1) Microarray analysis suite (MAS5) and robust multi-chip average (RMA) were used as preprocessing algorithms to analyze gene expression data and to extract genes differently expressed between ALDH1 positive and negative cells. 2) The network analysis was performed with extracted genes with MAS5 by the comprehensive information platform “KeyMolnetTM”.
Results: 1) 54,682 genes were extracted and 32,264 genes were selected after eliminating background noise. One hundred and four genes: 63 up-regulated and 41 down-regulated, were extracted in ALDH1-positive cells by MAS5, while only 2 up-regulated genes by RMA. H19 was a gene that was commonly extracted by both algorithms. 2) The network with 104 genes was constructed and BRD4, SMAD4, Pitx3, RARa, MUC1, HASH1 and C/EBPb were identified as genes with the closest distance to ALDH1.
Conclusions: Most of extracted 7 genes have been already known to exert critical roles for maintaining stem cell features, providing a rationale of ALDH1 for the stem cell marker of breast cancer. These genes including H19 could be targets of the cancer stem cell therapy for treating incurable breast cancer.
Citation Format: Takashi Ishikawa, Kazutaka Narui, Akimitsu Yamada, Kumiko Kida, Hidetaka Shima, Chiho Endo, Shoko Adachi, Sadatoshi Sugae, Yohei Miyagi, Yasushi Ichikawa, Itaru Endo. Seven genes were closely associated with ALDH1 in triple negative breast 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 1158.
Abstract 1161: Utility of evidence based mesenchymal gene signatures gene expression panel in predicting outcome in stage matched colorectal cancer patients
Authors: Johnson Benjamin , Ahluwalia Pankaj , Pundkar Chetan , Heneidi Saleh , Jones Kimya , Mondal Ashis , Kolhe Ravindra 
Published: August 2019

Abstract
Colorectal cancer (CRC) is third deadliest cancer in United States, only behind lung and prostate cancer. Although several therapies are available to treat colorectal cancer but there is need for new prognostic biomarkers to tailor appropriate personalized therapy. Mesenchymal Stem cells (MSCs) are multipotent stem cells which are attracted toward inflammatory sites. In colon cancer, they have been shown to assist in tumor progression. To assess the MSC gene signatures in colon cancer patients, we picked 5 genes from nCounter plexset Mesenchymal Stem cell panel. These genes named: SMAD4, PTK2, GTF3A, CASP3 and HDAC1 were quantified on Nanostring platform. The aim of the study is to quantify these Mesenchymal gene signatures in colorectal cancer patients. Under the IRB approved protocol, a total of 750 colon cancer patients at Medical College of Georgia with 5 years follow-up were initially selected. The patients were stratified on the basis of overall survival in two groups, with higher (&gt; 5 years) and lower survival (&lt;1 year) along with AJCC staging (I to IV), grade, gender and age. A total of 88 patients fitted in our inclusion criteria on the basis of survival duration after diagnosis. The FFPE blocks were acquired from Medical College of Georgia, Augusta. Total RNA was isolated and quantified through Nanodrop method. The statistical analysis of data was performed using student t-test and Pearson correlation.
We found PTK2 levels to be high in stage I patients (p = 0.02*). Also, patients with higher survival in stage I had high expression of PTK2 (p=0.04*). Additionally, PTK2 was expressed in higher amounts in lower surviving patient group (0.00*). GTF3 levels were higher in (p = 0.01) stage I. CASP3 showed higher expression in stage III and IV combined. HDAC1 expression was higher in Grade II patients compared to Grade I. HDAC1 expression was also higher in African American population.
Citation Format: Benjamin Johnson, Pankaj Ahluwalia, Chetan Pundkar, Saleh Heneidi, Kimya Jones, Ashis Mondal, Ravindra Kolhe. Utility of evidence based mesenchymal gene signatures gene expression panel in predicting outcome in stage matched colorectal cancer patients [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 1161.
Abstract 1165: Differential expression of CD44 variants drive the progression, invasion, drug-resistance and stemness characteristics in human oral squamous cell carcinoma
Authors: Kashyap Tanushree , Nagini Siddavaram , Rana Ajay , Mishra Rajakishore 
Published: August 2019

Abstract
Purpose: Cluster of differentiation 44 (CD44) is a cell-surface glycoprotein and plays role in the progression and severity of oral squamous cell carcinoma (OSCC). Here we report differential function of CD44 variants in OSCC progression.
Materials and methods: The expression of CD44 standard (CD44s) and variants (CD44v4, CD44v6); the activation of signaling pathways (MAPK, PI3K); the cell viability; and the MMP-9/-2 activity were assessed using RT-PCR, immunohistochemistry, Western blotting, MTT assay and gelatin zymography. These experiments were carried out using fresh human OSCC tissue specimens, including adjacent normal, noninvasive (N0), invasive tumor samples (N1-3) and chemo-radiation resistant tumor samples (RCRT). We also used OSCC cell lines, including parental (SCC9/SCC4) and Cisplatin-resistant (CisR-SCC9/-SCC4) to confirm our observation with human tissues. Knock down of CD44 variants or inactivation of MAPK/PI3K pathways was achieved for in vitro analysis in OSCC cells.
Summary: Differential expressions of CD44 variants (v4and v6) were associated with overall oral cancer aggressiveness. CD44v4 expression was positively correlated with the activation of MAPK pathway causing chemoresistance. Conversely, CD44v6 expression and activation of PI3K-Akt caused invasiveness of OSCC. Finally, an overlapping role of two major signal transduction pathways such as MAPK and PI3K, that impinge on the variants/ isoforms expressions of a single gene i.e. CD44 that leads to the OSCC aggressiveness.
Conclusion: Collectively, these results established that CD44 variants (v4and v6) expression driven by MAPK/PI3K are associated with the overall progression, drug-resistance, invasion, and stemness characteristics leading to the aggressiveness of OSCC. Hence targeting these pathways may be exploited for treating OSCC.
Keywords: OSCC, CD44s, CD44v4/6, MAPK, PI3K, Notch, Chemoresistance, Invasion/migration, stemness, aggressiveness of OSCC.
Note: This abstract was not presented at the meeting.
Citation Format: Tanushree Kashyap, Siddavaram Nagini, Ajay Rana, Rajakishore Mishra. Differential expression of CD44 variants drive the progression, invasion, drug-resistance and stemness characteristics in human oral 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 1165.
Abstract 117: Pharmacological targeting of activated PSC decreases resistance to gemcitabine and increases survival in murine PDA
Authors: Turaga Ravi Chakra , Sharma Malvika , Mishra Falguni , Liu Zhi-Ren 
Published: August 2019

Abstract
Background: Pancreatic ductal adenocarcinoma (PDA) is the most lethal form of cancer owing to its insensitivity to many chemotherapeutic drugs. Gemcitabine remains a cornerstone of PDA treatment despite suboptimal efficacy in clinics. One major mechanism by which PDA becomes resistant to gemcitabine is its conversion to inactive derivative, dFdU by upregulation of the enzyme, cytidine deaminase (Cda) in cancer cells. Activated pancreatic stellate cells (PSC) are the major source of IGF1 in the tumor microenvironment, which may be responsible for an increase in Cda expression in cancer cells. We previously reported a rationally designed protein, ProAgio that targets integrin αVβ3 at a novel site. Here we demonstrate that ProAgio specifically induces apoptosis of integrin αVβ3-expressing activated PSC and therefore circumvents gemcitabine resistance in murine PDA models.
Objective: To test whether targeting activated PSC restores chemotherapeutic sensitivity in previously unresponsive PDA tumors in a murine model.
Methods: To study the effect of ProAgio and gemcitabine combination in PDA, we used two murine PDA models: a) KP orthotopic mouse model where KPC cells were orthotopically injected into the pancreas and, b) LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mouse model. Mice were treated with 20 doses of ProAgio (10mg/kg; i.p.) and 10 doses of gemcitabine twice weekly (50mg/kg; i.p.). IGF1 and Cda levels were analyzed by ELISA and immunohistochemistry. The intratumoral levels of the gemcitabine prodrug 2′,2′-difluorodeoxcytidine (dFdC) and the inactivated and activated metabolites (2′,2′-difluorodeoxyuridine (dFdU) and gemcitabine triphosphate (dFdCTP) respectively were determined by LCMS.
Results: Our data in murine PDA models clearly demonstrate that pharmacological targeting of activated PSC by ProAgio can stabilize PDA, and when combined with gemcitabine significantly increased the survival benefit by 3-fold (p&lt;0.001). Pharmacological targeting of activated PSC by ProAgio consequently decreases IGF1R signaling in cancer cells. As a result, there is a decrease in Cda expression leading to an increase in active metabolite, dfdCTP in the tumor, which contributes to the enhanced efficacy of gemcitabine. In conclusion, our findings for the first time demonstrate the mechanistic approach to target activated PSC, resulting in decreased Cda expression and enhanced gemcitabine delivery, thereby restoring chemotherapeutic sensitivity in murine PDA models.
Citation Format: Ravi Chakra Turaga, Malvika Sharma, Falguni Mishra, Zhi-Ren Liu. Pharmacological targeting of activated PSC decreases resistance to gemcitabine and increases survival in murine PDA [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 117.