bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 207: CML as a prototypical malignancy
Authors: Sonkin Dmitriy , Simon Richard 
Published: August 2018

Abstract
Chronic myelogenous leukemia (CML) was the first malignancy for which clinical outcome was drastically improved by kinase inhibitor therapy. Kinase inhibitors targeting other well-known oncogenes have been introduced into clinical practice, but none have shown the same magnitude of clinical benefit as ABL1 inhibition in CML. CML is sometimes described as an atypical malignancy or a one-hit malignancy. However careful examination of accumulation of additional oncogenic alterations in genes such as TP53, CDKN2A/B, IKZF1 and RUNX1 during CML progression from chronic phase to blast phase indicates that this is not the case. Instead CML provides a window into how many types of cancer may look and behave at an early stage, prior to diagnosis and the development of additional genomic alterations. The remarkable clinical benefits of ABL1 inhibition is likely due to early detection of CML at a stage in which the tumor is driven by single oncogenic alteration which can be successfully controlled by the inhibitor. The majority of CML patients in chronic phase of the disease treated with ABL1 inhibitor achieve a major molecular response (MMR) which corresponds to 1000 times decrease in BCR-ABL fusion levels. As a result, there is drastic reduction in number of cells which may accumulate additional alterations in genes like TP53, CDKN2A/B, IKZF1, RUNX1 leading to greatly decreased chance of progression to blast crisis. Thinking of CML as a prototype for effective systemic treatment based on early cancer detection may help to provide strategies for improving treatment for other types of cancer.
Citation Format: Dmitriy Sonkin, Richard Simon. CML as a prototypical malignancy [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 207.
Abstract 2075: Whole genome sequence analysis informs precision medicine of pediatric cancers
Authors: Tanasa Bogdan , Lee Alex , Breese Marcus , Shah Avanthi , Leung Stan , Liu Heng-Yi , Spillinger Aviv , Hazard Kimberly , Rangaswami Arun , Spunt Sheri , Lacayo Norm , Cooney Tabitha , Sweet-Cordero Eric Alejandro 
Published: August 2018

Abstract
Several recent studies (including BASIC3, iCAT, INFORM, PEDS-MIONCOSEQ) have used whole exome sequencing (WES) and RNA-seq in order to identify targetable chromosomal alterations in a large variety of pediatric cancers. Few studies have attempted to evaluate whether a more comprehensive approach including WGS and RNA-seq could be used to identify novel events relevant to the pathogenesis of advanced pediatric cancer.
We analyzed a total of 59 patients (37 solid tumors, 11 brain tumors, and 10 leukemia/lymphomas) to determine the feasibility of using whole-genome sequencing (WGS) technology in conjunction with RNA-seq in order to identify actionable/druggable alterations in the pediatric cancer genomes. WGS analysis has been performed on 75 samples, that were collected from 45 patients, either at diagnosis or at relapse.
For WGS analysis of germline-tumor pairs, after performing the sequence alignment with BWA-MEM to gender-specific hg38 genomes, we have used and verified a set of computational methods: 1) MuTect2 for SNV calling, 2) cn.mops for CNV calling, 3) DELLY and LUMPY for SV calling.
Here we present our findings on the sets of SNV, CNV, SV, and gene fusions that we have identified by WGSA and RNA-seq, respectively, with a particular emphasis on the druggable alterations, and on the tumor response in the murine PDX models of the pediatric cancers. Consistent with previous observations, the mutational burden across pediatric cancers was low. While common mutations were identified, there was a long-tail of mutations that occurred at a low frequency. As anticipated, samples obtained post-chemotherapy had a higher mutational burden than treatment naive samples. TP53 was the most commonly mutated gene, but we also identified SNVs in other genes commonly mutated in cancer, such as ASXL1, NOTCH2, and RB1.
Other novel recurring variants were discovered, further analysis of which is ongoing. Our results indicate that integrated WGS and RNA-seq analysis is feasible in the clinical setting and can reliably identify variants reported on commercially available gene panel testing. However, this approach also resulted in additional clinically relevant findings and allows for novel discovery that will further advance our understanding of these rare and highly aggressive pediatric malignancies.
Citation Format: Bogdan Tanasa, Alex Lee, Marcus Breese, Avanthi Shah, Stan Leung, Heng-Yi Liu, Aviv Spillinger, Kimberly Hazard, Arun Rangaswami, Sheri Spunt, Norm Lacayo, Tabitha Cooney, Eric Alejandro Sweet-Cordero. Whole genome sequence analysis informs precision medicine of pediatric cancers [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 2075.
Abstract 2107: A novel real-time cell imaging assay to quantify macrophage efferocytosis
Authors: Bravo Daniel , Wang Jianyong , Shi Yongchang 
Published: August 2018

Abstract
Tumor-associated macrophages (TAMs) are found in the microenvironment of solid tumors, representing one of the most abundant immune cell types within tumor stroma. Studies have demonstrated that the presence of TAMs correlates with tumor progression and poor prognosis. The engulfment of apoptotic tumor cells by TAMs (a phagocytic process known as efferocytosis) results in clearance of neoplastic antigens, which prevents antigen presentation and activation of effector T cells. Additionally, it has been shown that TAMs produce cytokines that create an immunosuppressive environment that facilitates tumor evasion of immune surveillance and promotes tumor growth. Furthermore, TAMs have been reported to be key players in the promotion of tumor angiogenesis and metastasis. Since TAMs play such an important role in cancer progression, inhibition of their function in the tumor microenvironment becomes an attractive approach of cancer immunotherapy. Traditionally, quantifying efferocytosis in vitro has been a technically challenging task. Our lab has established a novel high-throughput assay that can be used to screen drug candidates that inhibit TAM efferocytosis. Our new assay uses the IncuCyte ZOOM real-time imaging platform to visualize macrophage efferocytosis of apoptotic cells that are labeled with a pH-sensitive probe (pHrodo) that only emits fluorescence in acidic enviroments. This technology enables us to quantify phagocytic events of apoptotic cells that have been processed into the phagolysosome. By using this method, we quantitatively characterized the efferocytosis activity of TAM-like macrophages that were differentiated from primary human monocytes. We tested several agents (including small-molecule compounds and antibodies) and quantified their activities in blocking efferocytosis of TAMs via IC50 concentrations and potency. This new high-throughput assay platform yields highly robust and reproducible data (Z'=0.69), is fully automated, noninvasive (no washing, fixing or lifting of cells), and works with low cell numbers. Our results show that our efferocytosis assay facilitates high-throughput functional screening and can be utilized to identify and characterize new cancer drug candidates, as well as enables research of efferocytosis mechanisms and functions of phagocytic cells.
Citation Format: Daniel Bravo, Jianyong Wang, Yongchang Shi. A novel real-time cell imaging assay to quantify macrophage efferocytosis [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 2107.
Abstract 2118: Single-cell analysis reveals dynamic interaction between myeloma and bone marrow microenvironment
Authors: Min Jaewoong , Ryu Daeun , Lee Hae-Ock , Jo Areum , Park Woong-Yang , Kim Seok Jin , Kim Kihyun 
Published: August 2018

Abstract
Multiple myeloma (MM) is a monoclonal plasma cell (MPC) malignancy primarily propagating in the bone marrow. To understand molecular signatures of MM in association with tumor microenvironment, we performed single-cell RNA sequencing for bone marrow biopsies from seven newly diagnosed myeloma patients. Clinical parameters of 7 MM patients differed, which were recapitulated in the single-cell transcriptome analysis. In comparison to the normal bone marrow from healthy donors, patient-specific monoclonal immunoglobulin gene expression as well as high levels of plasma cell markers distinguished the MPC clusters in myeloma patients. For other cell type identification, reference transcriptome for bone marrow immune cells were utilized. Major cell populations were determined to be monocytes, T cells, B cells, and erythroid cells. T cells manifested a mature phenotype encompassing from naïve to cytotoxic effector gene expression characteristics. B cells and erythroid cell populations were in various developmental stages. Monocytes demonstrated relatively constant gene expression throughout healthy donors to myeloma patients. In more advanced tumor stages, the composition and gene expression characteristics of MPCs and bone marrow immune cells were altered. Taken together, single cell RNA sequencing reveals gene expression characteristics of both myeloma and bone marrow immune cells which provide potential therapeutic strategies targeting tumor or immune compartment.
Citation Format: Jaewoong Min, Daeun Ryu, Hae-Ock Lee, Areum Jo, Woong-Yang Park, Seok Jin Kim, Kihyun Kim. Single-cell analysis reveals dynamic interaction between myeloma and bone marrow microenvironment [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 2118.
Abstract 2127: RSK2 phosphorylates T-bet to attenuate colon cancer metastasis and growth
Authors: Yao Ke , Peng Cong , Zhang Yuwen , Zykova Tatyana A. , Lee Mee-Hyun , Chen Hanyong , Ryu Joohyun , Rao Enyu , Ma Wei-Ya , liu kangdong , Bode Ann M. , Li Bing , dong zigang 
Published: August 2018

Abstract
Metastasis is the major cause of death for patients with solid malignancies. Approximately 80 and 20% of colorectal cancer (CRC) patients develop liver metastasis and lung metastasis, respectively. We found that at different stages of colon cancer, the patients' interferon (IFN) γ secretion from peripheral blood mononuclear cells (PBMCs), was decreased compared with healthy people. The ribosomal S6 kinase (RSK) family of kinases has multiple cellular functions, and we examined their role in this observed IFNγ decrease. Flow cytometry analysis of wild-type (WT) and RSK2 knockout (KO) mice, revealed that the level of IFNγ was significantly lower in RSK2 KO mice as compared to WT mice. Since IFNγ is a component of immunity, which contributes to protection against metastatic carcinomas, a colon cancer liver metastasis experiment was conducted. We found that metastasis was significantly increased in RSK2 KO mice, compared to WT mice. Transcription factor T-bet can directly activate Ifnγ gene transcription. In vitro kinase assay results showed that RSK2 phosphorylated T-bet at serines 498 and 502. We show that phosphorylation of T-bet by RSK2 is required for IFNγ expression, because knocking down RSK2 expression or over-expressing T-bet S498A/S502A mutants reduces IFNγ mRNA expression. To verify the function of the phosphorylation sites, a
constitutively active mutant T-bet (S498E/S502E) was over-expressed in bone marrow. Mutant T-bet restored the IFNγ mRNA levels and dramatically reduced the metastasis rate in these mice. Overall, these results indicate that phosphorylation of T-bet is required for inhibiting colon cancer metastasis and growth through a positive regulation of RSK2/T-bet/IFNγ signaling.
Citation Format: Ke Yao, Cong Peng, Yuwen Zhang, Tatyana A. Zykova, Mee-Hyun Lee, Hanyong Chen, Joohyun Ryu, Enyu Rao, Wei-Ya Ma, kangdong liu, Ann M. Bode, Bing Li, zigang dong. RSK2 phosphorylates T-bet to attenuate colon cancer metastasis and growth [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 2127.
Abstract 2131: Paracrine cytokine pathways mediate metastasis of breast cancer to lymphatics
Authors: Ji Kyungmin , Zhao Zhiguo , Moin Kamiar , Xu Yong , Gillies Robert J. , Mattingly Raymond R. , Sloane Bonnie F. 
Published: August 2018

Abstract
Lymphatics, rather than blood vessels, are the primary route for breast cancer metastasis. The presence of breast cancer cells in regional lymphatics, i.e., lymphatic metastasis, is an important prognostic factor for patients. Delineating molecular mechanisms by which the breast cancer cells migrate toward and infiltrate into lymphatics is crucial to designing new therapies to prevent metastatic dissemination. To study tumor:lymphatic interactions, we are using a three-dimensional (3D) heterotypic co-culture model of human breast cancer cells (hBCCs) grown with human microvascular lymphatic endothelial cells (hLECs) in novel chambers that we designed and fabricated. These chambers support growth of the 3D co-cultures, live-cell confocal imaging in real time and noninvasive collection of conditioned media for secretomic analyses. We use live-cell assays developed in our laboratory for quantitative analysis of temporal and dynamic changes in BCC:LEC interactions in correspondence with changes in their malignant and proteolytic phenotypes. We cultured hLECs in the presence and absence of human MDA-MB-231 (231) triple-negative BCCs in 3D cultures for 4 days. In mono-cultures, the 231 cells grow in clusters that exhibit a stellate morphology and hLECs form branching networks with central nodes. We observed that the volumes of 3D structures formed by LECs and 231 cells were significantly greater in co-cultures than in mono-cultures of either cell type. In addition, 231 cells infiltrate into the LEC networks with the infiltration increasing over the 4-day period as assessed by the degree of overlap between 231 cells and hLECs in 3D reconstructions of the co-cultures. Moreover, soluble factors from LECs increase invasive outgrowths of 231 structures. This was demonstrated in 231 cells grown in media conditioned by LECs and in parallel co-cultures of 231 cells and LECs. The induction of invasiveness by LEC conditioned media is reduced by boiling and repeated freeze/thawing, suggesting that the active factor(s) is a protein. Our preliminary results suggest that LECs secrete soluble factors that may be therapeutic targets for reducing invasion of BCCs into lymphatic networks.
Citation Format: Kyungmin Ji, Zhiguo Zhao, Kamiar Moin, Yong Xu, Robert J. Gillies, Raymond R. Mattingly, Bonnie F. Sloane. Paracrine cytokine pathways mediate metastasis of breast cancer to lymphatics [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 2131.
Abstract 2132: Anti-vascular inflammatory nanoparticles inhibit tumor progression and metastasis through vascular normalization
Authors: Choi Young Sun , Kang Soo Hyun , Bae Jong-Sup , Kim In-San , Lee You Mie 
Published: August 2018

Abstract
Vascular networks in cancer are structurally and functionally abnormal. Abnormal blood vessel development in cancer plays an important role in cancer growth and metastasis, and blocks delivery of chemotherapeutic drugs. Recent studies have revealed that the normalization of abnormal tumor vasculature is one of the promising approaches to treat cancer. Inflammatory microenvironment is one of the newly focused hallmarks of cancer, and tumor vasculature has similar features to that of inflammatory vessels. Thus, vascular inflammation is emerged as an attractive target for cancer treatment. We hypothesized that amelioration of vascular inflammation in tumor may induce vascular normalization leading to the inhibition of tumor progression and metastasis. Here, we investigated the function of ant-vascular nanoparticles in tumor growth and metastasis in LLC allograft tumor models and MMTV-PyMT, spontaneous breast tumor models using TFG and TFMG which are engineered a protein-cage nano-particle (ferritin) with both EPCR-targeting peptides (γ-carboxyglutamic acid (Gla) domain of protein C) and PAR-1-activating peptides (TRAP) of thrombin on its surface. As a result, tumor growth was significantly inhibited in the nanoparticle-injected group, and the lymph node metastasis was also decreased in both animal models. It has been found that the survival rate of the nanoparticle-injected group was prolonged. TFG and TFMG normalized abnormal tumor vasculature, that is, pericytes coverage in vasculatures was significantly increased but the hypoxic regions was decreased in the nanoparticle injected group. Furthermore, when the experiment was conducted by administering cisplatin and nanoparticles together in the LLC allograft tumor model, the tumor size was synergistically increased in the case of the nanoparticle and cisplatin combination administration compared to the cisplatin alone group. Taken together, anti-vascular inflammation nanoparticles with anti-vascular inflammatory properties normalized the abnormal blood vessels and inhibited tumor formation and metastasis. It is suggested that inducing normalization of cancer blood vessels by improving the inflammatory state of blood vessels may be a promising therapeutic method for effective cancer treatment.
Citation Format: Young Sun Choi, Soo Hyun Kang, Jong-Sup Bae, In-San Kim, You Mie Lee. Anti-vascular inflammatory nanoparticles inhibit tumor progression and metastasis through vascular normalization [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 2132.
Abstract 2139: Evaluation of a novel hypoxia-activated prodrug strategy in colorectal cancer cells
Authors: Hussain Omar , Johansson Henrik , Allison Simon J. , Pedersen Daniel S. , Phillips Roger M. 
Published: August 2018

Abstract
Introduction: Current chemotherapeutic drugs are often ineffective against cancer cells that reside within the tumor microenvironment due to contributing factors such as hypoxia (low O2 tension) and acidic extracellular pH (pHe). Hypoxia is known to drive the aggressive cancer phenotype in many solid tumors, making it a key component of drug development. The use of hypoxia-activated prodrugs (HAPs) has been extensively studied over 40 years but to date no HAP has been approved for use in humans, largely because of poor activity and toxicity profiles. The design of prodrugs that are activated by both hypoxia and acidic pHe may provide a greater degree of selectivity and activity than HAPs alone, and this study was designed to evaluate a series of novel bromosugar-based HAPs under hypoxic and acidic pHe conditions.
Method: A library of 13 HAPs was evaluated against HCT116 colorectal cancer cells and ARPE-19 human retinal epithelial noncancerous cell line. Cytotoxicity was determined under (i) aerobic condition (21% oxygen) at pHe 7.4 or mild acidic conditions (pHe 6.5) and (ii) hypoxic condition (0.1% oxygen) at pHe 7.4 or mild acidic conditions (pHe 6.5). ARPE-19 cells were only tested under aerobic conditions and pHe 7.4 to reflect normal physiologic conditions. Compounds were tested at different concentrations ranging from 0.1-100µM from which an IC50 value was determined. Cell survival was measured after a 96-hour continuous drug exposure using the MTT assay.
Results: Among the compounds screened, DS10 demonstrated the most enhanced potency against HCT116 cells under hypoxic conditions with an IC50 value of 28.18 ± 7.01 µM as compared to an IC50 value of 66.39 ± 8.10 µM under normoxic conditions at pHe 7.4. Potency was further increased when DS10 was evaluated under a combination of hypoxic and acidic pHe conditions with an IC50 value of 16.30 µM ± 4.11. ARPE-19 cells showed an IC50 value of 42.95 µM ± 5.03 under aerobic conditions.
Discussion: The results of this study demonstrated that bromosugar derivatives may have the potential to selectively target hypoxic cancer cells in an acidic extracellular environment. Specifically, DS10 exhibited potential HAP properties with the ability to target cells that reside within the hypoxic and acidic microenvironment of tumors. Selectivity to tumor cells as opposed to noncancer cells was observed under these conditions, suggesting that DS10 is a promising compound to take forward for further evaluation.
Citation Format: Omar Hussain, Henrik Johansson, Simon J. Allison, Daniel S. Pedersen, Roger M. Phillips. Evaluation of a novel hypoxia-activated prodrug strategy in colorectal cancer cells [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 2139.