bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5270: A potential role of branched chain amino acid metabolism in breast cancer cell invasiveness
Authors: Colonna Maxwell B. , Edison Arthur S. , Zhao Shaying 
Published: August 2019

Abstract
Carcinomas have two broadly distinct modes of invasion: collective and individual. Collective invasion is characterized as groups of cells that migrate while retaining cell-cell contacts. Individual invasion occurs through mechanisms such as the acquiring of mesenchymal-like features by cancer cells. While these different modes of invasion have been well studied at the genomic and transcriptional levels, their metabolic alterations remain much less understood. To address this deficiency, we performed untargeted NMR metabolomics, in conjunction with RNA-seq, on two variants of MCF7, a widely used breast cancer cell line. We report herein several findings. First, the two MCF7 variants, one parental (referred to as MCF-7 hereafter) and another having undergone many passages (referred to as Augusta hereafter), differ morphologically, with MCF-7 being more epithelial and Augusta being more mesenchymal-like. Importantly, fibroblast co-culture experiments indicate that MCF-7 cells resemble collective invasion, while Augusta cells resemble individual invasion. Furthermore, both scratch-assay and gene set enrichment analysis of RNA-seq data indicate that Augusta cells are more invasive. Second, our NMR metabolomics analysis reveals that branched chain amino acids (BCAAs) represent a significant metabolic difference between MCF-7 and Augusta cells. Partial least squares discriminant analysis of the metabolomics data identified BCAAs as essential distinguishing features between the two cell lines. Specifically, compared to MCF-7 cells, BCAAs are significantly depleted inside Augusta cells, consistent with the upregulation of several key BCAA degradation genes. We hypothesize that Augusta cells can more efficiently utilize BCAAs, and are performing 13C-labeled BCAA flux analysis to test this hypothesis. Previous studies have shown that an aberrantly expressed BCAA metabolism gene sustains growth and enhances invasiveness of breast cancer cells. However, increased catabolism of BCAAs has not been reported in literature on this subject. Our simple cell line model allows for a deeper molecular understanding of BCAA metabolism in breast cancer cell invasion.
Citation Format: Maxwell B. Colonna, Arthur S. Edison, Shaying Zhao. A potential role of branched chain amino acid metabolism in breast cancer cell invasiveness [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 5270.
Abstract 5273: Multi-omics approaches reveal potential role for corticosterone in prostate cancer
Authors: Mahmud Iqbal , Lee Bongyong , Perera Ranjan , Garrett Timothy J. 
Published: August 2019

Abstract
Prostate cancer (PCa) is the most commonly diagnosed cancer in American men. In 2018, 164,690 new cancer cases and 29,430 cancer deaths are projected to occur in the United States. Currently, there is no efficient diagnostic and safe treatment option for the management of PCa. Using Ultra-High Performance Liquid Chromatography coupled High Resolution Mass Spectrometry (UHPLC-HRMS), we globally profiled more than 1400 metabolites across 79 urine samples related to PCa (19 control, 23 benign prostate hyperplasia (BPH), 11 prostatitis, and 26 PCa samples). Among all, corticosterone was identified as a top differential metabolite. Corticosterone levels were markedly elevated in PCa urine samples and modest but significant elevation of the corticosterone in BPH and prostatitis urine samples compared to controls, with an excellent area under the receiver operating characteristic curve of 0.95, 0.94, and 0.93, respectively. In addition, the expression of corticosterone biosynthetic gene, Steroid 11-beta-hydroxylase (CYP11B1), was elevated in PCa tissues, cell lines, and urine samples, while Corticosteroid 11-beta-dehydrogenase isozyme 2 (HSD11B2), which metabolize corticosterone, were markedly reduced in prostate tumors. With the understanding that androgen signaling is the key factor for prostate cancer, we investigated the role of androgen in regulating CYP11B1 and HSD11B2. We analyzed several androgen treated PCa cell lines derived global gene expression datasets and revealed that treatment with androgen increase in CYP11B1 expression and a concomitant decrease in HSD11B2 expression levels. Interestingly, we uncover that genetic knockdown of Androgen Receptor (AR) diminished CYP11B1 expression and alternatively, increased HSD11B2. Moreover, AR based chromatin occupancy (ChIP-seq) data also suggest direct binding of AR to the promoter of CYP11B1 in multiple PCa cells. The role of corticosterone in PCa is previously unknown. Our multi-omics approaches thus indicate that corticosterone might be potential prognostic marker for PCa. The tumor biology and mechanism through which corticosterone associates with PCa is being investigated in our laboratory.
Citation Format: Iqbal Mahmud, Bongyong Lee, Ranjan Perera, Timothy J. Garrett. Multi-omics approaches reveal potential role for corticosterone in prostate 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 5273.
Abstract 538: LC-MS based catabolite identification study of an ADC with DM21-C, a novel maytansinoid linker-payload
Authors: Lau Janet , Salomon Paulin , Sinkevicius Kerstin , Costoplus Juliet , Fuller Megan , Xu Raymond , Hicks Stuart , Chari Ravi , Widdison Wayne , Yoder Nicholas , Keating Thomas 
Published: August 2019

Abstract
ImmunoGen’s newest antibody-drug conjugate (ADC) design uses the novel maytansinoid linker-payload, DM21-C that bears a peptidase/protease cleavable linker. These ADCs show good bystander killing of proximal antigen negative cells, suggesting the generation of cell-permeable catabolites. The goal of this study was to identify the catabolites generated upon incubation in antigen-positive cancer cells (both cell pellet and media), in mouse plasma, as well as in in vitro catabolic systems. Upon incubation with a cysteine-conjugated DM21-C ADC, the small molecule fraction was extracted with an organic solvent and analyzed by high resolution mass spectrometry after chromatographic separation. Through comparison to reference standards, mass spectral signal extraction of possible products, and database search of unknown peaks, the potential in vitro catabolite products of DM21-C conjugate were identified. Information on linker-payload stability in these model systems, including plasma stability, in vitro metabolism of the ADC, and catabolic products that were both retained and effluxed from cancer cells was obtained. As a result, we identified DM51 (the thiol- resulting from self-immolation of the cleaved linker-payload) as a major catabolite of the DM21-C ADC.
Citation Format: Janet Lau, Paulin Salomon, Kerstin Sinkevicius, Juliet Costoplus, Megan Fuller, Raymond Xu, Stuart Hicks, Ravi Chari, Wayne Widdison, Nicholas Yoder, Thomas Keating. LC-MS based catabolite identification study of an ADC with DM21-C, a novel maytansinoid linker-payload [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 538.
Abstract 543: Dinutuximab binds specifically to disialoganglioside-2
Authors: Yaghoubi Shahriar , Harrison Travis , Messerschmidt Gerald , Corritori Suzana 
Published: August 2019

Abstract
Dinutuximab is a human/murine chimeric monoclonal antibody, approved for maintenance treatment of pediatric patients with high-risk neuroblastoma (NB) in the US, and currently under investigation in a phase III trial (NCT03098030) for 2nd line treatment of relapsed/refractory small cell lung cancer (SCLC). Despite four decades of development, the specificity of dinutuximab binding to its intended target, disialoganglioside-2 (GD2), has not been fully elucidated. Although GD2 is a relatively cancer cell specific antigen, other cell surface gangliosides are ubiquitously expressed on the outer membrane of healthy human cells. Therefore, the main goal of this study was to confirm binding specificity of dinutuximab to GD2. We also compared relative affinity of dinutuximab to GD2 with 14G2a, which is the original murine anti-GD2 antibody from which dinutuximab was derived. To measure dinutuximab and 14G2a binding kinetics to various relevant gangliosides (GD1a, GD1b, GM3, GD3, GM4, GM2 and GD2), an in vitro assay was developed and optimized using the Biacore surface plasmon resonance platform. The results showed that GD2 was the only ganglioside that binds to dinutuximab (relative KD=0.000337M). The relative affinity of GD2 to dinutuximab and 14G2a antibody were comparable and within 2-fold of each other (Table). In conclusion, dinutuximab specifically binds to GD2. The absence of binding to GM3, GD3, GD1a, or GD1b suggests that an exposed N-acetylgalactosamine (GalNAc) moiety is necessary for antibody recognition. The absence of binding to GM2 or GT2 (sugar moiety), which differ from GD2 by the number of sialic residues attached to the basal galactose moiety, suggests that the number of sialic acid residues is also critical for antibody recognition.
GD2 binding kinetics of Dinutuximab and 14G2aLigandKD (M)ka (1/Ms)kd (1/s)Chi2 (RU2)Dinutuximab3.37E-042.48E+028.34E-020.78614G2a2.00E-047.11E+021.42E-010.0273
Citation Format: Shahriar Yaghoubi, Travis Harrison, Gerald Messerschmidt, Suzana Corritori. Dinutuximab binds specifically to disialoganglioside-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 543.
Abstract 545: Preclinical development of a bispecific antibody-trap selectively targeting CD47 and CD20 for the treatment of B cell lineage cancer
Authors: Tian Wenzhi , Li Song , Chen Dianze , Liang Guangjun , Zhang Li , Zhang Wei , Tu Xiaoping , Peng Liang , Weng Jie , Zhao Gui , Liu Dandan , Guo Huiqin , Yang Chunmei , Zhang Ruliang 
Published: August 2019

Abstract
Tumor cells over expressing CD47 can evade immune surveillance through delivering a “Don’t eat me” signal to macrophages. Developing CD47-targeted modalities has been a hot pursue in the pharmaceutical industry. However due to the ubiquitous expression of CD47 in normal tissues, especially in red blood cells (RBC), severe antigenic sink as well as hemotoxicity including anemia set up a higher bar for this particular targeted therapy development. To overcome these hurdles, we have developed a bispecific recombinant antibody-trap, IMM0306, designed to simultaneously target CD47 and CD20 on B cells but avoid binding to human RBCs. Extensive in vitro characterization demonstrated that IMM0306 binds to both CD47 and CD20 with affinity 3-8 folds lower than either single-targeted molecule, but has strong pro-phagocytosis activity over CD47-positive target cells, and even stronger ADCC activity than Rituximab. Intriguingly, IMM0306 has no binding activity at all toward human RBCs, albeit much lower binding activity toward monkey RBCs. Treatment of tumor-implanted SCID mice with IMM0306 significantly inhibited tumor growth and led to eradication of the tumor cells from 5 out of 8 mice, which is much more effective than Rituximab and than co-administration of Rituximab and SIRPα-Fc (IMM01), although profound synergistic effect has been observed for the co-administration. Preclinical study in non-human primates demonstrated a favorable pharmacokinetic profile with no obvious hemotoxicity following single as well as multiple administrations at different dosage. Our study suggests that antibody-trap like IMM0306 might be an ideal approach for CD47-targeted immunotherapy development since selective avoidance of RBC mediated antigen-sink as well as anemia could be achieved along with the robust anti-tumor activity.
Citation Format: Wenzhi Tian, Song Li, Dianze Chen, Guangjun Liang, Li Zhang, Wei Zhang, Xiaoping Tu, Liang Peng, Jie Weng, Gui Zhao, Dandan Liu, Huiqin Guo, Chunmei Yang, Ruliang Zhang. Preclinical development of a bispecific antibody-trap selectively targeting CD47 and CD20 for the treatment of B cell lineage 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 545.
Abstract 61: ECM scaffolds to elucidate the role of Col11a1 in head and neck cancer progression
Authors: Thomas Sufi M. , Enders Jonathan , Isai Greta , Czirok Andras 
Published: August 2019

Abstract
Cancer progression is linked to physical properties, cellular and biochemical composition of the tissue environment including the extracellular matrix (ECM). The ECM not only provides signaling cues by presenting ligands, but also plays a key role in mechano-sensing: modulation of biochemical pathways by physical forces. Collagens are one of the most abundant components of the ECM. We previously reported that head and neck squamous cell carcinoma (HNSCC), which is the 6th most common cause of cancer mortality worldwide with &lt; 40% 5-year survival rates, express higher levels of collagen 11a1 (Col11a1) than normal adjacent mucosa. Col11a1 is a minor fibrillar collagen whose main physiologic role is to regulate the diameter of major collagen fibrils in the cartilage. Although reported that Col11a1 facilitates HNSCC proliferation and invasion, not much is known about its role in the tumor microenvironment. We tested the hypothesis that Col11a1-cancer interdependence facilitates tumor adhesion and metastatic colonization. We developed ECM substrates from cell lines and HNSCC tumor tissue that were characterized by scanning electron microscopy and immunofluorescence microscopy. Electrospun meshes with ECM substrates were developed and used to assess HNSCC adhesion, proliferation and motility. We used a 3D multi-cell type spheroid culture model called the primitive-lung-in-a-dish (PLiD) to demonstrate that Col11a1 siRNA targeting attenuates HNSCC colonization in the lung. Further, using homogenized and lyophilized decellularized ECM from mouse lungs, we demonstrate that Col11a1 regulates motility of HNSCC. Overall, we have used several models to elucidate the role of Col11a1 in HNSCC adhesion and metastatic colonization.
Citation Format: Sufi M. Thomas, Jonathan Enders, Greta Isai, Andras Czirok. ECM scaffolds to elucidate the role of Col11a1 in head and neck 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 61.
Abstract 711: p53 causes butein-mediated apoptosis of chronic myeloid leukemia cells
Authors: Lee SeoYeon , Choi Yu-Jeong , Kim Myeong-sun , Kang Sooyeon , Kim Ji Hye , Woo Sang Mi , Ko Seong-Gyu , Oh Sukjoong 
Published: August 2019

Abstract
Progression of chronic myeloid leukemia, marked by the oncogenic Bcr-Abl mutation, is tightly associated with an alteration of the p53 pathway. It is known that butein extracted from various plants represses cancer growth. Although the anticancer effects of butein are widely accepted, the mechanisms by which butein induces apoptosis of chronic myeloid leukemia cells remains to be elucidated. The present study demonstrated that butein-induced apoptosis was mediated by p53. KBM5 chronic myeloid leukemia (CML) cells expressing wild-type p53 were more sensitive to butein compared with p53-null K562 CML cells in terms of apoptotic cell death. In addition, butein arrested KBM5 cells at S-phase and altered the expression levels of certain cyclins and the p53-downstream targets, MDM2 and p21. In addition, while butein reduced the protein expression of MDM2 in the KBM5 and K562 cells, it resulted in proteasome-independent MDM2 degradation in p53-expressing KBM5 cells, however, not in p53-null K562 cells. Therefore, the present study suggested that p53 causes the butein-mediated apoptosis of leukemic cells.
Citation Format: SeoYeon Lee, Yu-Jeong Choi, Myeong-sun Kim, Sooyeon Kang, Ji Hye Kim, Sang Mi Woo, Seong-Gyu Ko, Sukjoong Oh. p53 causes butein-mediated apoptosis of chronic myeloid leukemia 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 711.
Abstract 73: Inhibition of ACK1 delays and overcomes acquired resistance of EGFR mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib
Authors: Gu Jiajia , He Xia , Mahajan Nupam P. , Owonikoko Taofeek K. , Ramalingam Suresh S. , Sun Shi-Yong 
Published: August 2019

Abstract
The approval of osimertinib (AZD9291) as a third generation EGFR inhibitor for treating non-small cell lung cancer (NSCLC) patients with activating EGFR mutations (first-line) or those who have become resistant to 1st generation EGFR inhibitors through the T790M mutation (second-line) have generated tremendous benefits to these NSLCL patients. However, the unavoidable development of acquired resistance to osimertinib limits the long-term benefits of patients. Thus, effective treatment options are urgently needed. Activated Cdc42-associated kinase 1 or ACK1 (also named as TNK2) is a non-receptor tyrosine kinase with oncogenic function. Although ACK1 gene is amplified in lung squamous cell carcinoma, its involvement in lung cancer including regulation of drug resistance has largely not been investigated. We found that inhibition of ACK1 with (R)-9bMS, a specific ACK1 inhibitor, synergized with AZD9291 in inhibiting the growth of EGFR mutant NSCLC cell lines. Similar results were also generated when ACK1 is genetically inhibited through transient shRNA gene knockdown. The combination of AZD9291 and (R)-9bMS enhanced induction of apoptosis as evaluated by detecting annexin V-positive cells with flow cytometry and PARP cleavage using Western blotting. In an in vitro long-term resistance delay assay, the combination of (R)-9bMS and AZD9291 clearly prevented the emergence of AZD9291-resistance as evaluating resistant cell colony formation and growth. Beyond the combination was also effective in inhibiting the growth of EGFR mutant NSCLC cell lines with acquired resistance to AZD9291. In some resistant cell lines, the combinations induced senescence in addition to induction of apoptosis. These preliminary findings suggest that ACK1 inhibition might be a potential and innovative strategy for preventing and overcoming AZD9291 acquired resistance. Hence further in vivo and mechanistic studies are warranted. (This work was supported by the NIH/NCI R01 CA223220 and Winship lung cancer pilot award to SYS; NIH/NCI R01 CA208258, Bankhead Coley Award-6BC08 and Prostate Cancer Foundation (PCF) Challenge award-17CHAL06 to NPM).
Citation Format: Jiajia Gu, Xia He, Nupam P. Mahajan, Taofeek K. Owonikoko, Suresh S. Ramalingam, Shi-Yong Sun. Inhibition of ACK1 delays and overcomes acquired resistance of EGFR mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib [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 73.
Abstract 733: Characterizing the genetic profile of endometrioid ovarian carcinoma using exome sequencing
Authors: Pierson William E. , Peters Pamela , Quigley David A. , Chen Lee-may , Chapman Jocelyn S. 
Published: August 2019

Abstract
Objective: Endometrioid ovarian carcinoma is poorly understood at the genomic level. Prior sequencing investigations have been limited to small gene panels. In order to characterize the etiology of this disease and identify potential therapeutic targets, we sought to build an unbiased genetic profile of coding gene alterations in endometriod ovarian tumors.
Methods: We sequenced the exomes of primary endometrioid ovarian tumors obtained from our institutional gynecologic oncology tissue bank from 1996 - 2011. We analyzed somatic point mutations, copy number alterations, structural variations and mutational signatures and integrated these data to determine genetic drivers. Demographic and clinical data were collected by retrospective chart review.
Results: Seventeen primary endometrioid ovarian tumors were sequenced. Median age at surgical resection was 51 years (range 33-77 years). The majority of patients presented with early stage disease (71%), many had a history of endometriosis (47%) and 19% had a synchronous primary uterine carcinoma. Microsatellite instability (MSI) was present in 18% (3/17) tumors. All three of these tumors with MSI exhibited a high tumor mutational burden with an average of 174 mutations per megabase of DNA, and two of them had confirmed loss or inactivation of mismatch repair proteins. Approximately half of all cases (47%) had inactivation or truncating mutations in PTEN. 59% of cases (10/17) had alterations in WNT pathway genes, including 6/17 (35%) with missense mutations in the regulatory domain of beta catenin (CTNNB1). 2/17 (12%) had TP53 mutations. We identified one case with a mutation in the exonuclease domain of POLE (P286R), which also exhibited a characteristic POLE-mutant mutation signature.
Conclusion: Using whole exome sequencing, we identified that endometrioid ovarian carcinomas are commonly hypermutated and often harbor microsatellite instability. These findings highlight the importance of genetic sequencing to determine which patients may benefit from targeted immunotherapies.
Citation Format: William E. Pierson, Pamela Peters, David A. Quigley, Lee-may Chen, Jocelyn S. Chapman. Characterizing the genetic profile of endometrioid ovarian carcinoma using exome sequencing [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 733.
Abstract 776: Posttransriptional control of steroid biosynthesis pathway in prostate cancer
Authors: Bhattarai Asmita , Shukla Girish C. 
Published: August 2019

Abstract
Prostate cancer (PCa) depends on androgens for growth and maintenance. Despite curative therapeutics of the androgen-sensitive PCa, one-third of patients relapse to a more aggressive form of the disease known as castration-resistant PCa (CRPC). Androgen signaling mediated via Androgen receptor (AR) continues to promote CRPC and therapeutic resistance. The synthesis of testosterone (T) and dihydrotestosterone (DHT) via Intratumoral steroidogenesis appears to play a crucial role in CRPC. It appears that PCa cells synthesize de-novo androgen from cholesterol from acetyl-coA via Terpenoid backbone and Steroid biosynthesis pathways. We found that several enzymes of the intracellular cholesterol synthesis pathways including HMGS1, HMGCR, SREBP1, FASN, SCARB1 are potential targets of hsa-miR-149 5p. Currently, we are characterizing miR-149-5p mediated posttranscriptional regulation of these genes and determining its potential therapeutic application in CRPC.
Citation Format: Asmita Bhattarai, Girish C. Shukla. Posttransriptional control of steroid biosynthesis pathway in prostate 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 776.