bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3241: Novel anti-CD40 antibodies demonstrate anti-tumor activity in humanized mouse models
Authors: Guo Chaoshe , Yang Benny(Yi) , Ni Jian , Guo Yanan , Gan Tian 
Published: August 2019

Abstract
CD40 (Cluster of Differentiation 40) is a member of the TNF-receptor superfamily. CD40 is a co-stimulatory protein found primarily on antigen presenting cells, including B cells, macrophages and dendritic cells. Its ligand, CD40L (CD154) is predominantly expressed on T helper cells, whose engagement activates antigen presenting cells and induces a variety of positive downstream effects. Whereas most immune checkpoint receptors are expressed on the surface of T cells, CD40 stands out as it is expressed by antigen presenting cells and controls the proper activation of these cells. In turn, CD40 activation exerts a significant impact on T cell-mediated activity against cancer cells. Several pharmaceutical companies are pursuing anti-CD40 therapies for treating hematological and solid cancers.
Therefore, it is imperative to develop novel CD40 antibodies to boost cancer patients’ own immunity in light of other successful immune checkpoint modulators. We asked whether we could find suitable anti-CD40 reagents that successfully combat developed tumors in preclinical settings. We designed a powerful screening strategy based on Biocytogen’s in vivo drug screening platform. Candidate antibodies were generated by immunizing wild-type mice with recombinant hCD40 protein. Hybridomas were then screened by high-throughput flow cytometry. Instead of examining the immune modulating activity in cell culture, we tested these antibodies in B-hCD40 mice bearing MC38 tumors and monitored the tumor growth. Through this straightforward screening strategy, several clones stood out by their unparalleled benefits. These clones were further selected for humanization. Furthermore, we identified that one clone works in concert with Keytruda in the dual humanized model of h-CD40 and h-PD1. In conclusion, we uncovered CD40 antibody candidates with the most potent anti-tumor activity which are promising as tools for cancer treatment in the preclinical setting.
Citation Format: Chaoshe Guo, Benny(Yi) Yang, Jian Ni, Yanan Guo, Tian Gan. Novel anti-CD40 antibodies demonstrate anti-tumor activity in humanized mouse models [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 3241.
Abstract 3277: IACS-9779, a development candidate that inhibits 2,3-dioxygenase (IDO) activity by blocking heme incorporation into IDO apoenzyme
Authors: Mseeh Faika , Hamilton Matthew M. , Marszalek Joseph R. , Rogers Norma E. , Parker Connor A. , Yu Simon S. , Liu Zhen , Reyna Naphtali J. , McAfoos Timothy , Virgin-Downey Brett W. , Leonard Paul G. , Cross Jason B. , Feng Ningping , Harris Angela L. , Zuniga Andy M. , Mikule Keith , Tremblay Martin , Jiang Yongying , Mahendra Mikhila , Pang Jihai , Wu Qi , Xu Quanyun , Heffernan Timothy P. , Jones Philip , Lewis Richard T. 
Published: August 2019

Abstract
Increased expression of IDO1 is believed to create a tumor microenvironment that is immunosuppressive. In the course of our research directed at identifying potent and selective inhibitors of IDO1, we identified a class of compounds that inhibited IDO1 activity in a cellular context, but not in isolated enzymatic assays. We have conducted detailed mechanistic studies and shown that these molecules inhibit IDO1 by binding to the apo-enzyme, thus preventing the incorporation of the heme-cofactor into the active site of the holo-enzyme.
Through an extensive medicinal chemistry campaign, we optimized a series of orally bioavailable, highly potent and selective inhibitors of IDO1 that possess excellent pharmacological properties. For several lead molecules, pharmacokinetic (PK) - pharmacodynamic (PD) relationships were established in whole blood and SKOV3 xenograft assays. The inhibition of IDO1 in a human whole-blood assay correlated well with the suppression of tumor kynurenine (KYN) that was observed in SKOV3 xenografts. At plasma concentrations of 3 µM, IACS-9779 supressed tumor KYN levels by 90%. IACS-9779 was well tolerated with excellent in vivo PK properties across multiple preclinical species, and a human PK prediction consistent with a low daily dose needed for full suppression of KYN production via IDO1.
Note: This abstract was not presented at the meeting.
Citation Format: Faika Mseeh, Matthew M. Hamilton, Joseph R. Marszalek, Norma E. Rogers, Connor A. Parker, Simon S. Yu, Zhen Liu, Naphtali J. Reyna, Timothy McAfoos, Brett W. Virgin-Downey, Paul G. Leonard, Jason B. Cross, Ningping Feng, Angela L. Harris, Andy M. Zuniga, Keith Mikule, Martin Tremblay, Yongying Jiang, Mikhila Mahendra, Jihai Pang, Qi Wu, Quanyun Xu, Timothy P. Heffernan, Philip Jones, Richard T. Lewis. IACS-9779, a development candidate that inhibits 2,3-dioxygenase (IDO) activity by blocking heme incorporation into IDO apoenzyme [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 3277.
Abstract 3304: CNS metastases in prostate cancer: an analysis of SEER database
Authors: Mei Lin , Al-Juhaishi Taha , Poklepovic Andrew , Paul Asit 
Published: August 2019

Abstract
Metastases to central nervous system (CNS) from various solid tumors, such as lung cancer (40-50%), breast cancer (15-25%) and melanoma (5-20%), are relatively common and confer a poor prognosis. CNS metastases from prostate cancer are uncommon. Due to the rarity of this disease and lack of studies, little is known about the clinical and pathological characteristics as well as outcome of these patients. CNS metastases also have therapeutic implications in terms of targeting hypothalamic-pituitary axis for androgen deprivation as well as CNS penetration of systemic chemotherapy agents. The objective of this study is to analyze clinicopathologic features and outcome of prostate cancer patients with CNS metastases in Survival, Epidemiology, and End Result (SEER) database. Between 2010 and 2015, a total of 23,776 patients with metastatic prostate were identified. Among them, 23,468 cases were adenocarcinoma and 308 cases were prostate cancer with neuroendocrine differentiation. A number of variables, including age, race, prostate-specific antigen (PSA) level, Gleason score, and prior radiotherapy, site of metastases were extracted. Primary outcome were overall survival (OS) and disease specific survival (DSS). CNS metastases were identified in 208 (0.89%) and 11 (3.57%) patients with adenocarcinoma and neuroendocrine tumor, respectively. Majority of patients (56.2%) were 65 years or older. Median OS and DSS were 13 months and 14 months, respectively. In comparison to patients with lymph nodes metastases only (n=8,103), the median OS and DSS were 40 months and 58 months, respectively. In patients with bone dominant metastasis (n=14,407), the median OS and DSS were 27 months and 34 months, respectively. Multivariate analysis identified age was an adverse predictive factor in patients with CNS metastasis. Race, high Gleason score (≥9), high PSA level (≥98ng/ml) and prior radiotherapy were not associated with OS and DSS. In conclusion, CNS metastases are more common in neuroendocrine tumor than in adenocarcinoma of prostate, and it confers poor survival outcome irrespective of histological subtypes. OS and DSS were worse in patients with prostate cancer and CNS metastases compared to those with lymph node metastases only or bone-dominant metastases.
Note: This abstract was not presented at the meeting.
Citation Format: Lin Mei, Taha Al-Juhaishi, Andrew Poklepovic, Asit Paul. CNS metastases in prostate cancer: an analysis of SEER database [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 3304.
Abstract 3561: MicroRNA-214 inhibits prostate cancer cell proliferation, migration, invasion and increases drug sensitivity by targeting PTK6
Authors: Cagle Patrice , Niture Suryakant , Srivastava Anvesha , Ramalinga Malathi , Rios-Colon Leslimar , Chimeh Uchechukwu , Kumar Deepak 
Published: August 2019

Abstract
MicroRNAs (miRNAs) are involved in numerous physiological and pathological processes and play a critical role in cancer progression and the role miRNA-214 (miR-214) in prostate cancer remains elusive. In the present study, we investigated the effect of expression of miR-214 on cell survival/migration/invasion, cell cycle regulation, and apoptosis. Differential expression of miR-214 was found between Caucasian, African American prostate cancer cells compared with normal prostate epithelial cells. Expression of miR-214 in prostate cancer cells inhibited cell proliferation and colony forming capability, and induced apoptosis. miR-214 also inhibited cell migration and 3D spheroid invasion in prostate cancer cells. Interestingly, miR-214 targets protein tyrosine kinase 6 (PTK6) and reduced PTK6 expression. The restoration of PTK6 expression significantly blocked the inhibitory effect of miR-214 on cell proliferation. Moreover, inactivation of PKT6 by ibrutinib and expression of miR-214 significantly enhanced the cell death in prostate cancer cells. Collectively the data suggest that miR-214 functions as a tumor suppressor in prostate cancer, and may become a potential therapeutic target in prostate cancer.
Citation Format: Patrice Cagle, Suryakant Niture, Anvesha Srivastava, Malathi Ramalinga, Leslimar Rios-Colon, Uchechukwu Chimeh, Deepak Kumar. MicroRNA-214 inhibits prostate cancer cell proliferation, migration, invasion and increases drug sensitivity by targeting PTK6 [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 3561.
Abstract 3571: Identification of a novel imatinib upregulated lncRNA family that is required for efficient cellular transformation by Abl oncogene
Authors: Chen Jilong , Wang Xuefei 
Published: August 2019

Abstract
Bcr-Abl oncogene is generated by a reciprocal translocation between chromosome 9 and 22 in human genome, giving Bcr-Abl protein with constitutive tyrosine kinase activity that causes chronic myeloid leukemia (CML) . Few acute lymphoblastic leukemia (ALL) patients also contain Bcr-Abl oncogene. Owing to the development of imatinib, over 90% of CML patients can be cured in recent years. However, the functional relevance of lncRNAs in Bcr-Abl-mediated leukemia remains obscure. Here, we identified a conserved, imatinib-upregulated lncRNA (IUR) family, named lncRNA-IUR37. Upregulation of lncRNA-IUR37 has been detected in both human and mouse Abl-transformed cell lines after imatinib treatment. Interestingly, lncRNA-IUR37 expression levels were significantly lower in leukemic cells derived from Bcr-Abl-positive ALL patients than those in normal control group. Furthermore, altering lncRNA-IUR37 expression remarkably affected survival of Abl-transformed leukemic cells, and tumorigenesis induced by these leukemic cells in xenograft mouse model. Knockdown of lncRNA-IUR37 in transgenic mice significantly promoted Bcr-Abl-mediated primary bone marrow transformation, and leukemia development in leukemia mouse model. These results indicate that lncRNA-IUR37 functions as a suppressor gene in Bcr-Abl-induced tumorigenesis. In addition, we demonstrated that lncRNA-IUR37 directly bound and affected the phosphorylation of STAT5, thereby impacting expression of transferrin receptor protein (TfR or CD71) to regulate leukemic cell survival. Together, our observations suggest that lncRNA-IUR37 is critically involved in Bcr-Abl-mediated leukemogenesis, and provide novel insights into complicated mechanisms underlying cellular transformation by Bcr-Abl oncogene.
Citation Format: Jilong Chen, Xuefei Wang. Identification of a novel imatinib upregulated lncRNA family that is required for efficient cellular transformation by Abl oncogene [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 3571.
Abstract 3595: DSP-0692, a selective SCD inhibitor, enhances the anti-tumor activity of anti-PD1 antibody
Authors: Sugaru Eiji , Furuta Yudai , Nagagaki Yoshikazu , Ikeda Satoshi , Fukunaga Yuichi , Umehara Hiroki , Otsubo Tsuguteru , Watanabe Manabu , Tojo Shingo , Hashizume Miki , Matsuki Yasushi , Ban Hitoshi 
Published: August 2019

Abstract
SCD (Stearoyl-CoA Desaturase), a key enzyme for lipid metabolism, is overexpressed in various types of cancer and plays an important role in cancer cell proliferation. We have previously shown that the identification and the functional characterization of DSP-0692, a novel and selective SCD inhibitor. SCD expression was induced in tumor cells cultured in sphere conditions, which were resistant to conventional agents within therapeutic concentration. DSP-0692 showed strong growth inhibition when tumor cells were cultured in sphere conditions, but had little impact on cells cultured under adherent conditions. In addition, DSP-0692 decreased the expression of stemness-related genes in tumor cells as well as in tumor tissues. Treatment with DSP-0692 suppressed tumor growth in multiple models both in single agent or in combination with conventional chemotherapies. DSP-0692 also inhibited WNT/beta-catenin signaling pathway through two different mechanisms (inhibition of Wnt3A secretion and nuclear translocation of beta-catenin). DSP-0692 exhibited lower IC50 value to sphere cells carrying mutations related to WNT/beta-catenin signaling pathway than those without these mutations. Blockade of the coinhibitory checkpoint molecule PD-1 has emerged as an effective treatment for many cancers. However, despite successes in the clinical setting, only a limited subpopulation respond to PD-1 blockade. We hypothesized that the deregulated lipid metabolism of tumor cells and microenvironment function as a barrier to antitumor immunity, and therefore that normalization of lipid metabolism with DSP-0692 might restore response to immunotherapy. Combination of DSP-0692 with anti-PD-1 antibody in the syngeneic CT-26 colon model, a resistant model to anti-PD-1 antibody, augmented tumor regressions relative to each single agent alone. DSP-0692 induced PD-L1 and PD-L2 expression in CT-26 cells, indicating that it is one of a mechanism of restoration of the effect of anti-PD-1 antibody. Our data suggest that remodeling the lipogenic tumor microenvironment has potential to convert patients resistant to immunotherapy into those who may receive clinical benefit of immunotherapy.
Citation Format: Eiji Sugaru, Yudai Furuta, Yoshikazu Nagagaki, Satoshi Ikeda, Yuichi Fukunaga, Hiroki Umehara, Tsuguteru Otsubo, Manabu Watanabe, Shingo Tojo, Miki Hashizume, Yasushi Matsuki, Hitoshi Ban. DSP-0692, a selective SCD inhibitor, enhances the anti-tumor activity of anti-PD1 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 3595.
Abstract 3673: The BMI1/Sp1/IGF1R pathway mediates pemetrexed resistance in non-small cell lung cancer cells
Authors: Wang Wen-Ling , Chien Peng-Ju , Chang Wen-Wei , Wang Bing-Yen 
Published: August 2019

Abstract
Background: Lung cancer is the leading cause of cancer death in Taiwan and worldwide and non-small cell lung cancers (NSCLCs) account for more than 85% of lung cancers. Pemetrexed is approved for several steps of nonsquamous NSCLC therapy but drug resistance often occurs in long-term treatment. Cancer stem cells (CSCs) are considered as the rare subpopulation of cancer cells with the features of tumor initiation, drug resistance, and metastatic capability. The signaling pathway and potential targets contribute to the maintenance of pemetrexed-resistant cancer stem cell remain unknown.
Methods: To investigate the mechanism of pemetrexed resistance in lung cancers, the pemetrexed-resistant A549 cells were established (A400). The sphere-formation assay, western blot analysis and real-time qPCR were employed to identify cancer stem cells and study their properties.
Result: We first discovered that the pemetrexed-resistant A549 cells (called A400) contained more CSC activity than the parental A549 cells including the increased number of tumorspheres and the upregulation of BMI1, c-Myc, Sox2 and p-IGF1Rtyr1165/1166 expression. The treatment of PTC-209, a BMI1 inhibitor, displayed a greater inhibitory effect in cell proliferation in A400 than A549 cells and it suppressed tumorsphere formation capability of A400 cells. In addition, PTC-209 treatment downregulated the expression of IGF1R, p-IGF1Rtyr1165/1166, and Sp1, a positive regulatory transcriptional factor in IGF1R expression, in A400 cells. We also found that Sp1 was increased in A400 when compared to parental A549 cells. With the treatment of Sp1 inhibitor in A400 cells, the expression of IGF1R was suppressed without changing BMI1 level. Finally, we examined the therapeutic effect of BMI1 inhibition in vivo and resulted found that intraperitoneal administration of PTC-209 enhanced the pemetrexed efficacy in NOD/SCID mice harboring A400 xenograft tumors.
Conclusion: Our data reveal that BMI1/Sp1/IGF1R pathway is upregulated in pemetrexed resistant NSCLCs and targeting BMI1 could be a therapeutic strategy in NSCLCs when pemetrexed resistance occurs.
Citation Format: Wen-Ling Wang, Peng-Ju Chien, Wen-Wei Chang, Bing-Yen Wang. The BMI1/Sp1/IGF1R pathway mediates pemetrexed resistance in non-small cell lung 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 3673.
Abstract 3701: Fn14 overexpression in RCAS/tv-a rat gliomas promotes tumor progression, increases invasion and decreases survival
Authors: Connolly Nina , Ames Heather , Tran Nhan L. , Kim Anthony , Winkles Jeff , Woodworth Graeme 
Published: August 2019

Abstract
Fibroblast growth factor-inducible 14 (Fn14) is the cell surface receptor for the tumor necrosis factor (TNF) family member TNF-like weak inducer of apoptosis (TWEAK). The Fn14 gene is not normally expressed in healthy tissues, but expression is significantly increased in many primary solid tumor types, including glioblastoma (GBM). High Fn14 expression in tumors is often associated with the stimulation of cancer cell invasion leading to diffuse, aggressive tumors and metastasis. To investigate the effects of increased Fn14 expression in brain tumors, two different tumor types were developed using the RCAS/tv-a transgenic rat model: a low-Fn14, “proneural-like” (PDGFA/shP53 derived) tumor and a high-Fn14 (PDGFA/shP53/Fn14-derived) tumor. Interestingly, rats with high-Fn14 brain tumors had a significantly shorter median survival compared to those with low-Fn14 with 42 days and 70 days median survival, respectively. Using MR proton spectroscopy, both tumor types exhibited the markers of a malignant glioma such as increases in choline to creatinine ratio (Cho/Cr) and decreases in neuronal activity (NAA); however, high-Fn14 tumors also displayed an increase in lactate during tumor progression which is often a sign of high grade, necrotic tumors and poor prognosis. Morphologically, the two tumor subtypes appear quite different. H&E staining of the high-Fn14 tumors showed a highly malignant tumor with several areas of pseudopalisading necrosis within the tumor core. This is different than the somewhat more homogeneous morphology of the low-Fn14 proneural-like tumor. The pattern of tumor cell invasion also differs between the two brain cancer subtypes. High-Fn14 tumors show a more human GBM-like pattern by invading along the white matter tracts whereas low-Fn14 tumors appear to invade more locally with minimal white matter invasion. High-Fn14 tumors were positive for Fn14 throughout the tumor including the invasive rim of the tumor, which is also seen in human GBM, whereas the low-Fn14 tumor revealed very little staining even at the invasive rim. These findings indicate that increased Fn14 expression creates a more malignant brain tumors that develops and behaves more aggressively then low-Fn14 tumors.
Citation Format: Nina Connolly, Heather Ames, Nhan L. Tran, Anthony Kim, Jeff Winkles, Graeme Woodworth. Fn14 overexpression in RCAS/tv-a rat gliomas promotes tumor progression, increases invasion and decreases survival [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 3701.
Abstract 3724: Molecular mechanisms of TTField action determined by measurements and modelling of electro-conductive properties of microtubules
Authors: Kalra Aarat P. , Patel Sahil , Bhuiyan Asadullah , Preto Jordane , Rezania Vahid , Lewis John D. , Shankar Karthik , Tuszynski Jack 
Published: August 2019

Abstract
Biological effects of AC electric fields at frequencies between 100-300 kHz discovered a decade ago are being applied to cancer cells as a therapeutic modality in the treatment of glioblastoma multiforme (GBM). They are called Tumor Treating Fields (TTFields) as they disrupt cell division. Based on our electro-conductive measurements and modeling, we provide an assessment of possible molecular-level mechanisms. Computer simulations and experimental measurements carried out for microtubules and actin filaments are presented. Charge and dipole values for monomers and dimers as well as polymerized forms of these proteins are summarized. Continuum approximations for cable equations describing actin filaments and microtubules compare favorably to measurements in buffer solutions showing soliton waves and transistor-like amplification of ionic signals, respectively. AC Conductivity and capacitance of tubulin and microtubules have been measured and modeled in the range of frequencies between 1 Hz and 1 MHz. A dramatic change in conductivity occurs when tubulin forms microtubules. In living cells, this signals a conductive phase transition coinciding with mitosis in dividing cells. This process is allowed by TTField penetration into the cleavage furrow in dividing cells and provides the most significant mechanistic explanation of the observed effects. We provide estimates of the forces, energies and power involved in the action of TTFields on microtubules and kinesin motors. These calculations are compared and contrasted with typical values experienced at a cell level and provide strong arguments for real physical effects of TTFields in dividing cells. We also show results of DLS and TEM measurements on microtubules and tubulin oligomers in solution, which allow us to quantify these processes under controlled conditions. In conclusion, the most likely candidates to provide a quantitative explanation of these effects are ionic condensation waves around microtubules as well as dielectrophoretic effects on the dipole moments of microtubules.
Citation Format: Aarat P. Kalra, Sahil Patel, Asadullah Bhuiyan, Jordane Preto, Vahid Rezania, John D. Lewis, Karthik Shankar, Jack Tuszynski. Molecular mechanisms of TTField action determined by measurements and modelling of electro-conductive properties of microtubules [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 3724.