bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A003: Anti-angiogenic activity of the CXCR4 antagonist balixafortide
Authors: Zimmermann Johann , Obrecht Daniel , Remus Tobias 
Published: March 2020

Abstract
Background: Balixafortide is a potent and selective antagonist of the chemokine receptor CXCR4, and is in PhIII for metastatic HER2-negative breast cancer in combination with eribulin (NCT03786094). Clinical proof-of concept of the combination with comparable tolerability to that of eribulin monotherapy was demonstrated in a recent PhI single arm dose-escalation trial (NCT01837095). Balixafortide can inhibit tumor growth through several mechanisms including chemosensitization in combination with chemotherapy (e.g. eribulin), suppression of metastasis, and activation of immune cell response in the tumor microenvironment. In addition, data regarding the co-regulation of the angiogenic factor VEGF and CXCR4 in colorectal cancer (CRC) tissue suggest a possible anti-angiogenic activity of Balixafortide. Methods: VEGF alpha-induced migration of endothelial cells and vascular permeabilization were assessed in vitro. Changes in VEGF alpha levels were determined in CXF260 CRC PDX tumor samples by Nanostring and in CXF260 cells in vitro by qPCR. Results: Balixafortide potently inhibited VEGF alpha-induced migration and permeabilization of an endothelial monolayer in vitro and reduced VEGF alpha levels in both, cultured CXF260 tumor cells in vitro and CXF260 tumors in vivo. Conclusions: Balixafortide modulates angiogenic mechanisms in vitro and in vivo and suggests further investigation of balixafortide in anti-angiogenic therapies.
Citation Format: Johann Zimmermann, Daniel Obrecht, Tobias Remus. Anti-angiogenic activity of the CXCR4 antagonist balixafortide [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A003. doi:10.1158/1535-7163.TARG-19-A003
Abstract A006: Preclinical models from rare aggressive tumors: Establishment, drug sensitivity and genomic analyses of mesothelioma PDX as models for oncology drug development
Authors: Becker Michael , Brzezicha Bernadette , Rolff Jana , Conrad Theresia , Rau Beate , Walther Wolfgang , Hoffmann Jens 
Published: March 2020

Abstract
Malignant mesothelioma is a rare but aggressive disease with few therapeutic options and a poor prognosis. The main cause of the disease is the exposition to asbestos, even after 50 years of latency. Intended therapeutic goals, such as increase of patient survival and improvement of quality of life have only been achieved to a limited extent. Curative treatment is currently still not possible. Therefore, there is a strong clinical need for translational models. For this, we have characterized patient-derived xenograft models (PDX) of mesothelioma to evaluate their suitability for preclinical research. For PDX establishment, tumor tissue from surgically resected pleura or peritoneum mesotheliomas, was implanted subcutaneously into immunodeficient mice and serially passaged for at least 3 in vivo-passages. Established PDX models were characterized towards sensitivity to standard of care drugs. PDX tissue was collected for RNA sequencing and immunohistochemistry. The generated molecular profiles (comparative gene expression and sequence variations) of the models were analyzed comprehensively. A panel of 6 mesothelioma PDX has been established. In these PDX models, characteristic histological structure of the original patient tumor was preserved. The PDX models responded individually to standard of care drugs like pemetrexed, cisplatin, and gemcitabine as well as combinations thereof. The combination of pemetrexed or gemcitabine with cisplatin showed a stronger tumor growth inhibition than the respective monotherapies. The analyzed mutational and gene expression landscape resembles the known pattern of mesotheliomas. In summary, our established mesothelioma PDX will serve as a preclinical tool to investigate cellular and molecular mechanisms of drug sensitivity and resistance. They will provide a valuable preclinical model system to identify and validate biomarkers and to develop new therapeutic approaches.
Citation Format: Michael Becker, Bernadette Brzezicha, Jana Rolff, Theresia Conrad, Beate Rau, Wolfgang Walther, Jens Hoffmann. Preclinical models from rare aggressive tumors: Establishment, drug sensitivity and genomic analyses of mesothelioma PDX as models for oncology drug development [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A006. doi:10.1158/1535-7163.TARG-19-A006
Abstract A012: Mammary fat pad injections: An alternative implantation method for syngeneic tumor models
Authors: Obodozie Cynthia , Ruf Susanne , Bijelic Gojko , Moor Sandra , Giesen Bianca , Leisegang Ulrike , Dempe Sebastian , Weber Holger 
Published: March 2020

Abstract
Syngeneic tumor models used for discovery of immune therapeutics should have several features such as a long study duration, responsiveness to checkpoint inhibitors, high immune cell infiltration and a high homogeneity in tumor growth. Moreover, models should consider the ethical rules (3R reduce, refine, replace). At present, the standard implantation method for syngeneic tumor models is subcutaneous tumor cell inoculation. We have developed an alternative implantation method for syngeneic tumor models: inoculation into the mammary fat pad. Both implantation sides are heterotopic related to the original tumor entity except for syngeneic breast tumor cells. In addition, both tumor inoculation methods can easily be applied and monitored by calipering reducing the costs. We compared the two implantation methods with models MC38-CEA, Ct26wt, Hepa1-6, RENCA, LL-2, AB12, CloneM3, B16.F10, 4T1 and EMT-6 tumor cells in respect to growth characteristics and immune response. Intra-mammary tumor growth showed more homogeneity with higher final tumor volumes compared to the subcutaneous tumor growth. Moreover, in all tested syngeneic models, tumor ulceration was prevented by almost 100% when injecting the tumor cells into the mammary fat pad. In contrast, animals of the subcutaneous tumors were mainly euthanized due to tumor ulceration. Both findings favor the mammary fat pad injection with regard to the 3R rules by strongly reducing tumor ulceration (refinement) and animal number due to a more homogenous growth (reduction). In addition, the immune checkpoint inhibitor treatment was tested and found comparable between the intra-mammary and subcutaneous models. The presence of immune cell populations was investigated in the Ct26wt colon tumor model time-dependently by flow cytometry using a 17 marker-staining panel . The number of isolated cells per gram tumor mass was more than doubled in the intra-mammary tumors. In conclusion, tumor models of the heterotopic intra-mammary implantation side are found to be superior compared to the traditional subcutaneous tumor models: a higher tumor homogeneity with no tumor ulceration, combined with a high number of immune cells and connective stroma tissue, making the mammary fat pad implantation of syngeneic tumor cells the implantation side of choice.
Citation Format: Cynthia Obodozie, Susanne Ruf, Gojko Bijelic, Sandra Moor, Bianca Giesen, Ulrike Leisegang, Sebastian Dempe, Holger Weber. Mammary fat pad injections: An alternative implantation method for syngeneic tumor models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A012. doi:10.1158/1535-7163.TARG-19-A012
Abstract A038: Assessment of angiogenesis markers in advanced cervical carcinoma patients that received chemoradiation therapy plus/minus neoadjuvant chemotherapy
Authors: ARAI ROBERTO JUN , COSTA THIAGO RODRIGUES DA , FERREIRA SILVANEIDE , SICHERO LAURA , DIZ MARIA PILAR ESTEVEZ 
Published: March 2020

Abstract
The expression profile of angiogenesis associated proteins was assessed in patients with locally advanced cervical cancer included in a prospective, randomized phase II study. The majority of patients had squamous cell carcinoma (87.8%). Group A individuals were treated with neoadjuvant chemotherapy (cisplatin and gemcitabine) (NAC), followed by chemoradiation with cisplatin (CRT). Group B patients received CRT. Serum samples from patients in group A were collected at 03 different time points (at baseline (n=34), after NAC (n=24), and after CRT (n=27)). Samples of group B were collected in 02 different time points (at baseline (n=40) and after CRT (n=34)). Samples were grouped and evaluated with a non-parametric Mann-Whitney test where we considered the points as independent groups. The Friedman test (ANOVA) was used for analysis of group A (with three evaluation points). The levels of different proteins associated with angiogenesis (EGF, angiopoietin, G-CSF, endothelin-1, FGF-1, follistatin, IL-8, HGF, HB-EGF, PLGF, VEGF- D, VEGF-A and FGF-2) were assessed by a Multiplex Assay using the Luminex® technology. HB-EGF, IL-8 and VEGF-C were significantly decreased in patients from group A, whereas all others biomarkers did not present intra or intergroup differences. NAC was associated with an inferior PFS (progression free survival), with 3-year PFS rates of 40.9% compared with 60.4% in the CRT arm (HR, 1.84; 95% CI, 1.04 – 3.26; P = .033). NAC was also associated with a lower OS (overall survival) (3-year OS, 60.7% vs 86.8%; HR, 2.79; 95% CI, 1.29-6.01; P=0.006). After treatment completion, complete response rates were 56.3% in the NAC arm and 80.3% in the CRT arm (P=0.008). Toxicities were similar in both arms, with the exception of hypomagnesemia and neuropathy that were more commonly observed within NAC individual. We can conclude, within the limitations of presented study, that the NAC in group A results in significant alterations in specific markers associated with angiogenesis.
Citation Format: ROBERTO JUN ARAI, THIAGO RODRIGUES DA COSTA, SILVANEIDE FERREIRA, LAURA SICHERO, MARIA PILAR ESTEVEZ DIZ. Assessment of angiogenesis markers in advanced cervical carcinoma patients that received chemoradiation therapy plus/minus neoadjuvant chemotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A038. doi:10.1158/1535-7163.TARG-19-A038
Abstract A090: A novel THO complex member LENG8 connects mRNP export, genome integrity and tumorigenesis
Authors: Zhang Nan , Zhao Yongxu , Chen Jianxia , Ding Qiurong , Liu Feng 
Published: March 2020

Abstract
THO/TREX complex is evolutionarily conserved from yeast to human and required for both of mRNP export and genome integrity, but the underlying mechanism remains unknown. Here we demonstrate that DNA damage represses mRNA biogenesis and export, and recruits mRNP to the DNA damage foci. LENG8, an evolutionarily conserved nuclear protein, is a novel member of THO/TREX complex and connects the mRNP machinery with poly(ADP-ribosyl)transferase PARP1. The expression of THOC1 and LENG8 are lower in various human tumors including gastric tumors as well as lung cancers, and their abundancy correlates with poor prognosis of patients. We show that knockdown of THOCs or LENG8 promotes proteolytic cleavage of PARP1, suppresses DNA repair and therefore increases tumor growth both in vitro and in vivo. Our findings suggests THO/TREX complex as a novel regulator of genome integrity and a potential therapeutic target in cancer prevention and treatment.
Citation Format: Nan Zhang, Yongxu Zhao, Jianxia Chen, Qiurong Ding, Feng Liu. A novel THO complex member LENG8 connects mRNP export, genome integrity and tumorigenesis [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A090. doi:10.1158/1535-7163.TARG-19-A090
Abstract B010: SOX2-mediated 5hmC dysregulation in GBM Stem Cells
Authors: Lopez-Bertoni Hernando 
Published: March 2020

Abstract
Primary brain tumors are among the most devastating forms of cancer and glioblastoma (GBM) represents the most aggressive and lethal form of the disease. We now know that GBM contain small subsets of cells that display tumor-propagating stem-like phenotypes (i.e. glioma stem cells or GSCs) that act as critical determinants of GBM resistance to current treatments and tumor recurrence for which there is no proven therapy. Altered patterns of DNA methylation are widely reported in human GBM. However, substantial knowledge gaps remain in our understanding of the molecular mechanisms responsible for this epigenetic dysregulation, its downstream consequences and role in the GBM tumor propagating phenotype. Understanding and ultimately targeting the epigenetic mechanisms that induce and maintain these tumor-propagating cell subsets is critical to improving GBM therapy and patient outcomes. DNA methylation generally occurs in cytosine-guanine (CpG) sequences and is established by DNMTs, which catalyze the conversion of cytosine to 5-methylcytosine (5mC). DNA methylation is a reversible process and is partially mediated by the ten-eleven translocation (TET) family of enzymes which function as deoxygenases to catalyze the conversion of 5mC to 5-hydroxymethylcytosine (5hmC). Levels of 5hmC closely track with the differentiation state of cells with terminally differentiated cells containing high levels of 5hmC and less differentiated cells having very low levels. Multiple studies found negative correlations between 5hmC levels and glioma grade and loss of 5hmC correlates with poor prognosis of GBM patients, strongly suggesting that these enzymes activate tumor suppressing mechanisms. Our preliminary data shows that exogenous SOX2 represses the TET2 demethylase and decreases 5hmC, the enzymatic product catalyzed by TET proteins, in GSCs. TET2 repression using 2 independent shRNA hairpins efficiently decreases 5hmc levels and significantly enhanced self-renewal capacity and tumor growth capacity of low-passage GSC isolates. We also show that SOX2 induces expression of miR-10b-5p, a known onco-miR predicted to target TET2, and inhibiting this miRNA partially rescues the reduction in 5hmC expression observed in GSCs expressing transgenic SOX2, thus implicating miR-10b-5p as a critical mediator of SOX2-induced onco-methylation, GSC induction and glioma malignancy. Our preliminary results support a mechanism in which SOX2 represses TET2 leading to 5hmC loss by directly activating miR-10b-5p transcription and predicts that targeting this novel mechanism of epigenetic dysregulation by inhibiting miR-10b-5p in vivo will can lead to pre-clinical GBM therapeutics.
Citation Format: Hernando Lopez-Bertoni. SOX2-mediated 5hmC dysregulation in GBM Stem Cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B010. doi:10.1158/1535-7163.TARG-19-B010
Abstract B036: Targeting Hsp90-Cdc37 complex in glioma harboring FGFR3-TACC3
Authors: Li Tao , Mehraein-Ghomi Farideh , Namjoshi Sanjeev V. , Song Qian Qian , Ballard Elizabeth A. , Forbes Mary E. , Chou Ping-Chieh , Yang Xuejun , Zhang Wei 
Published: March 2020

Abstract
Glioblastoma is one of the most lethal central nervous system tumors with the poorest prognosis. Fusion genes are common chromosomal aberrations in malignancies that can be used as prognostic markers as well as drug targets in clinical practice. The FGFR3-TACC3 (F3T3) fusion gene was discovered in glioblastoma, with an occurrence rate of up to 8.3% and leading to uncontrolled proliferation and chromosomal instability. Our previous study has shown that F3T3, generated by a rearrangement of chromosome, led to the loss of the 3′-UTR of FGFR3, blocking epigenetic regulation of miR-99a and enhancing expression of the fusion gene. To further explore whether there is a post-translational regulation on F3T3 protein, we immunoprecipitated (IP) the proteins that interact with F3T3 in U251 glioblastoma cells overexpressing the F3T3 or wild-type FGFR3, followed by LC-MS/MS analyses. Quantitative proteomic analysis suggest a stronger interactions of the F3T3 fusion protein with Hsp90 and Cdc37 proteins when compared with wild-type FGFR3. To test inhibition of F3T3 association with the Hsp90-Cdc37 complex, we treated U251 and LN229 cells constitutively expressing F3T3 with either Hsp90 inhibitors or siRNA of Cdc37. Targeting Hsp90-Cdc37 complex significantly suppressed the activation of F3T3 and downstream signaling pathways. Intriguingly, both Hsp90 and Cdc37 inhibition caused a degradation of glycosylation form of F3T3 protein. F3T3 was found highly expressed in both the untreated and matched recurrence glioblastoma, indicating a resistance to the concurrent radiotherapy and temozolomide (TMZ) treatment. Our results provide evidence that the F3T3 fusion gene confers drug resistance to TMZ induced DNA damage and using Hsp90 inhibitor chemosensitizes F3T3 glioma cells to TMZ. In conlusion, our findings establish that F3T3 is an strong Hsp90 client that shows strong addiction to the Hsp90-Cdc37 complex and suggests a novel strategy for targeting F3T3 fusion gene in glioma.
Citation Format: Tao Li, Farideh Mehraein-Ghomi, Sanjeev V. Namjoshi, Qian Qian Song, Elizabeth A. Ballard, Mary E. Forbes, Ping-Chieh Chou, Xuejun Yang, Wei Zhang. Targeting Hsp90-Cdc37 complex in glioma harboring FGFR3-TACC3 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B036. doi:10.1158/1535-7163.TARG-19-B036
Abstract B068: The establishment of a large tumor organoid biobank using a well characterized/annotated patient-derived xenograft (PDX) library to enable drug discovery and translational research
Authors: Xu Xiaoxi , Shang Limei , Wang Lili , Li Chunmei , Liu Yan , Han Peng , Sun Zhongman , Qu Yaping , Zhang Likun , Chen Bonnie Xiaobo , Ouyang Davy Xuesong , Huang Yujun , Li Henry Qixiang 
Published: March 2020

Abstract
Background: Patient derived xenograft (PDX), a cancer stem cell (CSC) derived in vivo model, is an accepted model of choice for preclinical and translational research due to its proven predictive power. Patient derived cancer organoids (PDOs), also CSC-derived 3D culture of carcinoma with defined structures, harbor carcinoma’s multicellular components and mimics cancer lesion structures/heterogeneity, both genomicly and histopathologically. PDO was first described by Hans Clevers Lab and proven to be a predictive model for preclinical research, similar to PDX. Method: We have used the Hubrecht organoid technology (HUB approach to systematically create the worlds-first biobank of organoids derived from a well annotated PDX library (the world’s largest with &gt;2,500, covering a variety of carcinomas, with extensive pathology, genomic and treatment information), referred to as PDXOs. We then systematically profiled these PDXOs by WES (whole exome sequencing)/RNAseq (transcriptome sequencing), histopathology and standard of care (SOC) treatment. Results: At present, we have established &gt; 100 PDXOs covering &gt; 9 cancer types, including bladder, breast, colorectal, gastric, liver, lung, ovarian and pancreatic cancer, cholangiocarcinoma, etc. Histopathological analysis showed cellular/structural similarities (ductal, mucous or carcinoid) between PDXO and original PDX, suggesting that tissue specific structural features were maintained in the 3D organoids. A high throughput screening (HTS in 384 well) format was established using the PDXOs and SOC sensitivity testing was conducted. The preliminary results largely correlated to the SOC response seen in vivo for the corresponding PDXs. Conclusion: In summary, we have successfully established a large biobank of the PDXOs that mirror the original PDXs, creating a unique library of matched in vitro/in vivo models with high translational power and enabling HTS, thus likely become an important tool for the future oncology drug discovery and development tools.
Citation Format: Xiaoxi Xu, Limei Shang, Lili Wang, Chunmei Li, Yan Liu, Peng Han, Zhongman Sun, Yaping Qu, Likun Zhang, Bonnie Xiaobo Chen, Davy Xuesong Ouyang, Yujun Huang, Henry Qixiang Li. The establishment of a large tumor organoid biobank using a well characterized/annotated patient-derived xenograft (PDX) library to enable drug discovery and translational research [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B068. doi:10.1158/1535-7163.TARG-19-B068
Abstract B078: Inhibition of the MAPK pathways enhances the sensitivity of triple negative breast cancer cells to chemotherapeutic drugs
Authors: Bhatt Akshita B. , Wright Thomas D. , Patel Saloni , Chakrabarty Suravi , Barnes Van , Burow Matthew , Flaherty Patrick T. , Cavanaugh Jane 
Published: March 2020

Abstract
Triple negative breast cancer is characterized by the loss of hormone receptors and lack of targeted therapy. Most invasive cancers, including triple negative (TNBC) breast cancer have a mesenchymal phenotype, which is associated with increased chemoresistance. Activation of the MEK1/2 and MEK5 pathways plays a crucial role in the activation of the epithelial to mesenchymal transition program and increases the survival, proliferation, and migration of the cancer cells. Disruption of actin skeleton via ras and src mediated activation of extracellular regulated kinase 1/2 (ERK1/2) and ERK5 is reported, indicating their role in oncogenic transformation. Moreover, inhibition of either pathway results in a compensatory increase in the PI3K/AKT pathway. These crosstalk mechanisms are involved in mediating therapeutic drug resistance. MDA-MB-231, a BRAF and KRAS mutant TNBC cell line has more than 90% of high CD44+/CD24-/low stem cell population, and high ERK5 and ERK1/2 expression; hence it was used as the model for our experiments. Moreover, MDA-MB-231-ERK5-KO cells were utilized to confirm the mechanism of action. To target TNBC, known inhibitors of the MEK1/2 pathway: trametinib, an FDA approved drug for BRAF mutant melanoma, VX-11-e, an ERK2 inhibitor, and XMD-8-92, an ERK5 inhibitor were used in combination with the chemotherapeutic drugs paclitaxel and doxorubicin to examine cell viability. We have shown that dual inhibition of the ERK5 and AKT signaling pathways synergistically reduces TNBC cell viability and enhances sensitivity of the cells to paclitaxel. A series of novel quinazoline derivatives was generated to dually target the ERK5 and the AKT pathway. The effect of novel quinazolines on cell viability in combination with the chemotherapeutic agent paclitaxel was examined in the TNBC cells and some encouraging results were obtained. The overall significance of this research is to enhance the anti-cancer activity of chemotherapeutic agents and reduce off-target toxicity by dose-reduction strategy.
Citation Format: Akshita B. Bhatt, Thomas D. Wright, Saloni Patel, Suravi Chakrabarty, Van Barnes, Matthew Burow, Patrick T. Flaherty, Jane Cavanaugh. Inhibition of the MAPK pathways enhances the sensitivity of triple negative breast cancer cells to chemotherapeutic drugs [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B078. doi:10.1158/1535-7163.TARG-19-B078