bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3764: Trabectedin activity in patient-derived mesothelioma xenografts
Authors: Licandro Simonetta Andrea , Frapolli Roberta , Bello Ezia , Libener Roberta , Orecchia Sara , Grosso Federica , D’Incalci Maurizio 
Published: July 2016

Abstract
Malignant pleural mesothelioma (MPM) incidence is increased over the past two decades and it is predicted to increase further in the next 20 years especially in developing countries where asbestos has not yet been banned. Surgery is not an option for the majority of patients due to the diffuse growth of MPM, making chemotherapy the treatment of choice, but prognosis remains very poor with a median survival time of 10-17 months. Trabectedin (ET-743, Yondelis) is a marine alkaloid used for the 2nd line therapy of ovarian cancer (combined with pegylated doxorubicin) and soft tissue sarcomas. It binds the DNA minor groove modulating transcription of cancer cells and has an anti-inflammatory effect modifying tumor microenvironment and reducing tumor associated macrophages.
The aim was to test antitumor activity of trabectedin in newly established patient derived xenografts of MPM.
MPM473, MPM484 and MPM487 xenografts were obtained in athymic nude mice by s.c. injection of 107 cells isolated from the pleural effusion of MPM patients and maintained by serial passages in mice. H&E staining and immunohistochemistry were performed. Mice were randomized when tumor reached about 200 mg to receive trabectedin, cisplatin, pemetrexed, gemcitabine, and imatinib. Antitumor activity was expressed as T/C% were T and C are the mean tumor weight of treated and control mice, respectively.
The three xenografts reproduced the morphology and the histochemical profile of the human tumors. As reported in the table trabectedin was able to induce a 50% reduction in tumor growth in MPM473 and MPM 487 xenografts and only a marginal effect in MPM484 xenograft. TreatmentDose (mg/kg)ScheduleBest T/C% (Day)MPM473MPM484MPM487Cisplatin5i.v. q7dx361.9 (69)66.1 (69)67.3 (39)Gemcitabine100i.p. q4dx583.2 (41)67.7 (48)49.7 (56)Imatinib200p.o. qdx1568.9 (76)89.4 (55)87.1 (39)Pemetrexed250i.p. q4dx477.4 (52)76.8 (49)84.3 (39)Trabectedin0.15i.v. q7dx351.0 (73)63.6 (69)51.3 (56)
In conclusion we report three new MPM xenografts able to mimic the pathological features of human MPM. Although trabectedin showed only a moderate antitumor activity in our experimental models, its efficacy is comparable or better than that of the other drugs currently used for this disease. Studies are in progress in syngenic models that are more appropriate to test also the ability of trabectedin to modulate the immune system.
Citation Format: Simonetta Andrea Licandro, Roberta Frapolli, Ezia Bello, Roberta Libener, Sara Orecchia, Federica Grosso, Maurizio D’Incalci. Trabectedin activity in patient-derived mesothelioma xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3764.
Abstract 3785: Targeting PDLIM5 for lung cancer
Authors: Park Deborah , Cheng Han , Chen Tianji , Tor Merve , Khatib Nour , Huang Jason , Zhou Qiyuan , Rong Lijun , Zhou Guofei 
Published: July 2016

Abstract
Rationale: Lung cancer is the most common cause of cancer-related death in the United States and worldwide. Despite decades of efforts on research and smoking cessation, the 5-year survival rate of lung cancer patients remains poor at 15%, and the population of adenocarcinoma cases in nonsmokers is rising. PDLIM5, a member of the Enigma subfamily of PDZ and LIM domain protein family, contains an N-terminal PDZ domain and 3 LIM domains at its C-terminus. We have previously shown that PDLIM5 regulates TGF-β/Smad family, which are known to participate in the pathogenesis of lung cancer. In this study, we aim to investigate whether PDLIM5 plays a role in lung cancer and establish a high throughput screening (HTS) platform for PDLIM5-targeted drug discovery.
Methods: We searched the Oncomine data base for PDLIM5 gene expression. We suppressed PDLIM5 in A549 cells and determined the expression levels of epithelial-mesenchymal transition markers. We exposed A549 cells to hypoxia or treated them with TGF-β1 and measured the expression levels of PDLIM5. We generated a stable mink lung epithelial cell line (MLEC) containing a TGFβ/Smad luciferase reporter with lentivirus-mediated suppression of PDLIM5 (MLEC-shPDLIM5) and measured levels of Smad2/3 and pSmad2/3. We used MLEC-shPDLIM5 and a control cell line (MLEC-shCTL) to screen the Prestwick library (1,200 compounds). We treated MLEC and A549 cells with paclitaxel and determined levels of Smad2/3 and pSmad2/3.
Results: We found that PDLIM5 was overexpressed in non-small-cell lung carcinoma (NSCLC) patients and that the expression levels of PDLIM5 inversely correlated with the survival rate of lung cancer patients. Hypoxia but not TGF-β1 induced PDLIM5 expression levels. Suppression of PDLIM5 induced E-cadherin levels while decreased levels of vimentin and α-SMA. In MLEC, suppression of PDLIM5 decreased Smad-dependent luciferase activity, smad3, and pSmad2. More importantly, we identified and validated that paclitaxel as a PDLIM5 inhibitor in MLEC. Furthermore, we showed that paclitaxel inhibited Smad2 expression and Smad3 phosphorylation in A549 cells.
Conclusions: We have shown that PDLIM5 is overexpressed in lung cancer cells and its upregulation is hypoxia-dependent but TGF-β independent. Loss of PDLIM5 inhibits EMT. We have identified paclitaxel as a PDLIM5 inhibitor. This system is robust and suitable for PDLIM5 targeted drug discovery. Support: a UIC UICentre Arm1 Inception Grant, a Gilead Sciences Research Scholars Program in Pulmonary Arterial Hypertension award and R01 HL123804 (G. Zhou).
Citation Format: Deborah Park, Han Cheng, Tianji Chen, Merve Tor, Nour Khatib, Jason Huang, Qiyuan Zhou, Lijun Rong, Guofei Zhou. Targeting PDLIM5 for lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3785.
Abstract 3961: Methodological considerations in the preparation of biomimetic reference materials for ctDNA assays
Authors: Harkins Seth B. , Tomson Farol L. , Anekella Bharathi , Garlick Russell 
Published: July 2016

Abstract
Clinical utilization of cell-free DNA (cfDNA) has become commonplace for NIPS testing and has recently been more widely deployed to quantitate cell-free circulating tumor DNA (ctDNA) for use in cancer patient care longitudinally across the treatment spectrum from subclinical, to diagnosis and through treatment. The scarcity and unstable nature of the cfDNA analyte in human plasma is problematic and thus the lack of robust detection methods has limited clinical validation. In this work we sought to avoid the inherent limitations of plasma-based patient reference materials and developed a strategy to prepare a biomimetic reference material which is sufficiently equivalent to the cfDNA found in patients with malignant cancers. Thus far the scarcity and physical form of ctDNA in human plasma has attenuated the validation of assays for clinical utility. To this end, we have generated a biosynthetic construct with short DNA fragments containing relevant cancer mutation sequences, including single-nucleotide variations, insertions and deletions in BRAF, EGFR, KRAS, NRAS, PIK3CA or HER/ERBB2. The mutant fragments were titrated into normal human reference DNA, GM24385, and ultrasonically sheared to ∼160 bp. Precise allele frequency blends were verified by digital PCR (dPCR) prior to encapsulation to enhance stability and compatibility with commutable plasma. The reference material is formulated to 20 ng/mL of extractable DNA in modified Seracare Matribase™ to confer commutability in pre-analytic processes. These materials have been quantitated by dPCR and/or Next Generation Sequencing (NGS). A dilution panel was prepared at 10%, 5%, 2.5%, 1.25%, 0.1% allele frequency (mutant:normal DNA). Linearity (R2 = 0.9997) was observed by dPCR (measured vs. expected) and the NGS detected, Swift Accel-Amplicon 56G Oncology Panel (R2 = 0.997). Due to the low abundance of ctDNA, a characterized reference set is critical to validate assays that are developed with extremely low limit of detection. Data will be presented to show the breadth of this methodology and its utility in validating NGS and dPCR assays.
Citation Format: Seth B. Harkins, Farol L. Tomson, Bharathi Anekella, Russell Garlick. Methodological considerations in the preparation of biomimetic reference materials for ctDNA assays. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3961.
Abstract 4026: Epigenetic changes in T cells in response to immune checkpoint blockade
Authors: Goswami Sangeeta , Chen Jianfeng , Zhao Hao , Zhang Xuejun , Sharma Padmanee 
Published: July 2016

Abstract
Immune checkpoint blockade therapy has led to clinical success and have established immunotherapy as one of the primary modality of cancer treatment. It leads to a durable response in around 20% of the patients (responders). Success of immune checkpoint blockade therapy relies on the increase of effector T cells and decrease of regulatory T cells in the tumor microenvironment. However, the underlying mechanism that govern the ratio of effector and regulatory T cells between responder and non-responder to checkpoint blockade is not understood. Understanding the process could reveal novel mechanisms to boost efficacy of immune checkpoint blockade. Differentiation of naïve T cells into effector and regulatory phenotype requires lineage-specifying transcription factors and epigenetic modifications that allow appropriate repression or activation of gene transcription. One key epigenetic modification for T cell differentiation is trimethylation of lysine 27 on histone H3 (H3K27me3). Loss of H3K27me3 results in increased Th-1 plasticity whereas presence of H3K27me3 on Foxp3 locus is required to maintain the function of T-regulatory cells. We hypothesize that immune checkpoint blockade changes the epigenetic landscape in tumor infiltrating T cells that results in an effector phenotype and epigenetic modification of H3K27me3 could promote an anti-tumor immune microenvironment in tumor bearing mice.We showed that in-vivo inhibition of H3K27me3 in combination with anti-CTLA4 results in reduction of tumor size and also reduction in regulatory T cells in a B16-F10 melanoma mice model compared to anti-CTLA4 treatment alone, suggesting H3K27me3 inhibition could increase the efficacy of checkpoint blockade therapy. Future studies will aim to elucidate epigenetic changes in H3K27me3 and define an epigenetic signature as a result of immune checkpoint therapy by ChIP-sequencing. Data generated in this project will greatly enhance our understanding of epigenetic regulation of T cell differentiation is response to immune checkpoint blockade and aid identifying key changes that could be further modified to overcome resistance to immune checkpoint blockade in non-responders.
Citation Format: Sangeeta Goswami, Jianfeng Chen, Hao Zhao, Xuejun Zhang, Padmanee Sharma. Epigenetic changes in T cells in response to immune checkpoint blockade. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4026.
Abstract 4260: 3D colorectal cancer organoids as preclinical models for assessment of activity of RAF inhibitor BGB-283
Authors: Wu Xiaoran , Fu Chunyan , Yuan Xi , Zhang Lianhai , Wang Xiaohong , Ji Jiafu , Luo Lusong 
Published: July 2016

Abstract
Tumor organoids are three-dimensional (3D) cultures of cancer cells. They can be derived from the tumor cell lines, patient-derived xenografts and tumor tissues from cancer patients, thereby providing an attractive in vitro assay to optimize anticancer treatment. Oncogenic B-RAF, which drives cell transformation and proliferation, has been detected in 5-15% of colorectal cancers (CRC). Despite the remarkable clinical activities achieved by vemurafenib in treating B-RAF V600E metastatic melanoma, their clinical efficacy in B-RAF V600E CRC is far less impressive. BGB-283, currently under clinical development for RAF and RAS mutated solid tumors, is a novel inhibitor of the RAF dimer with inhibitory activities against RAF family kinases. In this study, we evaluated the anti-proliferative effect of BGB-283 and compared it to BRAF inhibitor vemurafenib in CRC patient tumor derived organoids models. BGB-283 exhibited therapeutic potentials in tumors with mutations in the MAPK pathway. Herein, we reported the establishment of tumor organoid models from 19 CRC patients’ tumor tissues with a success rate of 83%. Organoids maintained many characteristics of their original tumors based on their histology. Our studies using primary CRC tumor organoids showed that in contrast to vemurafenib, which only inhibited B-RAF V600E CRC tumors, BGB-283 had inhibition effect on both B-RAF V600E and KRAS mutated tumors. These findings support BGB-283 as a promising clinical stage antitumor agent in treating CRC harboring B-RAF V600E and KRAS mutations. In addition, we showed that patient-derived organoids can be a valuable tool to test drug sensitivity in a personalized treatment and help to fill the gap between tumor genetics and patient trials.
Citation Format: Xiaoran Wu, Chunyan Fu, Xi Yuan, Lianhai Zhang, Xiaohong Wang, Jiafu Ji, Lusong Luo. 3D colorectal cancer organoids as preclinical models for assessment of activity of RAF inhibitor BGB-283. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4260.
Abstract 4293: Combination of hepatocyte growth factor, genistein and daidzein concentrations as a biomarker for gastric cancer risk: A nested case-control study
Authors: Jang Jieun , Hwang Yunji , Ahn Choonghyun , Ko Kwang-Pil , Yoo Keun-Young , Park Sue K. 
Published: July 2016

Abstract
Backgrounds: Hepatocyte growth factor (HGF) induces ERK pathway which is associated with carcinogenesis by promoting cell proliferation. Inhibition of ERK signal transduction pathways by genistein, one of the isoflavones, has been reported by several in vitro studies. Therefore, gastric cancer risk by HGF and isoflavone concentrations was evaluated in this study.
Methods: Nested case-control study with 93 gastric cancer cases and 1:1 matched controls was conducted within the Korean Multi-center Cancer Cohort (KMCC). HGF and ISF (genistein, daidzein, equol) concentrations in plasma were measured with enzyme-linked immunosorbent assay and time-resolved fluoroimmunoassay, respectively. Odds ratios (ORs) and 95% confidence intervals (95% CIs) on gastric cancer risk according to HGF and ISF level was calculated using conditional logistic regression models.
Results: Compared to the group with low level of HGF (&lt;315pg/mL) and high level of genistein (≥212.5nmol/L), the group having high level of HGF and lower level of genistein was associated with increased gastric cancer risk (OR = 5.08, 95% CI = 1.39-18.57). Elevated gastric cancer risk in the subjects having high HGF level and low daidzein level than subjects with low HGF and high daidzein levels was also shown (OR = 3.67, 95% CI = 1.18-11.45). There was significant interaction between HGF and genistein levels on gastric cancer was found (p for interaction&lt;0.01). Continual increase in gastric cancer risk according to the counts of risky status by HGF, genistein, and daidzein levels was found (p for trend = 0.03).
Conclusion: Our study suggests that combination of HGF, genistein and daidzein concentrations has potential as a biomarker for gastric cancer risk.
Citation Format: Jieun Jang, Yunji Hwang, Choonghyun Ahn, Kwang-Pil Ko, Keun-Young Yoo, Sue K. Park. Combination of hepatocyte growth factor, genistein and daidzein concentrations as a biomarker for gastric cancer risk: A nested case-control study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4293.
Abstract 4313: Periodic fasting mimicking diet delays cancer development and progression
Authors: Brandhorst Sebastian , Navarrete Gerardo , Wei Min , Morgan Todd E. , Longo Valter D. 
Published: July 2016

Abstract
Dietary intake and composition can have profound effects on aging and age-related pathologies including cancer. As such, studies of fasting (the complete withdrawal of food) and dietary restriction (DR, generally described as a 20- 40% reduction in calories) have contributed to the understanding of the relationship between nutrients, cellular aging, cancer development and cancer cell survival. DR may only be feasible in delaying tumor development but might not present an effective treatment modality due to the time required to achieve beneficial effects. Further, chronic DR may also have negative impacts on wound healing, which could be detrimental in patients undergoing surgery. Our findings in yeast indicated that starvation decreases age-dependent mutations whereas in mouse xenograft tumor models fasting alone can be as effective as chemotherapy drugs in delaying the progression of certain tumor types, in part through the reduction of extracellular glucose and IGF-1 concentration/signaling. Fasting, although results indicate efficacy as a treatment option, on the other hand may not be feasible for patients at risk for undernutrition or cachexia.
To address the need for a dietary based intervention that both delays cancer development and progression, we developed a fasting-mimicking diet (FMD) to ensure micronutrient supply and tested its effectiveness in rodent models. Periodic bi-weekly FMD cycles had a significant impact on the development and progression of multiple cancer models while allowing the preservation of lean body mass even at old age and extending longevity in healthspan study. As a treatment modality, FMD cycles alone significantly reduced tumor progression and sensitized various cancer models to chemotherapeutic drugs.
Citation Format: Sebastian Brandhorst, Gerardo Navarrete, Min Wei, Todd E. Morgan, Valter D. Longo. Periodic fasting mimicking diet delays cancer development and progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4313.
Abstract 4718: ABBV-075, a novel BET family bromodomain inhibitor, represents a promising therapeutic agent for a broad spectrum of cancer indications
Authors: Sarthy Aparna , Li Leiming , Albert Daniel H. , Lin Xiaoyu , Scott Warder , Faivre Emily , Bui Mai H. , Huang Xiaoli , Wilcox Denise M. , Magoc Terry , Buchanan Fritz G. , Tapang Paul , Sheppard George S. , Wang Le , Fidanze Steve D. , Pratt John , Liu Dachun , Hasvold Lisa , Hessler Paul , Uziel Tamar , Lam Lloyd , Rajaraman Ganesh , Fang Guowei , Elmore Steven W. , Rosenberg Saul H. , McDaniel Keith , Kati Warren , Shen Yu 
Published: July 2016

Abstract
Small molecule inhibitors of the bromodomain and extraterminal domain (BET) proteins have emerged as a promising option for cancer therapy. ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered Phase 1 clinical trials. It binds bromodomains of BRD2/4/T with similar affinities (Ki of 1-2.2 nM), but exhibits roughly 10-fold weaker potency towards BRD3 (Ki of 12.2 nM). ABBV-075 is highly selective for 18 bromodomain proteins tested (Kd &gt; 1 μM; more than 600-fold selectivity vs. BRD4) and has moderate activity towards CREBBP (Kd = 87 μM; 54-fold selectivity vs. BRD4). ABBV-075 exhibited robust single agent activity in cell viability assays across cancer cell lines derived from solid tumors, leukemia and lymphomas. Further characterization of cancer cell responses to ABBV-075 indicated that ABBV-075 manifested diverse mechanisms of action in different cancer settings. These include 1): disruption of cell cycle control leading to G1 arrest followed by senescence, 2) inhibition of oncogenesis drivers leading to apoptosis and 3) potentially targeting tumor microenvironment to provide additional therapeutic benefit. Consistent with its broad spectrum of activities in vitro, ABBV-075 has comparable or superior efficacies to standard of care agents in flank xenograft mouse models of non-small-cell and small cell lung cancers, pancreatic, breast, prostate, head & neck cancers, multiple myeloma, diffuse large B cell lymphoma and leukemia. These results support the development of ABBV-075 in diverse hematological malignancies and solid tumor indications.
Citation Format: Aparna Sarthy, Leiming Li, Daniel H. Albert, Xiaoyu Lin, Warder Scott, Emily Faivre, Mai H. Bui, Xiaoli Huang, Denise M. Wilcox, Terry Magoc, Fritz G. Buchanan, Paul Tapang, George S. Sheppard, Le Wang, Steve D. Fidanze, John Pratt, Dachun Liu, Lisa Hasvold, Paul Hessler, Tamar Uziel, Lloyd Lam, Ganesh Rajaraman, Guowei Fang, Steven W. Elmore, Saul H. Rosenberg, Keith McDaniel, Warren Kati, Yu Shen. ABBV-075, a novel BET family bromodomain inhibitor, represents a promising therapeutic agent for a broad spectrum of cancer indications. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4718.
Abstract 4719: Varlitinib demonstrates potent antitumor efficacy in patient-derived gastric cancer xenograft models
Authors: Ooi A. G. Lisa , Lindmark Bertil E. , McHale Mark , Hung Huynh T. , Ong Richard 
Published: July 2016

Abstract
Varlitinib is a potent, reversible pan-HER inhibitor of the ATP-binding site of EGFR (IC50 = 7 nM), HER2 (IC50 = 2 nM) and HER4 (IC50 = 4 nM). Gastric Cancer is the fifth most common cancer worldwide, with 952,000 cases diagnosed in 2012, constituting 6.8% of total cancer diagnosis. Prognosis for gastric cancer is poor, with the overall 5-year survival rate for gastric cancer in the US at ∼29%. Current clinical guidelines recommend use of trastuzumab combined with chemotherapy for HER2+ (amplified) patients with advanced gastric cancer. However the majority of patients (∼80%) do not have HER2 amplification. Studies have implicated dysregulation of HER signaling in gastric cancer and there is strong scientific rationale for testing of pan-HER therapies in Gastric Cancer. We tested the anti-tumour activity of Varlitinib as a single agent in patient-derived gastric cancer xenograft in SCID mice (GC22-0808 & GC11-0414) with over-expression of HER proteins. Varlitinib is very active in tumour growth inhibition studies, causing dose-dependent inhibition with tumour stasis observed at dosing of 50 mg/kg BID and tumour regression observed at dosing of 100 mg/kg BID. Tumour protein lysates after two-day treatment with Varlitinib and vehicle were also analysed to elucidate the mechanism of action. Multiple proliferation and anti-apoptosis pathways were inhibited by Varlitinib, including AKT, PI3K and Survivin pathways. In view of the robust anti-tumour activity inhibiting multiple survival and proliferation pathways, as well as the safe tolerabilty profile of Varlitinib, ASLAN has initiated Phase 2 clinical trials of Varlitinib in gastric cancer.
Citation Format: A. G. Lisa Ooi, Bertil E. Lindmark, Mark McHale, Huynh T. Hung, Richard Ong. Varlitinib demonstrates potent antitumor efficacy in patient-derived gastric cancer xenograft models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4719.