bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3168: Overcoming acquired drug resistance by TPX-0005, an ALK, ROS1 and pan-TRK inhibitor
Authors: Deng Wei , Huang John , Zhai Dayong , Rogers Evan , Cui Jean 
Published: July 2017

Abstract
The inevitable development of clinical drug resistance presents a common challenge for targeted cancer therapy. In non-small cell lung cancer (NSCLC) patients with ALK and ROS1 rearrangements, the emergence of mutations in the targeted oncogenes was identified as one of the mechanisms that confer drug resistance. In particular, a group of mutations known as solvent front mutations, such as ALKG1202R and ROS1G2032R, render common resistance to ALK and ROS1 inhibitors. Similar solvent front mutations, such as TRKAG595R and TRKCG623R, have also been identified in cancer patients with rearrangement of NTRK family genes who developed resistance to TRK-targeted therapies. TPX-0005, a compact three-dimensional macrocyclic molecule, was designed to completely locate at the adenine binding site of ATP in order to efficiently target the active kinase conformation and systematically circumvent the steric interference from various clinical resistant mutations, especially the solvent front mutations. TPX-0005 is an orally available and potent ATP-competitive inhibitor against ALK, ROS1, TRKA, TRKB and TRKC recombinant kinases and their corresponding clinical resistant mutants. TPX-0005 demonstrated potent anti-proliferative activity in the range of sub-nanomolar to low nanomolar in a number of human cancer cell lines and engineered stable cell lines expressing the targeted oncogenes or their solvent front mutants, accompanied by inhibition of target phosphorylation and concomitant inactivation of downstream effectors such as ERK, AKT and STAT3. In patient derived xenograft tumor models, TPX-0005 treatment resulted in significant regression of tumors harboring the oncogenic ALK, ROS1 and TRKC fusions. Moreover, in a series of mouse xenograft tumor models, TPX-0005 exhibited marked anti-tumor activity not only in tumors harboring the wildtype oncogenic targets but also in tumors harboring the oncogenes with the solvent front mutations via inhibition of the target phosphorylation. Taken together, these pre-clinical studies have demonstrated the potent activities of TPX-0005 against not only wild type oncogenic ALK, ROS1, TRK fusions but also their corresponding solvent front mutations, which will bring in a new therapy for cancer patients resistant to currently available ALK, ROS1, and TRK inhibitors in clinic.
Citation Format: Wei Deng, John Huang, Dayong Zhai, Evan Rogers, Jean Cui. Overcoming acquired drug resistance by TPX-0005, an ALK, ROS1 and pan-TRK inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3168. doi:10.1158/1538-7445.AM2017-3168
Abstract 3200: Targeting PHF5A for the treatment of glioblastoma and other Myc-driven cancers
Authors: Mhyre Andrew J. , Turnbaugh Shanon , Morris Shelli M. , Xin Hu , Paddison Patrick J. , Ferrer Marc , Olson James M. 
Published: July 2017

Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive and invasive types of brain cancer, but targeted treatment options remain elusive. The standard of care (surgery chemotherapy and radiation) falls far short of where it should be with two-year survival rates less than 10%. Using stem cell isolates from GBM patients, we found that perturbing PHF5A, a component of the spliceosome machinery, was lethal and caused hundreds of genes to be mis-spliced. These mis-splicing events included both exon skipping and intron inclusions. In contrast, similar levels of PHF5A suppression in normal control stem cells and astrocytes failed to induce cell death and mis-splicing, indicating that PHF5A plays a specific role in the cancer biology. Moreover, when normal astrocytes were transformed with the Myc oncogene, they became sensitive to PHF5A perturbation. Taken together, these results suggested that specifically inhibiting PHF5A would be an effective therapy for glioblastoma and other Myc-driven cancers. Specifically targeting PHF5A would also likely result in reduced side-effects seen with general spliceosome inhibitors. Unfortunately, there are currently no known inhibitors that target PHF5A.
In order to discovery novel PHF5A inhibitors, we created a mini-gene mis-splicing reporter assay that was sensitive to both general spliceosome inhibitors and PHF5A perturbation. In a 96-well assay format, the assay was robust with a 200-fold assay window and Z’ values over 0.8. Following miniaturization to a 1536-well format, we conducted a high throughput screening (HTS) campaign testing 450,000 small molecule compounds. The initial hits were retested and counter-screened yielding 381 confirmed actives and we are further interrogating these actives in secondary and tertiary assays. Future efforts will focus on developing an SAR of the lead and backup series and identifying potential liabilities that will be addressed, if necessary, in further lead optimization efforts. We are enthusiastic about the potential of developing a targeted PHF5A inhibitor as a novel and effective therapy for patients and their families fighting GBM and other Myc-driven cancers.
Citation Format: Andrew J. Mhyre, Shanon Turnbaugh, Shelli M. Morris, Hu Xin, Patrick J. Paddison, Marc Ferrer, James M. Olson. Targeting PHF5A for the treatment of glioblastoma and other Myc-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3200. doi:10.1158/1538-7445.AM2017-3200
Abstract 3278: Particulate matter and traffic-related exposures in relation to breast cancer survival
Authors: DuPre Natalie , Poole Elizabeth M. , Holmes Michelle D. , Hart Jaime E. , James Peter , Beck Andrew , Kraft Peter , Laden Francine , Tamimi Rulla 
Published: July 2017

Abstract
Background: Outdoor air pollution is considered a human carcinogen by the International Agency for Research on Cancer, particularly for its influence on lung cancer incidence and prognosis. While air pollution has not been consistently associated with breast cancer incidence, only one study has examined the impacts of air pollution on survival from breast cancer and was unable to consider important predictors of breast cancer mortality. We assessed whether PM exposures (PM2.5, PM2.510, and PM10) were associated with breast cancer specific-death and all-cause mortality.
Methods: The Nurses’ Health Studies (NHS and NHSII) are ongoing nationwide cohorts with detailed longitudinal data on medical history, addresses, lifestyle factors, and causes of death. We included women with confirmed Stage I-III breast cancer and collected additional clinical information from medical records. PM was estimated using GIS-based spatio-temporal models linked to addresses between 1989-2007. We performed Cox proportional hazards models to assess associations of breast cancer specific-death and overall mortality with PM exposures starting at diagnosis and updated over follow-up through June 2014.
Results: There were 1,211 breast-cancer specific deaths among 8,936 women with Stage I-III breast cancer. Overall, increases in PM were not associated with breast cancer survival (PM2.5: HR=1.09 95% CI 0.87, 1.36; PM2.5-10: HR=1.03 95% CI 0.85, 1.24; PM10: HR=1.05, 95% CI 0.89, 1.24, each per 10 μg/m3). However, each 10 μg/m3 increase in PM2.5 was associated with breast cancer death among participants with Stage I disease after adjusting for clinical, demographics and pre-diagnostic lifestyle factors (HR=1.69 95%CI 1.16, 2.47) and after additionally adjusting for post-diagnostic lifestyle factors (HR=1.64 95% CI 1.11, 2.43). Furthermore, PM exposures were associated with a 9-12% increase in all-cause mortality.
Conclusion:
Overall, PM exposures were not associated with breast cancer survival; however, increases in PM2.5 did appear to adversely impact prognosis among Stage I breast cancer patients.
Acknowledgments:
This work was funded by the NIH T32 CA 09001 and by a grant from the Susan G. Komen for the Cure ® (IIR13264020). We thank the NHS and NHSII participants and coordinators.
Citation Format: Natalie DuPre, Elizabeth M. Poole, Michelle D. Holmes, Jaime E. Hart, Peter James, Andrew Beck, Peter Kraft, Francine Laden, Rulla Tamimi. Particulate matter and traffic-related exposures in relation to breast cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3278. doi:10.1158/1538-7445.AM2017-3278
Abstract 3475: Inhibitory effects of ZFP36L1 and ZFP36L2 on the cell proliferation in human colorectal cancer cells
Authors: Suk Fat-Moon , Chen Ya-Ting , Liang Yu-Chih 
Published: July 2017

Abstract
ZFP36 family members include ZFP36 (also named TTP and TIS11), ZFP36L1 (also called BRF1, ERF1 or TIS11B) and ZFP36L2 (also called BRF2, ERF2 and TIS11D), which belong to the CCCH-type zinc finger protein with 2 tandem zinc finger region (TZF). These ZFP36 family proteins can function as RNA-binding protein through binding to AU-rich elements (AREs) in the 3’ untranslated region (3’ UTR) of mRNA, which promote the mRNA degradation or translation repression. Previously, ZFP36 has been found to inhibit cell proliferation through p53-dependent manner. In this study, we’d like to investigate whether ZFP36L1and ZFP36L2 have anti-proliferative activity as same as ZFP36 work. Tetracycline-inducible (Tet-On) system was used to induce the overexpression of ZFP36L1 or ZFP36L2 proteins in T-REx-293 cells by doxycycline (Dox) treatment. While ZFP36L1 or ZFP36L2 was overexpressed, we found that cell proliferation was dramatically inhibited, but didn’t cause cell death significantly. The importance of TZF was confirmed by using TZF mutants, and found that cell proliferation was deprived in HEK-293 cells with overexpression of ZFP36L1 mutant (C135/173R). Using western blot analysis, it was revealed that expression level of p53 protein was increased after the overexpression of ZFP36L1 or ZFP36L2 protein. Whereas, the levels of cell cycle-related proteins including cyclin B1, cyclin D1, cyclin A2 and p21 were decrease. Next, three human colorectal cancer cells HCT116 p53+/+, HCT116 p53-/- and SW620 (mutated p53) cells were used and ZFP36L1 or ZFP36L2 gene was transduced into these three cells by lentivirus. Overexpression of ZFP36L1 or ZFP36L2 also inhibited the cyclin D1 protein expression and cell proliferation in these three cells, however, increased the p53 and p21 protein expression in HCT116 p53+/+ cells, and decreased the c-Myc expression only in SW620 cells. On the other hand, knockdown of ZFP36L1 or ZFP36L2 increased cell proliferation, and mutation in TZF of ZFP36L1 (C135/173R) or ZFP36L2 (C174/212R) lost their anti-proliferative abilities in these three cells. Taken together, the results suggest that ZFP36L1 and ZFP36L2 play a negative role in cell proliferation of human colorectal cancer cells, and the underlying mechanisms might be mediated through downregulation of cyclin D1 and p53-independent pathway.
Citation Format: Fat-Moon Suk, Ya-Ting Chen, Yu-Chih Liang. Inhibitory effects of ZFP36L1 and ZFP36L2 on the cell proliferation in human colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3475. doi:10.1158/1538-7445.AM2017-3475
Abstract 3542: Coordination of glutamine and glucose metabolism in pancreatic cancer
Authors: Vernucci Enza , Gunda Venugopal , Shukla Surendra , Singh Pankaj K. 
Published: July 2017

Abstract
Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer related deaths in the United States. Due to early metastasis by the time it is diagnosed it advances to advanced stages and becomes unresectable. Oncogene mediated metabolic reprogramming has been shown to promote the growth, maintenance and metastasis of tumors in pancreatic ductal adenocarcinoma. Pancreatic tumors route majority of glucose and glutamine for biomass generation and maintenance of redox potential. The aim of this study was to investigate the link between glutamine and glucose metabolism in pancreatic cancer cells. We primarily focused on the role of glutamine mediated regulation of glucose metabolism. We observed that glutamine deprivation reduces pancreatic cancer cell growth as suggested by the previous studies. We further investigated how pancreatic cancer cells adapt to glutamine deprived conditions. We observed that glucose uptake increases significantly upon glutamine deprivation. However, GLUT1 expression showed a contrasting decreased expression under conditions of glutamine deprivation. Using tandem mass spectrometry based metabolomic analysis we observed that glutamine deprivation does not alter glycolysis. However, the TCA cycle, amino acid metabolism and glutathione metabolism were significantly impacted in glutamine deprived cells. We noticed a significant increase in the levels of hydroxyglutarate and succinyl CoA levels in the TCA cycle. These changes were accompanied with an increase in GSH to GSSG ratio that reflects a possibility for alternative pathways involved in redox maintenance under glutamine deprived conditions. Hence, we conclude that glutamine metabolism significantly impacts the uptake and metabolism of glucose in pancreatic cancer cells.
Citation Format: Enza Vernucci, Venugopal Gunda, Surendra Shukla, Pankaj K. Singh. Coordination of glutamine and glucose metabolism in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3542. doi:10.1158/1538-7445.AM2017-3542
Abstract 358: LTB and LTBR mediates alternative Nf-kB activation through NIk and RELB/NF-kB2 to promote cell migration of HNSCC
Authors: Das Rita , Coupar Jamie , saleh Anthony , Clavijo Paul E. , Chen Zhong , VanWaes Carter 
Published: July 2017

Abstract
Nuclear factor-κB (NF-κB) includes a family of NF-κB/REL transcription factors that regulate key inflammatory and cancer genes, and which are aberrantly activated in head and neck squamous cell carcinomas (HNSCC). Lymphotoxin beta/Lymphotoxin beta receptor (LTβ/LTβR) can mediate activation of the “alternative” NF-κB pathway that includes NF-κB-inducing kinase (NIK), Inhibitor-κB kinase α (IKKα), and transcription factors RELB/NF-κB2. While LTβ is expressed in lymph nodes where HNSCC spread, the role of this pathway in pathogenesis of HNSCC is not well studied. Analysis of The Cancer Genome Atlas (TCGA) data reveals that LTβR is amplified or overexpressed in larynx or oral cavity HNSCC, while LTα/β, NIK, (MAP3K14) and RELB are overexpressed in oropharynx and tonsil cancers. Similarly, we observed overexpression of LTβR, NIK, and RELB proteins in subsets of HNSCC cell lines. In UM-SCC46, LTβ enhanced nuclear translocation of RELB/NF-κB2 (p52) subunit proteins, while LTβR siRNA knockdown decreased the expression of its target kinase NIK and RELB/NF-κB2 (p52). NIK knockdown also decreased RELB/NF-κB2 (p52) protein expression, whereas LTβ treatment stabilized NIK, and RELB/NF-κB2 (p52). Functional LTβ-mediated NF-κB activation was examined using a stably transfected NF-κB reporter cell line for β-lactamase/Fret activity. Knockdown of LTβR and NIK decreased NF-κB activity, whereas treatment with LTβ partially restored it. Treatment with a NIK inhibitor (1, 3[2H, 4H]-Iso-Quinoline Dione) reduced the protein expression of NIK, IKKα, and RELB/NF-κB2 (p52) in the cytoplasm and/or in the nucleus, and blocked LTβ induced translocation of RELB to nucleus. NIK and RELB knockdown by siRNA or using NIK inhibitor slowed HNSCC migration. Knockdown of NIK inhibited the LTβ-induced expression of MET, and SERPINE1 genes involved in migration, and knockdown of MET by siRNA inhibited the migration of HNSCC cell lines. Our findings show that LTβ/LTβ receptor promotes activation of the alternative NIK-IKKa-RELB/NF-κB2 pathway, to enhance MET-mediated cell migration in HNSCC. This may help explain why HNSCC exhibit migration and metastasis to local lymph nodes, where LTβ is expressed. The constitutive and LTβ induced activation of NIK and downstream NF-κB alternate pathway proteins, RELB and NF-κB2/p52 could be therapeutic targets in HNSCC.
(Supported by NIDCD intramural projects ZIA-DC-000016, 74)
Citation Format: Rita Das, Jamie Coupar, Anthony saleh, Paul E. Clavijo, Zhong Chen, Carter VanWaes. LTB and LTBR mediates alternative Nf-kB activation through NIk and RELB/NF-kB2 to promote cell migration of HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 358. doi:10.1158/1538-7445.AM2017-358
Abstract 3630: Preclinical evaluation of a BiTE® antibody construct with extended half-life that targets the tumor differentiation marker mesothelin
Authors: Sternjak Alexander , Lee Fei , Wahl Joachim , Rock Dan , Thomas Oliver , Stienen Sabine , Lutterbuese Ralf , Hoffmann Patrick , Raum Tobias , Kufer Peter , Rattel Benno , Coxon Angela , Friedrich Matthias , Bailis Julie 
Published: July 2017

Abstract
Bispecific T cell engager (BiTE®) antibody constructs redirect T cells to induce lysis of tumor cells. The anti-CD19/CD3 BiTE® Blincyto® can deplete target cells in both the blood and tissue compartment in B cell malignancies, suggesting that the BiTE® mechanism of action will also be effective against solid tumors. The tumor differentiation antigen mesothelin (MSLN) is an attractive target for the BiTE® approach. MSLN is highly expressed in &gt;80% of ovarian and pancreatic tumors and mesothelioma. Expression of MSLN in normal tissues appears restricted to mesothelial cell surfaces such as the pleural, pericardial, and peritoneal layer.
Here, we report the preclinical characterization of an anti-MSLN/CD3 BiTE® antibody construct with extended half-life. The BiTE® antibody construct binds MSLN and CD3 with low nM affinity and has low pM cytotoxic activity against MSLN-positive ovarian, pancreatic and lung cancer cell lines in vitro. Activity of the anti-MSLN/CD3 BiTE® antibody construct is observed at low effector to target cell ratios, and in cancer cells that express low levels of MSLN. This BiTE® antibody construct is also cytotoxic to cell lines that are resistant to chemotherapy. In mice, significant tumor growth inhibition of an established ovarian tumor xenograft model was achieved by IV dosing of the anti-MSLN/CD3 BiTE® antibody construct every 5 days. Pharmacokinetic evaluation of the anti-MSLN/CD3 BiTE® antibody construct in non-human primates demonstrated a half-life of 4-10 days. The potency and specificity of the anti-MSLN/CD3 BiTE® antibody construct, together with projected ability to dose once a week IV in humans, supports development of this BiTE® for treatment of MSLN-positive tumors.
Citation Format: Alexander Sternjak, Fei Lee, Joachim Wahl, Dan Rock, Oliver Thomas, Sabine Stienen, Ralf Lutterbuese, Patrick Hoffmann, Tobias Raum, Peter Kufer, Benno Rattel, Angela Coxon, Matthias Friedrich, Julie Bailis. Preclinical evaluation of a BiTE® antibody construct with extended half-life that targets the tumor differentiation marker mesothelin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3630. doi:10.1158/1538-7445.AM2017-3630
Abstract 3855: Excavation of therapeutic targets based on the molecular signature of patient-derived tumor xenografts in gastric cancer
Authors: Chen Zuhua , Gao Jing , Shen Lin 
Published: July 2017

Abstract
Objective: The optimal preclinical models in new targeted drug development are patient-derived tumor xenografts (PDXs) models with definite molecular signatures, which will be excavated and validated in this study. Methods: The genomic profiles of 50 PDXs from advanced gastric cancer (AGC) were analyzed by targeted next-generation sequencing. The Epstein-Barr virus (EBV) infection, microsatellite instability (MSI) status, and expressions of EGFR, HER3, c-Met, PTEN and c-Myc were determined by in situ hybridization and immunohistochemisty, respectively. Results: A total of 581 non-synonymous single nucleotide variations (SNV), 513 Indels, and 225 amplifications were identified in 50 PDXs. Pathway analysis revealed recurrent alterations in the MAPK signaling, ErbB signaling, VEGF signaling, mTOR signaling and cell cycle pathway. The ErbB family amplified in 8% (EGFR), 10% (ERBB2), 2% (ERBB3) and 2% (ERBB4) of the 50 PDXs respectively. Meanwhile, several activating mutations in EGFR (L858R and G719S), ERBB3 (P1212S) and ERBB4 (R1174Q) were also detected in our study. Moreover, we detected 7 PDXs harboring PIK3CA activating mutations (E545K, Q546K, H1047R) and 2 PDXs with PTEN loss. Whether PI3K/Akt/mTOR inhibitors could turn over the primary or acquired resistance of anti-HER2 therapies remains further researches. Genes in the cell cycle pathway altered in 70% of the 50 PDXs. The mutation rates of TP53, BRCA1 and BRCA2 were 28%, 8% and 14%. We also detected amplifications of CCNE1, CCND1 and MYC in 16%, 6% and 20% of the xenografts. In this study, 9 PDXs (18%) were EBV positive, with frequent alterations of ARID1A but rare mutations of TP53, and a robust expression of PD-L1. However, we didn’t observe any loss of MMR protein expressions. Conclusions: Several potential therapeutic targets were identified based on the molecular signature of PDXs in advanced gastric cancer, which will provide evidences for drug development.
Citation Format: Zuhua Chen, Jing Gao, Lin Shen. Excavation of therapeutic targets based on the molecular signature of patient-derived tumor xenografts in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3855. doi:10.1158/1538-7445.AM2017-3855