tbuckley/cabot-search huggingface dataset:
Abstract 3294: Breast cancer extent and survival in diabetic women in a Finnish population based cohort
Authors: Mika Murto, Miia Artama, Kala Visvanathan, Teemu Murtola
Journal: Cancer Research (2017)

Abstract Introduction: Breast cancer and diabetes are two major health problems for women. Around 1.7 million new breast cancer cases are diagnosed each year, making breast cancer the most common cancer type in women. Number of people with diabetes is estimated to be 415 million worldwide, thus one in 11 adults have diabetes. However, evidence on the association between diabetes and breast cancer prognosis is controversial. We estimated breast cancer extent at diagnosis and survival in a Finnish population-based cohort of female breast cancer patients. Materials and methods: All newly diagnosed breast cancer cases among women in Finland between 1995 and 2013 were identified from comprehensive national Finnish Cancer Registry. To minimize possible bias due to differing participation in cancer screening the study population was limited to women with at least one mammography screening before the diagnosis. In total 45,786 cases were included in our study cohort. Information on recorded diagnoses of diabetes, hypertension, hypercholesterolemia and obesity from in- and outpatient hospital visits during 1995-2013 were obtained from national Care Register for Health Care maintained by National Institute for Health and Welfare. Logistic regression was used to evaluate the risk of having cancer extended to axillary lymph nodes or beyond at diagnosis. Cox regression was used to evaluate risk of breast cancer death and overall mortality after the diagnosis. Analyses were adjusted for age, comorbidities and number of mammography screens before the diagnosis. Survival analyses were further adjusted for tumor extent and primary treatment. Results: In total 1,419 women had diabetes. Compared to non-diabetic women, breast cancer was more often advanced to axillary lymph-nodes (OR 1.19; 95% CI 1.05-1.34) or metastatic at diagnosis (OR 1.58; 95% CI 1.26-1.97) in diabetic women. Nevertheless, during the median follow-up of 6.9 year after the diagnosis, risk of breast cancer death did not differ between diabetic and non-diabetic women (0.99; 95% CI 0.81-1.21). Overall risk of death was elevated among diabetic women (HR 1.34; 95% CI 1.19-1.51). Conclusion: Diabetic women have more often advanced tumor extent at diagnosis compared to non-diabetic women. However, diabetes did not affect disease-specific survival within 6.9 years after the diagnosis. Citation Format: Mika Murto, Miia Artama, Kala Visvanathan, Teemu Murtola. Breast cancer extent and survival in diabetic women in a Finnish population based cohort [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 3294. doi:10.1158/1538-7445.AM2017-3294
Abstract 937: Plasticity in heterogenous cancer stem cells promotes glioblastoma radioresistance
Authors: Mutsuko Minata, Alessandra Audia, Junfeng Shi, Songjian Lu, Marat Pavlyukov, Yancey Gillespie Gillespie, Krishna Bhat, Ichiro Nakano
Journal: Cancer Research (2017)

Abstract Some cancers including Glioblastoma (GBM) have hierarchical cellular architecture with cancer stem cells (CSCs) as a minor tumorigenic subpopulation. While CSCs have been touted to contribute to initiate recurrence, post-surgical therapy-induced phenotypic changes in CSCs remain elusive. Here we report that treatment of GBM cells with ionizing radiation (IR) promotes a wound-healing mesenchymal signature, accompanied by conversion of naïve CSCs expressing CD133 to post-treatment more radioresistant CSCs expressing the GPI-anchored, TGFb-inhibitory protein CD109 in an ATM, NF-kB, CEBP-b dependent manner. In post-IR GBM, these therapy-escaped CD133-/CD109+ GBM cells, but not the rest of the tumor, uniquely retain clonogenic, tumorigenic, and multi-potent capacities both in vitro and in vivo. CD109 silencing unexpectedly eliminates cancer stemness via controlling YAP/TAZ as the downstream target and this CD109-YAP/TAZ signaling axis is evolutionally conserved between drosophila and human brain tumors. Clinically, both CD133 and CD109 are independently associated with poorer prognosis of GBM patients, while the poorest prognosis group of GBM expressed both CD133 and CD109 at higher rates. These data indicate a possibility of the post-IR CSC plasticity and subsequent heterogeneity, and the activation of the CD109-YAP/TAZ signaling axis as previously unidentified therapeutic targets for post-IR recurrent GBM. Citation Format: Mutsuko Minata, Alessandra Audia, Junfeng Shi, Songjian Lu, Marat Pavlyukov, Yancey Gillespie Gillespie, Krishna Bhat, Ichiro Nakano. Plasticity in heterogenous cancer stem cells promotes glioblastoma radioresistance [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 937. doi:10.1158/1538-7445.AM2017-937
Abstract 1177: Targeting NEDD8 to uncover an exceptional responder molecular subtype in glioblastoma
Authors: Lauren K. Hartman, Darren Finlay, Peiwen Pan, Seungchan Kim, Gil Speyer, Jeff Kiefer, Harshil Dhruv, Kristiina Vuori, Michael Berens
Journal: Cancer Research (2017)

Abstract Neddylation is a post-translational mechanism that marks proteins for degradation through activity of NEDD8 Activating Enzyme (NAE). NAE blocks cullin-RING ligases from initiating proteosomal degradation of select substrates including cell cycle regulators and apoptosis modulators. MLN4924, or Pevonedistat, targets NAE and inhibits Neddylation and induces apoptosis in sensitive cells. We have discovered, in a cohort of glioblastoma PDX models, an exceptional responder to MLN4924 (GBM102). Most pertinently the effects we observe are in a PDX cultured as 3D neurospheres that more closely resemble the true tumor architecture, heterogeneity, and “stem-like” phenotype characteristic of tumor growth. We have leveraged RNAseq expression data from Cancer Cell Line Encyclopedia (CCLE) and Pevonedistat response data from The Cancer Therapeutics Response Portal (CTRP) to apply a network-based analysis to identify pathways enriched with differential dependencies between cell lines sensitive and non-sensitive to MLN4924. The analysis also identifies potential mediating genes that appear to play critical roles in such differential dependency networks. Identified differential networks and mediators provide insight for cellular mechanisms underlying drug response. Additionally, we also investigated the efficacy of MLN4924 against orthotopic glioma PDX models (GBM102 and GBM116) in vivo to validate our findings in vitro. Thus genomic characterization of patient samples may lead to the identification of a molecular signature which is associated with a subset of GBMs vulnerable to MLN4924. As the treatment options for GBM are extremely limited, this may highlight a novel alternative opportunity to treat a select fraction of patients with this aggressive disease. Citation Format: Lauren K. Hartman, Darren Finlay, Peiwen Pan, Seungchan Kim, Gil Speyer, Jeff Kiefer, Harshil Dhruv, Kristiina Vuori, Michael Berens. Targeting NEDD8 to uncover an exceptional responder molecular subtype in glioblastoma [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 1177. doi:10.1158/1538-7445.AM2017-1177
Abstract 694: TK-216: a novel, first-in-class, small molecule inhibitor of EWS-FLI1 in early clinical development, for the treatment of Ewing Sarcoma
Authors: Saravana P. Selvanathan, Eric Moseley, Garrett T. Graham, Katti Jessen, Brian Lannutti, Aykut Üren, Jeffrey A. Toretsky
Journal: Cancer Research (2017)

Abstract One of the most significant challenges in creating more potent, less toxic treatments for patients is to identify new cancer therapeutic targets that distinguish the malignant from normal cells. EWS-FLI1 is a well-established Ewing sarcoma (ES) oncogene that has the potential to be an ideal therapeutic target by directly impacting malignant cells. We have previously reported the discovery and characterization of YK-4-279, an enantiomer-specific inhibitor of EWS-FLI1, which has been demonstrated to induce apoptosis, inhibit EWS-FLI1 transcription, block RNA helicase A co-immunoprecipitation with EWS-FLI1, and result in alternative splicing to mimic EWS-FLI1 knockdown. Continuous efforts in structure-guided medicinal chemistry has yielded TK-216, an analog of YK-4-279 inhibitor of EWS-FLI1, which is 3-4 fold more potent with excellent drug-like properties. TK-216 potently inhibits the proliferation of ES cells. Induces apoptosis in a dose -dependent manner as measured by caspase-3 activity in multiple ES cell lines with distinct translocation variants. The effects of TK-216 on alternative splicing (AS) were further validated using genes including ARID1A, CLK1, CASP3, PPFIBP1 and RUNX2. The splicing pattern was similar between TK-216 and YK-4-279. In addition to the in vitro activity of TK-216 , we show that TK-216 displays anti-tumor activity in a number of ES xenograft models. In summary, TK-216, a novel, first-in-class therapeutic which directly inhibits EWS-FLI1, offers a promising approach for the treatment of Ewing Sarcoma and is currently in Phase 1 clinical trials in patients with relapsed or refractory Ewing Sarcoma (clinicaltrials.gov - NCT02657005). Citation Format: Saravana P. Selvanathan, Eric Moseley, Garrett T. Graham, Katti Jessen, Brian Lannutti, Aykut Üren, Jeffrey A. Toretsky. TK-216: a novel, first-in-class, small molecule inhibitor of EWS-FLI1 in early clinical development, for the treatment of Ewing Sarcoma [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 694. doi:10.1158/1538-7445.AM2017-694
Abstract 272: Circadian disruption and cancer risk in the United States
Authors: Neil E. Caporaso, Fangyi Gu, Shangda Xu, Susan S. Devesa, Fanni Zhang, Elizabeth B. Klerman, Barry Graubard
Journal: Cancer Research (2017)

Abstract Circadian disruption is a probable human carcinogen. Dawn and dusk times occur latter in western compared to eastern regions of each time zone, producing discrepancies between individuals’ biological clock and social time which may lead to circadian disruption and increased risk of cancer. We examined associations between longitude distance from the time zone meridian and age-standardized county-specific cancer incidence rates for total and 23 specific cancers by gender. Four million whites were diagnosed with cancer during 2000-2012 in the Surveillance, Epidemiology and End Results Program in residents of 607 counties in 11 continental US states. The models were adjusted for latitude, poverty, smoking, and state as well as rural/urban location, obesity, and Hispanic composition. The total cancer incidence rates for counties located in the western regions of time zones were significantly elevated for both men and women after Bonferroni correction. The rate ratio (RR) per five degrees of longitude toward the west (corresponding to 20 minutes delay of sunrise) was 1.03 (95% confidence intervals, CI, 1.02-1.04, p=2.7×10-6) for men and 1.04 (95% CI, 1.03-1.05, p=3.8 ×10-10) for women. Chronic lymphocytic leukemia rates for counties in the western portions of time zones were significantly elevated for both men (RR=1.13, 95% CI=1.08-1.20, p=3.1 x10-6) and women (RR=1.12, 95%CI=1.05-1.19, p=3.7 x10-4). Among men, western location within a time zone was associated with elevated risk of prostate cancer (RR=1.04, 95% CI=1.02-1.07, p=4.8 x 10-4). Among women, western location within a time zone was associated with an increase in breast cancer (RR=1.04, 95% CI=1.02-1.06, p=6.5 x 10-5) and corpus uteri cancer (RR=1.10, 95% CI=1.07-1.14, p=2.4 x 10-9 among others. The increased cancer risk with western residency within a time zone is in accord with the circadian disruption hypothesis. Our findings suggest that circadian disruption is not a rare phenomenon affecting only shift workers or international travelers but may be widespread in the general population which has broader implications for public health than generally appreciated. Citation Format: Neil E. Caporaso, Fangyi Gu, Shangda Xu, Susan S. Devesa, Fanni Zhang, Elizabeth B. Klerman, Barry Graubard. Circadian disruption and cancer risk in the United States [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 272. doi:10.1158/1538-7445.AM2017-272
Abstract 679: Serine/threonine kinase inhibitors on improving symptoms of neuroendocrine tumor
Authors: I-Hua Liu, Yusian Ding, Chiung-Wen Liou, Jia-Ming Chang
Journal: Cancer Research (2017)

Abstract Recently, neuroendocrine tumors (NETs) are increased and mostly occurred in gastrointestinal tract and lung in the worldwide. It secretes functional hormones and non-functional neural transmitters to affect patients unwell so called carcinoid syndrome. In clinically, surgical removal and somatostatin treatment are used to ease the syndrome by NETs. A new strategy for advanced NETs is used by targeting mTOR signaling and neovascularization. In 2011, Everolimus, an mTOR inhibitor, was approved for the treatment of progressive NETs of pancreatic origin in patients with unresectable, locally advanced or metastatic disease, but safety and effectiveness of everolimus have not been established. In this study, low dose of mTOR inhibitor was investigated for capability in modifying the carcinoid syndrome. In an NCI-H727 NET xenograft model, the level of chromogranin A (CgA) was determined in accordance with tumor volume. With multiplexing the serum hormones, alpha-melanocyte-stimulating hormone (alpha-MSH) and beta-endorphin were lowered in tumor-bearing mice, but they were rebound when animals treated with Everolimus. Another mTOR inhibitor INK 128 had no apparent tumor inhibition in the same model with doses ranged from 0.25-1 mg/kg. There was no change in the level of CgA in INK128-treated tumor-bearing mice but alpha-MSH level was restored compared with normal mice at a dose-dependent manner. In conclusion, we discovered that low dose of mTOR inhibitor could modify the carcinoid syndrome, where alpha-MSH and beta-endorphin may serve as biomarkers for prognoses of mTOR treatment. Citation Format: I-Hua Liu, Yusian Ding, Chiung-Wen Liou, Jia-Ming Chang. Serine/threonine kinase inhibitors on improving symptoms of neuroendocrine tumor [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 679. doi:10.1158/1538-7445.AM2017-679
Abstract 5224: Identification of drug-target interactions through rapid selection of drug resistant protein variants generated by CRISPR/Cas9-induced NHEJ
Authors: Jasper E. Neggers, Bert Kwanten, Tim Dierckx, Dirk Daelemans
Journal: Cancer Research (2017)

Abstract Identification and validation of the cellular target of bioactive hits identified in a phenotypic screen is crucial for their further development into a drug. The gold standard proof for identification of a small molecule's target is the discovery of mutations that confer resistance. However, selection of drug resistance and subsequent deconvolution of the relevant mutations that confer drug resistance remains time consuming. Therefore, a methodology that can accelerate the drug resistance selection process and that can simplify identification of relevant drug resistance mutations would benefit the drug discovery and development process greatly. Here we report a simple method to rapidly identify the mechanism of action of small molecules with anti-cancer activity. The method utilizes the positive selection of in-frame drug resistance mutations in the target protein of a small molecule derived from the localized genetic variation created by non-homologous end joining (NHEJ) repair of CRISPR/Cas9-induced double strand breaks. In brief, we introduced double strand breaks in the target proteins of selinexor, ispinesib and triptolide and treated these cells with the respective drug. Resistance was obtained rapidly and sequencing of resistant colonies revealed known as well as many new drug resistant protein variants. Next, we investigated whether this approach can be applied as a screening strategy on a subset of genes to identify the direct cellular target protein of a small molecule. We therefore, as proof of concept, designed a pooled sgRNA tiling library targeting all PAM sites of multiple genes and applied this to ispinesib. Drug resistant colonies formed rapidly and were enriched with sgRNAs targeting the ispinesib binding site in KIF11, ispinesib’s target protein. Further sequencing of the sgRNA target gene locus revealed drug resistance mutations in KIF11, validating the feasibility of the methodology to uncover the target of a small molecule from a small pool of candidate genes. To conclude, we provide a new method for identification of the cellular target protein and binding site of a small molecule based on positive selection of drug resistant protein variants generated by targeted CRISPR/Cas-induced NHEJ repair. Citation Format: Jasper E. Neggers, Bert Kwanten, Tim Dierckx, Dirk Daelemans. Identification of drug-target interactions through rapid selection of drug resistant protein variants generated by CRISPR/Cas9-induced NHEJ [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 5224. doi:10.1158/1538-7445.AM2017-5224
Abstract 912: ADAM9-plectin interaction involved in prostate cancer malignancy progression
Authors: Che-Ming Liu, Chia-Ling Hsieh, Shian-Ying Sung
Journal: Cancer Research (2017)

Abstract Introduction: To identify a specific biomarker for malignant prostate cancer progression and therapeutic target, we had demonstrated the correlation of ADAM9 expression and cancer progression. The aim is to clarify the association of ADAM9 and interactive proteins in malignant phenotypic progression. Methods: Knockdown of ADAM9 expression was conducted to explore its role in cell motility and metastasis activities. Pull-down assays were performed to identify the proteins that interact with ADAM9 during cancer cell migration. Proximity ligation assay (PLA) was carried out to validate the protein-protein interaction. Transmission electron microscope (TEM) analysis to confirm ADAM9 and plectin interaction. Protein degradation test was conducted to determine the regulation pathway. Results: Our study demonstrated that ADAM9 play an important role in the regulation of prostate cancer migration, invasion and metastasis in the in vitro assay and xenograft animal models. The combination of ADAM9 pull-down assays and mass spectrum analysis demonstrated hemidesmosome components, plectin, ladinin, and cytoskeleton were pull-down with ADAM9. However, the key element of hemidesmosome, integrin α6β4, did not pull-down together. Both TEM and PLA confirmed the interaction of ADAM9 and plectin in the protrusion end of migrating cells. This interaction can be strengthened after knockdown integrin β4; and vice verse, knockdown of ADAM9 increased interaction of integrin β4 and plecin. These results indicated ADAM9 and integrin β4 compete for plectin binding. Furthermore, shADAM9 attenuated the degradation of integrin β4. Clinical evaluation of 96 patient samples in TMU demonstrated increased of ADAM9 and plectin interaction in tumor region when compared to the benign part of the same patient. Conclusions: Our studies demonstrated that ADAM9 promotes cancer metastasis through alteration of hemidesmosome dynamic by enhancing of integrin β4 degradation. Therefore, these results indicated possible to use ADAM9-plectin interaction to predict prostate cancer malignancy progression. Citation Format: Che-Ming Liu, Chia-Ling Hsieh, Shian-Ying Sung. ADAM9-plectin interaction involved in prostate cancer malignancy progression [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 912. doi:10.1158/1538-7445.AM2017-912
Abstract 4780: Crucial role of S100A14 in blocking cancer stem cells and sensitizing to chemotherapy through STAT3 destabilization in human colorectal cancer
Authors: Jaebeom Cho, Hye-Young Min, Ji-Sun Lee, Ho-Young Lee
Journal: Cancer Research (2017)

Abstract Colorectal cancer (CRC) is a major type of human cancers in terms of incidence and mortality worldwide. Chemotherapy is one of the standard protocols for the treatment of CRC but drug resistance is recognized as the main cause of treatment failure. Resistance to anticancer therapy is a multifactorial event involving a number of interrelated or independent mechanisms. Growing evidence supports a critical role of cancer stem cell (CSC) in development, progression, and resistance to anticancer therapies in CRCs. However, the molecular and cellular mechanisms underlying the CSC's chemoresistance are not completely defined, and a comprehensive understanding of the biology of the CSCs is urgently needed. We have investigated mechanisms of chemoresistance, focusing on those mediated by CSCs, through the employment of CRC stem-like cell populations that are: 1) sorted out by using well-characterized stemness markers; ii) established via serial passage through increasing doses of oxaliplatin or 5-FU; or iii) enriched by culturing in sphere forming condition. We then assessed changes involved in CSC maintenance and found a novel role of S100A14 in CSCs of CRC. We found that transcriptional down-regulations of S100A14 expression conferred phenotypes of CSCs in the stem-like cell populations of CRC. Consistently, elevation of S100A14 expression sensitized the stem-like cell populations to the treatment with 5-FU in vitro and in vivo. Mechanistically, S100A14 directly interacted with STAT3 and promoted its degradation via the ubiquitin-proteasome pathway, leading to decreases in STAT3 target gene expression and colony forming capacity of the stem-like cell populations. Further, S100A14 expression was markedly downregulated in human CRC tissue specimens compared with their normal counterparts. Moreover, the expression level of S100A14 was inversely correlated with clinical outcomes in patients with CRC. These results collectively suggest that S100A14 is a novel target for the treatment of colorectal cancer by targeting CSCs. Citation Format: Jaebeom Cho, Hye-Young Min, Ji-Sun Lee, Ho-Young Lee. Crucial role of S100A14 in blocking cancer stem cells and sensitizing to chemotherapy through STAT3 destabilization in human colorectal 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 4780. doi:10.1158/1538-7445.AM2017-4780