tbuckley/cabot-search huggingface dataset:
Childhood adiposity and risk of type 1 diabetes: A Mendelian randomization study
Authors: J. C. Censin, Christoph Nowak, Nicholas Cooper, Peter Bergsten, John A. Todd, Tove Fall
Journal: PLoS Medicine (2017)

Background The incidence of type 1 diabetes (T1D) is increasing globally. One hypothesis is that increasing childhood obesity rates may explain part of this increase, but, as T1D is rare, intervention studies are challenging to perform. The aim of this study was to assess this hypothesis with a Mendelian randomization approach that uses genetic variants as instrumental variables to test for causal associations. Methods and findings We created a genetic instrument of 23 single nucleotide polymorphisms (SNPs) associated with childhood adiposity in children aged 2–10 years. Summary-level association results for these 23 SNPs with childhood-onset (<17 years) T1D were extracted from a meta-analysis of genome-wide association study with 5,913 T1D cases and 8,828 reference samples. Using inverse-variance weighted Mendelian randomization analysis, we found support for an effect of childhood adiposity on T1D risk (odds ratio 1.32, 95% CI 1.06–1.64 per standard deviation score in body mass index [SDS-BMI]). A sensitivity analysis provided evidence of horizontal pleiotropy bias (p = 0.04) diluting the estimates towards the null. We therefore applied Egger regression and multivariable Mendelian randomization methods to control for this type of bias and found evidence in support of a role of childhood adiposity in T1D (odds ratio in Egger regression, 2.76, 95% CI 1.40–5.44). Limitations of our study include that underlying genes and their mechanisms for most of the genetic variants included in the score are not known. Mendelian randomization requires large sample sizes, and power was limited to provide precise estimates. This research has been conducted using data from the Early Growth Genetics (EGG) Consortium, the Genetic Investigation of Anthropometric Traits (GIANT) Consortium, the Tobacco and Genetics (TAG) Consortium, and the Social Science Genetic Association Consortium (SSGAC), as well as meta-analysis results from a T1D genome-wide association study. Conclusions This study provides genetic support for a link between childhood adiposity and T1D risk. Together with evidence from observational studies, our findings further emphasize the importance of measures to reduce the global epidemic of childhood obesity and encourage mechanistic studies.
Abstract 70: Elucidating the roles of antibody pharmacokinetics and maleimide stability in the toxicology of antibody-drug conjugates
Authors: Haley Neff-LaFord, Franciso Zapata, Wendi Schultz, Cindy Balasubramanian, Paul Pittmen, Shawna Hengel, Russell Sanderson, Nagendra Chemuturi, Jocelyn Setter, Robert P. Lyon
Journal: Cancer Research (2017)

Abstract Antibody-drug conjugates (ADCs) continue to emerge as effective therapeutics in a variety of oncology indications, with two agents currently approved and many more in late-stage clinical trials. These ADCs employ drug-linkers that were developed many years ago, and are now recognized to have properties that may adversely impact the activity and toxicology of the ADCs prepared with them. Two such properties that are now well appreciated are the reversibility of maleimide-based drug conjugation, and the impact of drug conjugation on the pharmacokinetics of the ADC. We recently reported advances in drug-linker design that independently address both of these properties, resulting in the irreversible conjugation of drugs which have minimal impact on antibody pharmacokinetics, even at high levels of drug loading (Nature Biotechnology 32, 1059-1062 (2014), Nature Biotechnology 33, 733-735 (2015)). We have now prepared drug-linkers of monomethylauristatin E (MMAE) that orthogonally employ these features to enable a systematic evaluation of the relative contributions of maleimide instability and accelerated plasma clearance on the in vivo behavior of MMAE ADCs. Biodistribution studies with these molecules have revealed that the concentration of released MMAE in normal tissues is greatly impacted by the rate of ADC clearance (fast clearance results in greater Cmax of free drug), while stabilization of the maleimide has a relatively small effect. These differences in observed free drug concentrations were paralleled in tolerability studies, with ADC clearance rates exerting a greater impact on hematology parameters than maleimide stability. Collectively, these results suggest that ADC pharmacokinetics dominate the biodistribution and toxicology profiles for a given drug payload, with conjugate stability playing a relatively minor role. Citation Format: Haley Neff-LaFord, Franciso Zapata, Wendi Schultz, Cindy Balasubramanian, Paul Pittmen, Shawna Hengel, Russell Sanderson, Nagendra Chemuturi, Jocelyn Setter, Robert P. Lyon. Elucidating the roles of antibody pharmacokinetics and maleimide stability in the toxicology of antibody-drug conjugates [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 70. doi:10.1158/1538-7445.AM2017-70
Abstract 1063: Benefit from combination cancer therapy arising from patient-to-patient variability rather than additive or synergistic drug action
Authors: Adam C. Palmer, Peter K. Sorger
Journal: Cancer Research (2017)

Abstract Combination cancer therapy is an important means to increase rates and durability of drug response. Superior responses to combination therapies are commonly interpreted as evidence that individual tumors respond more strongly to a combination than to a monotherapy, and combinations are often developed based on pre-clinical observations of drug additivity or synergy. Here we explore an alternative hypothesis, namely that combination therapy can confer benefit simply by providing multiple chances of an above-average response to monotherapy. The benefit conferred by two-drug combination therapy in human clinical trials and PDX animals was compared with a model of independent drug action postulating that net response in each patient equals the better of two potential responses to drugs given individually with no benefit from the second agent. Data were derived from clinical trials of drug combinations in melanoma, ovarian, colorectal, pancreatic, and breast cancers treated with immunotherapies, chemotherapies and inhibitors of kinases, growth factor receptors, angiogenesis, and DNA repair enzymes; as well as analysis of 4,500 drug response measurements in patient-derived tumor xenografts, and a first-principles model of tumor kinetics and variability in drug response. A majority of approved combination cancer therapies analyzed confer benefits consistent with independent drug action. This benefit arises from high inter-subject variability, which can be assessed from clinical trials, and low correlation in responsiveness to different drugs, assessed from PDX studies. In a minority of cases responses exceed this expectation, sometimes dramatically, and are likely to represent true drug interaction. Therefore, independent drug action, without any assumption about additive or synergistic effects, provides a sufficient and more parsimonious explanation for the superiority of many clinically approved combination cancer therapies and changes how such data are interpreted mechanistically. Optimization of independent action also provides an alternative means for designing new drug combinations. Citation Format: Adam C. Palmer, Peter K. Sorger. Benefit from combination cancer therapy arising from patient-to-patient variability rather than additive or synergistic drug action [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 1063. doi:10.1158/1538-7445.AM2017-1063
Abstract DDT02-01: Discovery of GDC-0077, a highly isoform selective inhibitor of PI3Kα that promotes selective loss of mutant-p110α
Authors: Steven T. Staben
Journal: Cancer Research (2017)

Abstract PIK3CA, the gene that encodes for the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3Kα), is frequently mutated in cancer, with activating and transforming mutations of PIK3CA occurring in approximately 17% of cancers diagnosed annually. The narrow therapeutic index of PI3K inhibitors evaluated in the clinic thus far may be due to insufficient selectivity for PI3K isoform or mutant oncogenic driver. We report the results of our efforts directed at improving efficacy and safety of a class of benzoxazepin inhibitors of PI3K. A structure-, property-, and phenotype-guided strategy directed at high PI3K-isoform and PIKK-family selectivity, as well as a distinct cellular mechanism of action, culminated in the discovery of GDC-0077. Differences in primary and tertiary structure among PI3K isoforms were leveraged to achieve &amp;gt;300-fold selective inhibition of the PI3Kα isoform over the β, δ, and γ isoforms in biochemical assays. Very high selectivity over PIKK-family proteins such as mTOR, DNA-PK and VPS34 was also achieved through this process. In vitro and in vivo data indicate that GDC-0077 operates by a mechanism that promotes the selective degradation of “hotspot” p110α mutants (H1047R, E545K). Treatment of nude mice bearing PIK3CA-mutant breast tumor xenografts with oral GDC-0077 resulted in tumor regressions at well-tolerated doses. Together, the high degree of isoform selectivity, selective degradation of mutant-p110α, and in vivo PK/efficacy support the clinical evaluation of GDC-0077 as a treatment for patients with locally advanced or metastatic, PIK3CA-mutant cancer. Citation Format: Steven T. Staben. Discovery of GDC-0077, a highly isoform selective inhibitor of PI3Kα that promotes selective loss of mutant-p110α [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 DDT02-01. doi:10.1158/1538-7445.AM2017-DDT02-01
Abstract 3515: LHX9 is a novel oncogene bypassing KRAS addiction
Authors: Seav Huong Ly, Chao Dai, Andrew L. Hong, Nina Ilic, Elsa B. Krall, William C. Hahn
Journal: Cancer Research (2017)

Abstract Background Oncogenic mutations of RAS are detected in approximately 30% of human cancers. KRAS is highly mutated in pancreatic, colorectal and lung cancers. Direct therapeutic targeting of Ras and its membrane association has been challenging due to high affinity of GTP to Ras and unexpected mechanism of alternative post-translational modification. While few inhibitors of downstream RAS effectors - MAPK and PI3K pathways - show some clinical efficacy, they are complicated by complex feedback loops, and as single agents are not effective in KRAS-mutant cancers. Combination therapies may be promising yet limited by narrow therapeutic window. Identification of alternative strategies to directly inhibiting RAS and MAPK/PI3K pathways is key to address this unmet need. Methods To this end, we performed a genome-scale open reading frames screen to identify genes capable of restoring viability to KRAS-dependent cells following KRAS suppression. We tested the top 5-standard-deviation hits in low-throughput manner. One of the top hits included LIM homeobox 9 (LHX9), a homeobox family transcription factor essential for mouse gonad, limb, and brain development. While LHX9 is amplified in several cancers, little is known regarding its roles in cancers. We used hypothesis-driven as well as unbiased approaches including RNA-seq, ChIP-seq, and IP-mass spectrometry to investigate the basis of LHX9-mediated bypass of KRAS dependency. Results We showed that LHX9 rescued KRAS suppression in multiple cell lines as well as xenograft. LHX9 overexpression substituted for KRAS in KRAS-driven xenograft. Moreover, in activated-MEK-overexpressing HA1E cells, LHX9 formed tumors as robustly as myristoylated AKT. LHX9 rescued KRAS suppression by both restoring KRAS-dependent pathways and activating KRAS-independent pathways. First, LHX9 reactivated the main KRAS effectors - MAPK and PI3K pathways and conferred resistance to MEK inhibitor Trametinib. Second, using ChIP- and RNA-seq, we observed LHX9 binding to promoters/enhancers of genes whose expression was regulated by KRAS, particularly YAP1. Third, LHX9 increased expression and activation of KRAS-independent genes, including STAT3. Conclusions Here, we identified LHX9 as a novel bypass of KRAS addiction. Multiple unbiased approaches revealed at least three mechanisms by which LHX9 rescued KRAS suppression. Our findings contribute to our understanding of KRAS biology. Further investigation of downstream effectors of LHX9 may highlight potentially novel therapeutic targets for KRAS-dependent cancers. Citation Format: Seav Huong Ly, Chao Dai, Andrew L. Hong, Nina Ilic, Elsa B. Krall, William C. Hahn. LHX9 is a novel oncogene bypassing KRAS addiction [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 3515. doi:10.1158/1538-7445.AM2017-3515
Abstract 3819: Identification and quantification of isoforms of eukaryotic initiation factor 4E as biomarker in Mnk inhibitor-treated mouse model by capillary-based immunoassay platform
Authors: Zhiyuan Ke, Sifang Wang, Vithya Manoharan, Susmitha Vuddagiri, Esther Ong, Sharon Lim, Sin Tiong Ong, Kanda Sangthongpitag, Nacro Kassoum, Jeffrey Hill, May Ann Lee
Journal: Cancer Research (2017)

Abstract Elevated levels of the phosphorylated m7G cap binding protein, eukaryotic initiation factor 4E (eIF4E) are associated with neoplasia. An observed oncogenic signaling effect upon activation of Erk1/2 or p38 MAPKs in cells is the phosphorylation of eIF4E specifically at Serine 209 by downstream kinase MAP kinase-interacting kinase 1 and 2 (Mnks). Therefore, inhibiting Mnks could be a potential therapeutic approach that selectively targets cancer cells without introducing toxicity to normal cells. To measure the target engagement and efficacy of Mnk inhibitors, we have established a sensitive method to quantitatively detect phospho-eIF4E and non-phospho-eIF4E. Here, we report using NanoPro 100 system, an automated capillary-based immunoassay platform that could separate the phosphorylated and non-phosphorylated eIF4E isoforms based on different isoelectric points. Primary antibodies against both non-phospho eIF4E and Serine 209 phosphorylated eIF4E were used for identification and verification of eIF4E isoforms in protein samples obtained from cell lysate, blood samples and tumor samples. Two major isoforms of eIF4E with isoelectric point at 5.38 for phospho-eIF4E and 5.88 for non-phospho-eIF4E were identified in eIF4E-overexpressing K562 cells. siRNA knockdown of eIF4E expression reduced both isoforms, while treatment with Mnk inhibitor only reduced phospho-eIF4E level. The measurement and quantification of the relative changes of phosphorylated eIF4E by this method can potentially be used in monitoring the efficacy of Mnk inhibitors in xenograft and future clinical trials. Citation Format: Zhiyuan Ke, Sifang Wang, Vithya Manoharan, Susmitha Vuddagiri, Esther Ong, Sharon Lim, Sin Tiong Ong, Kanda Sangthongpitag, Nacro Kassoum, Jeffrey Hill, May Ann Lee. Identification and quantification of isoforms of eukaryotic initiation factor 4E as biomarker in Mnk inhibitor-treated mouse model by capillary-based immunoassay platform [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 3819. doi:10.1158/1538-7445.AM2017-3819
Abstract 1975: FAM83B: A novel regulator of cell plasticity in breast cancer
Authors: Courtney A. Bartel, Damian J. Junk, Mark W. Jackson
Journal: Cancer Research (2017)

Abstract Epithelial to mesenchymal transition (EMT) is an important process in both metastasis and cancer stem cell (CSC) enrichment. Recent studies suggest that instead of simply transitioning from one cell state to another, cancer cells exist along a continuum of epithelial and mesenchymal cell states. Identifying novel regulators of tumor cell plasticity will be critical to fully understand this continuum and to target metastasis and CSC phenotypes in the future. FAM83B is a novel oncogene identified by the Jackson Laboratory in a forward genetic screen for drivers of Human Mammary Epithelial Cell (HMEC) transformation. Previous work showed that FAM83B expression is elevated in triple negative breast cancers and that FAM83B also activates key cell signaling pathways (EGFR, MAPK, and PI3K) in breast cancers. Here, we implicate FAM83B as a novel regulator of epithelial-mesenchymal plasticity using a HMEC transformation model. Transformation of primary HMEC by expressing shp16, shp53, c-Myc, and RAS results in the generation of two distinct transformed cell populations. One population retains epithelial characteristics, while an emergent population spontaneously acquires a mesenchymal morphology and a CD24LOCD44HI (CSC) cell surface marker profile. Moreover, isolation of epithelial, CD24HICD44LO cells (non-CSC) and exposure to Oncostatin M (OSM), an EMT-inducing cytokine, can also generate cells with a mesenchymal/CSC phenotype. Interestingly, FAM83B expression was significantly elevated in the epithelial/non-CSC population compared to the mesenchymal/CSC population. Moreover, treatment of purified epithelial/non-CSC cells with OSM resulted in decreased FAM83B expression levels, indicating FAM83B expression is suppressed as the cells move through EMT. FAM83B expression also correlated with an epithelial phenotype in a panel of breast cancer cell lines. shRNA-mediated knock-down of FAM83B from epithelial/non-CSC resulted in increased spontaneous EMT, concomitant with elevated expression of the mesenchymal marker Vimentin and master EMT transcription factor Zeb1. Following treatment with OSM, sh83B cells maintain prolonged, elevated p-Stat3 and p-ERK signaling, known contributors to the mesenchymal/CSC phenotype. Conversely, OSM-induced EMT was blunted in epithelial/non-CSC expressing exogenous FAM83B. Thus, FAM83B expression is a determinant in maintaining an epithelial phenotype, while suppression of FAM83B is important during EMT. Future work will seek to define novel FAM83B-mediated signaling pathways important for regulating cellular plasticity. Citation Format: Courtney A. Bartel, Damian J. Junk, Mark W. Jackson. FAM83B: A novel regulator of cell plasticity in breast 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 1975. doi:10.1158/1538-7445.AM2017-1975
Predictability of later developed relapse in endometrial carcinoma in young women with functional imaging parameters of fes/FDG SUV ratio after fertility-sparing hormone treatment.
Authors: Yoshio Yoshida, Hidehiko Okazawa, Akiko Shinagawa, Yasushi Kiyono, Tetsuya Mori, Tetsuji Kurokawa
Journal: Journal of Clinical Oncology (2013)

e16502 Background: Even in responders of fertility-sparing hormone treatment for uterine endometrial carcinoma (EC) and atypical endometrial hyperplasia (AH) in young women, there have been high potential risks of later developed relapse. The aim of this study was whether changes in FDG and fluoroestradiol (FES) PET parameters following hormone treatment have the prognostic factor in prediction of later developed relapse. Methods: Eight young patients with EC and AH were treated by fertility-sparing treatment with a high-dose of medroxyprogesterone acetate (MPA) for 26 weeks. All patients underwent two FDG and FES-PET scans at baseline and 8 weeks after the beginning of MPA treatment, respectively. For each lesion, metabolic indices were calculated by standardized uptake values (SUV). All patients were followed up for 2 years. Values of FDG-SUV, FES-SUV and FES/FDG SUV ratio of tumors were retrospectively reviewed. The correlation between these parameters and clinical outcome of EC and AH for 2 years was evaluated. Results: An initial complete response was achieved in all patients. Two of 5 responders (40%) with AH and one of three (33%) responders with EC later developed (72-88weeks) relapse. One of those three patients underwent hysterectomy due to no response for additional MPA therapy. The tracer uptake of FDG and FES was decrease in all eight patients after 8 weeks. The FES/FDG ratio was increased in all three patients with later developed relapse, but the FES/FDG ratio was decrease in all patients without recurrence for 8 weeks. There was a significant difference of the change in FES/FDG ratio between later developed relapse patients and no relapse patients (0.113 vs -0.392; p = 0.044). Conclusions: This study suggests that an increase in the FES/FDG ratio after 8 weeks fertility-sparing hormone treatment with a high-dose of MPA may be a useful biomarker for predicting later developed relapse in EC and AH in young women.
Circulating and skin-derived Sézary cells: clonal but with phenotypic plasticity
Authors: Marie Roelens, Marc Delord, Caroline Ram-Wolff, Anne Marie-Cardine, Antonio Alberdi, Guitta Maki, Laurence Homyrda, Armand Bensussan, Martine Bagot, Antoine Toubert, Hélène Moins-Teisserenc
Journal: Blood (2017)