tbuckley/cabot-search huggingface dataset:
Abstract 2362: Mechanistic insights into phosphoinositide 3-kinase α
Authors: Sweta Maheshwari
Journal: Cancer Research (2017)

Abstract Phosphoinositide 3-kinases (PI3Ks) are at the center of mTOR pathway that plays key roles in regulating cell survival, proliferation, protein synthesis and vesicle trafficking. Dysregulation of the mTOR pathway has been implicated in various diseases such as cancer, diabetes, arthritis, inflammation and respiratory illnesses. PI3Ks have dual kinase specificity with a lipid kinase activity that phosphorylates the 3’-hydroxyl of phosphoinositides, and a protein kinase activity including auto-phosphorylation. In this study, we explored the roles of residues of the catalytic domain and regulatory subunit of human PI3Kα in the lipid and protein phosphorylation. We used site-directed mutagenesis and kinetic assays to precisely map the molecular basis of substrate recognition and catalysis in PI3Kα. Kinetic analysis of K776, located in the P-loop of PI3Kα, reveals that a lysine at this position is essential for the recognition of the lipid and ATP substrates. This same residue plays an important role in the auto-phosphorylation of the enzyme. Replacement of histidine residues–H936 and H917 in the activation and catalytic loops respectively with alanine residues results in a dramatic change in the kinetics of PI3Kα. While H936A inactivates the lipid kinase activity without affecting auto-phosphorylation, H917A abolishes both the lipid and protein kinase activities of PI3Kα. On the basis of kinetic and structural analysis, we proposed possible mechanistic roles of these critical residues in catalysis. Citation Format: Sweta Maheshwari. Mechanistic insights into phosphoinositide 3-kinase α [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 2362. doi:10.1158/1538-7445.AM2017-2362
Abstract 4468: Oncogenic activation of the RNA binding protein AGO2 in hepatocellular carcinoma
Authors: Hien T. Dang, Lucy Knight, Yotsawat Pomyen, Xin Wei Wang
Journal: Cancer Research (2017)

Abstract Global transcriptomic alterations of coding and non-coding RNAs are a ubiquitous feature of cancers including Hepatocellular carcinoma (HCC). Dysregulation of RNA-binding proteins (RBPs), key regulators of RNA processing such as RNA maturation and degradation, is one mechanism in which cancer cells select to promote tumorigenesis. RBPs are highly expressed in solid tumors and have been demonstrated to be drivers of carcinogenesis, however, the underlying mechanisms in which RBPs regulate the HCC transcriptome is unknown. We analysed genomic alterations amongst a family of more than 800 mRNA RBPs (mRBPs) in 1,225 clinical specimens from HCC patients and found that RBPs are significantly activated through gene amplification in a subset of tumors with poor prognosis, suggesting their potential oncogenic roles in HCC progression. Amongst the top candidates, Argonaute 2 (AGO2) was further characterized for its oncogenic role and effects on the HCC transcriptome. Elevated AGO2 mRNA expression was highly correlated with elevated somatic copy number alterations across five different cancer types including HCC. Moreover, AGO2 expression was associated with overall survival in two independent data sets (TCGA and the Liver Initiative Cancer), suggesting that AGO2 activation is oncogenic. While the activation of AGO2 induced an oncogenic phenotype, the abrogation of AGO2 in HCC cells significantly decreased cancer associated phenotypes such as cell proliferation, migration/invasion and tumorigenicity in vivo. Further analyses revealed that AGO2-associated genes were tumor-related, including c-Myc. Notably, c-Myc amplification was also found in AGO2 high HCC cells, suggesting an interplay between AGO2 and c-Myc. Our results demonstrate that oncogenic activation of AGO2 is a novel mechanism that may contribute to global transcriptome selective for the activation of c-Myc oncogenic. Our current work suggests that therapies focused on targeting AGO2 may be valuable for clinical treatment of many different tumors with activated c-Myc signalling, including HCC Citation Format: Hien T. Dang, Lucy Knight, Yotsawat Pomyen, Xin Wei Wang. Oncogenic activation of the RNA binding protein AGO2 in hepatocellular carcinoma [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 4468. doi:10.1158/1538-7445.AM2017-4468
Abstract 5637: An oral Androgen Receptor PROTAC degrader for prostate cancer
Authors: Taavi K. Neklesa, Lawrence B. Snyder, Mark Bookbinder, Xin Chen, Andrew P. Crew, Craig M. Crews, Hanqing Dong, Deborah Gordon, Jennifer Macaluso, Kanak Raina, AnnMarie Rossi, Ian Taylor, Nicholas Vitale, Jing Wang, Ryan R. Willard, Kurt Zimmermann
Journal: Cancer Research (2017)

Abstract The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Further, we sought to make an orally bioavailable AR PROTAC. Medicinal chemistry efforts yielded a small molecule AR PROTAC that simultaneously binds E3-ubiquitin ligase and AR, thus leading to ubiquitination and degradation of AR. This molecule has been characterized in in vitro and in vivo preclinical studies. Our lead oral AR PROTAC degrades approximately 98% of total AR in all cell lines tested, with 50% degradation concentration (DC50) &amp;lt; 1 nM. AR degradation suppresses the expression of AR-target gene PSA, inhibits cell proliferation, and induces potent apoptosis in VCaP cells. No activity is observed in AR-null cell lines, such as PC-3. While enzalutamide loses its activity in the presence of elevated androgens, AR PROTAC maintains its antiproliferative activity. Further, AR PROTAC is able to degrade all clinically relevant mutant AR proteins. A robust oral bioavailability is observed across multiple species and overall ADME properties are encouraging. Approximately 95% AR degradation is observed in AR-amplified VCaP xenografts at doses as low as 10 mg/kg. Congruent with AR degradation, a dose responsive tumor growth inhibition is observed in AR-dependent xenograft studies. In summary, we report the first orally bioavailable AR PROTAC that robustly degrades AR in vitro and in vivo. Citation Format: Taavi K. Neklesa, Lawrence B. Snyder, Mark Bookbinder, Xin Chen, Andrew P. Crew, Craig M. Crews, Hanqing Dong, Deborah Gordon, Jennifer Macaluso, Kanak Raina, AnnMarie Rossi, Ian Taylor, Nicholas Vitale, Jing Wang, Ryan R. Willard, Kurt Zimmermann. An oral Androgen Receptor PROTAC degrader for prostate 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 5637. doi:10.1158/1538-7445.AM2017-5637
Abstract 3724: PDL1 protein expression and tumor mutation burden in hematologic malignancies: correlation with Hodgkin and high grade lymphoma
Authors: Lina Abdul Karim, Peng Wang, Jose de Guzman, Brandi Higgins, Joeffrey Chahine, Christine Sheehan, Bhaskar Kallakury, Jeffrey S. Ross
Journal: Cancer Research (2017)

Abstract Background: The success of anti PD–1 therapy in Hodgkin lymphoma has led to clinical trials in other types of lymphomas. However, there is limited data on PD–L1 expression in acute leukemias. In this study, we analyzed PD–L1 protein expression and tumor mutational burden in various hematologic malignancies including leukemias, lymphomas and myelomas. Methods: In the IHC cohort, formalin fixed paraffin embedded sections from 92 hematologic malignancies including acute myeloid and lymphoblastic leukemia (AML, ALL), Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), low-grade non-Hodgkin lymphoma (LGNHL) and myeloma were immunostained using the FDA approved PD-L1 IHC 22C3 pharmDx assay [monoclonal mouse anti-PD–L1 antibody (DAKO clone 22C3)]. Any perceptible partial or complete membrane staining in all viable tumor cells was scored as follows: &amp;lt;1%-negative, 1-49%-low level and &amp;gt;50%-high level PD-L1 expression. In the second cohort of 2064 cases, comprehensive genomic profiling (CGP) was performed using a hybrid–capture, adaptor ligation assay to a mean depth of &amp;gt;672X. Tumor mutation burden (TMB) was calculated from a minimum of 1.11MB of sequenced DNA as previously described and reported as mutations/MB. High PD–L1 expression was noted in 100% of HL. DLBCL showed significantly higher PD–L1 positivity compared to LGNHL (p=0.01). No correlation for PD–L1 expression was noted between AML and ALL (p = 0.2). On CGP analysis of the second cohort, TMB was significantly higher in DLBCL as compared to LGNHL (p&amp;lt;0.0001). Conclusion: The high PD-L1 expression in both HL and DLBCL and high TMB in DLBCL may be linked to enhanced responsiveness to check point inhibitor therapy in these cancers. PD-L1 expression and TMB are relatively infrequent and at low levels in acute leukemias. Additionally, novel anti PD–1/PD–L1 therapeutic strategies are worthy of consideration for both advanced stage refractory/relapsed acute myeloid and lymphoblastic leukemias. Results: PD-L1 expression and TMB are tabulated below.PD-L1 IHCTMB (mutations/MB)Tumor typenLow PositiveHigh PositiveTotal Positive (%)n&amp;gt;=10.0&amp;gt;=20.0AML21505/21 (24%)50%0%ALL3212012/32 (38%)10%0%HL1001010/10 (100%)368%8%DLBCL10448/10 (80%)25344%15%LGNHL10202/10 (20%)930%0%Myeloma9202/9 (22%)NANANA Citation Format: Lina Abdul Karim, Peng Wang, Jose de Guzman, Brandi Higgins, Joeffrey Chahine, Christine Sheehan, Bhaskar Kallakury, Jeffrey S. Ross. PDL1 protein expression and tumor mutation burden in hematologic malignancies: correlation with Hodgkin and high grade lymphoma [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 3724. doi:10.1158/1538-7445.AM2017-3724
Abstract 5766: High-content microscopy-based screening of colorectal organoids
Authors: Niklas T. Rindtorff, Johannes Betge, Jan Sauer, Thilo Miersch, Tianzuo Zhan, Florian Heigwer, Claudia Scholl, Matthias Ebert, Bernd Fischer, Michael Boutros
Journal: Cancer Research (2017)

Abstract High-content screening of cells has become a widespread approach for cellular assays due to its capacity to capture complex biological processes. However, conventional cell culture is limited with respect to cell and tissue architecture. Organoids are a unique model system for the intact and diseased intestinal epithelium. The 3D model can be used for the functional study of cancer development and, potentially, prospective therapeutic testing of drugs in patient derived tumor organoids. Here, we present a high-content microscopy based screening workflow to study organoid self-organization and growth with up to single cell resolution. After seeding of organoid fragments in a basal membrane extract, screening plates are incubated to allow for organoid formation. Subsequent treatment and incubation is followed by staining and imaging on a high-throughput microscopy platform followed by automated image analysis using open-source software. Profiling of both complete organoids and their individual architecture enables the quantitative description of population and tissue heterogeneity in the context of various perturbations. We generated four distinct colon organoid lines from mice carrying mutations of APC and KRAS in different combinations. These are profiled for differential phenotypic responses to a library of &amp;gt;1000 drug-like compounds. Also, this methodology is used to screen for clinically relevant differential treatment responses in patient derived tumor and normal colon organoids. Hence, based on this work we are able to analyze gene-drug interactions in early colon cancer development and drug response of patient derived colorectal cancer organoids. Citation Format: Niklas T. Rindtorff, Johannes Betge, Jan Sauer, Thilo Miersch, Tianzuo Zhan, Florian Heigwer, Claudia Scholl, Matthias Ebert, Bernd Fischer, Michael Boutros. High-content microscopy-based screening of colorectal organoids [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 5766. doi:10.1158/1538-7445.AM2017-5766
Abstract 276: Retrospective analysis of epidemiological variants of malignancies in Sokoto, Northwestern Nigeria
Authors: Saddiku M. Sahabi, Kabiru Abdullahi
Journal: Cancer Research (2017)

Abstract Background: The burden of cancer in Nigeria is increasing. Information on incidence, prevalence, pattern, and high risk factors are essential for evaluation and cancer control. This report is a follow up from earlier previous report published in 2005 on cancers seen in Usmanu Danfodiyo University Teaching Hospital (UDUTH) Sokoto. Objectives: The aim of this study is to determine epidemiological variants of all malignancies seen from 1 January 2006 to 31 December 2015. Materials and Methods: This is a retrospective review of all malignancies seen at the Usmanu Danfodiyo University Teaching Hospital in Sokoto during the period 2006 to 2016. There was no restriction on gender or age groups. Mean, frequencies, percentages, and independent sample t-test were performed using SPSS version 21.0 for Windows. Significant level set at p &amp;lt; 0.05. Results: A total of 3933 cancer patients were seen during the ten-year period. There were more female malignancies (n=2260, 57.5%) compared to male malignancies (n=1673, 42.5%). The overall mean age (years) was 44.28, median age was 45.0, modal age was 50, and SD was 18.69; the age range was 1 to 99 years. Males (mean age 45.77, median age in male 50.0, modal age 60, and SD 21.03) were significantly older than females (mean age 43.18, median age 45.0, modal age 50, and SD 16.67). The adult malignancies account for 90.9% (n=3575) and childhood malignancies account for 9.1% (n=358). Overall, the ten most common malignancies were: breast 763 (19.4%), cervix 312 (7.9%), prostate 267 (6.8%), lymph node 248 (6.3%), skin 225 (5.7%), bladder 191 (4.9%), rectum 114 (2.9%), ovary 110 (2.8%), eye 97 (2.5%), soft tissue 95 (2.4%). In males, the ten most frequent malignancies were: prostate 267 (16.00%), bladder 160 (9.60%), skin 138 (8.20%), nasophraynx 87 (5.2%), lymph node 85 (5.10%), rectum 61 (3.60%), eye 55 (3.30%), salivary gland 38 (2.3%), larynx 37 (2.20%), and anal 37 (2.20%). In females, the ten most common malignancies were breast 731 (731%), cervix 302 (13.40%), lymph node 163 (7.20%), ovary 110 (4.90%), skin 87 (3.80%) endometrial 61 (2.70%), rectum 53 (2.30%), nasophraynx 45 (2.0%), soft tissue 43 (1.90%), and eye 42 (1.90%). Conclusion: Our study concludes that malignancies of the breast, cervix, and prostate are the three most common in our environment. These malignancies tend to present at younger age (less than 50 years of age) compared to other developing countries. Therefore, public education and well developed screening programs are urgently needed to overcome this burden. Citation Format: Saddiku M. Sahabi, Kabiru Abdullahi. Retrospective analysis of epidemiological variants of malignancies in Sokoto, Northwestern Nigeria [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 276. doi:10.1158/1538-7445.AM2017-276
Repurposing Medications—Chicken Manure, Erectile Dysfunction, and Finding the Golden Needle in the Haystack of Absurdity
Authors: Erik J. Stratman
Journal: JAMA Dermatology (2017)

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Abstract LB-202: A novel neoepitope screening platform for generating effective and safe neoantigen-based vaccines and immunotherapeutics in a hepatocellular carcinoma model
Authors: Cheng-chi Chao, Fengjiao Yuan, Geng Liu, Guanglei Li, Bo Li, Lian Lu, Yaomei Tian, Dongli Li, Bailing Zhou, Ting An, Yingzi Fan, Chongming Jiang, Yang Shu, Honggang Lin, Heng Xu, Hanshuo Yang, Rui zhang, Xueyan Zhang, Zhen Cheng, Rong Huang, Michael Dean, Ke Men, Xiuqing Zhang, Chaoheng Yu, Jian Wang, Shuang Cheng, Huanming Yang, Yantai Wang, Yong Hou, Yuquan Wei, Li Yang
Journal: Cancer Research (2017)

Abstract Immunotherapy has emerged as a novel and promising strategy for cancer treatment, while available markers for immunotherapy have poor effectiveness and safety. The advance of next-generation sequencing (NGS) technology enables us to identify tumor-specific neoantigen which could be more effective and safer for personalized immunotherapy. In this study, we demonstrated a novel workflow for the development of liver cancer personalized vaccine. Xenograft models for liver cancer were built in mice using Hepa1-6 cell lines. Tumor-specific candidate neoantigen were determined by performed whole exome sequencing (WES) and used a comprehensive bioinformatics pipeline integrating multiple factors such as MHCI-binding affinity fold change (FC), variant allele frequencies (VAFs) of somatic mutation, mRNA expression and hydrophobicity of peptides. The results showed that peptide vaccine of Gpr55 neoantigen not only triggered striking neo-antigen specific CD8+ T cell response, but also significantly inhibited the growth of tumors in both prophylactic and therapeutic models. Moreover, our results demonstrated that VAFs and FC were the effective and safety property for immunogenicity. The identified Gpr55 neoantigen was an ideal vaccine for Hepa1-6 induced xenograft models considering the immunogenicity, anti-tumor effect and safety evaluation. It was also possible to identify and develop highly effective personalized cancer vaccine by our workflow within 13 weeks. The results illustrated huge potential of tumor-specific neoantigen as a potent vaccine for clinical tumor therapy and the workflow built in this study could be used to develop more specific, safer, more effective treatments to all types of cancer patients. Note: This abstract was not presented at the meeting. Citation Format: Cheng-chi Chao, Fengjiao Yuan, Geng Liu, Guanglei Li, Bo Li, Lian Lu, Yaomei Tian, Dongli Li, Bailing Zhou, Ting An, Yingzi Fan, Chongming Jiang, Yang Shu, Honggang Lin, Heng Xu, Hanshuo Yang, Rui zhang, Xueyan Zhang, Zhen Cheng, Rong Huang, Michael Dean, Ke Men, Xiuqing Zhang, Chaoheng Yu, Jian Wang, Shuang Cheng, Huanming Yang, Yantai Wang, Yong Hou, Yuquan Wei, Li Yang. A novel neoepitope screening platform for generating effective and safe neoantigen-based vaccines and immunotherapeutics in a hepatocellular carcinoma model [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 LB-202. doi:10.1158/1538-7445.AM2017-LB-202
Abstract 71: Bystander activity andin vivoefficacy of a folate receptor α (FRα)-targeting antibody-drug conjugate with a novel peptide linker
Authors: Qifeng Qiu, Rui Wu, Leanne Lanieri, Erin Maloney, Anna Skaletskaya, Shan Jin, Lintao Wang, Olga Ab, Joe Ponte, Yulius Setiady, Wayne Widdison, Thomas Keating, Ravi Chari, Richard Gregory, Erica Hong
Journal: Cancer Research (2017)

Abstract Folate receptor α (FRα) is an antigen that is overexpressed on the cell surface of solid tumors including ovarian cancer. The differential expression on cancer cells makes FRα an attractive target for antibody-drug conjugates (ADCs), and an ADC targeting FRα, Mirvetuximab soravtansine, has demonstrated promising activity and safety profiles in the clinic. Here, we employed a new linker (NL) to enhance the bystander activity of ADCs, which is the ability of ADCs to generate cell-permeable catabolites that can diffuse into and kill proximal cancer cells with little or no target expression. With the goal of improving the potency of anti-FRα ADC in solid tumors with heterogeneous FRα expression, we constructed the M9346A-NL-DM. M9346A-NL-DM is a conjugate of the tubulin-disrupting maytansinoid (DM), linked via a novel linker to M9346A, a humanized antibody that binds FRα with high affinity. After cellular uptake and catabolism of the ADC, the new linker undergoes lysosomal cleavage followed by self-immolation to generate free DM that can readily penetrate neighboring cancer cells. Correspondingly, M9346A-NL-DM showed enhanced bystander cytotoxic activity against proximal antigen-negative cells in vitro. In the xenograft tumor models in vivo, M9346A-NL-DM demonstrated enhanced efficacy against tumors with heterogeneous expression of FRα. Interestingly, M9346A-NL-DM also showed improved antitumor activity against a tumor model with homogeneous expression of FRα, possibly due to better tumor penetration of the cell-permeable catabolite. In summary, M9346A-NL-DM is a novel ADC with enhanced bystander activity and antitumor activity that can target tumors with heterogeneous expression of FRα. Citation Format: Qifeng Qiu, Rui Wu, Leanne Lanieri, Erin Maloney, Anna Skaletskaya, Shan Jin, Lintao Wang, Olga Ab, Joe Ponte, Yulius Setiady, Wayne Widdison, Thomas Keating, Ravi Chari, Richard Gregory, Erica Hong. Bystander activity and in vivo efficacy of a folate receptor α (FRα)-targeting antibody-drug conjugate with a novel peptide linker [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 71. doi:10.1158/1538-7445.AM2017-71