tbuckley/cabot-search huggingface dataset:
Abstract 921: Cdyl2 is a chromodomain protein involved in the maintenance of pluripotency of stem cells
Authors: Naoko Hattori, Kana Kimura, Jumpei Taguchi, Toshio Imai, Yasuhiro Yamada, Toshikazu Ushijima
Journal: Cancer Research (2017)

Abstract Reader proteins of histone modifications are required to translate the information of histone marks into the cellular phenotypes, including pluripotency and malignancy. For example, a reader protein BRD4 has its target specificity and becomes a target of cancer therapy. Here, we aimed to identify reader proteins involved in the pluripotency of stem cells. Using the UCSC database, 11 genes coding chromo- or PHD-domain proteins were isolated as actively transcribed in mouse ES cells (ESCs). Among the 11 genes, Cdyl2, chromodomain protein Y-like2, was found to be down-regulated upon ESC differentiation using RT-qPCR. Immunofluorescence and ChIP assay revealed that Cdyl2 recognized H3K27me3 of the specific regions, including differentiation-associated genes. Cdyl2-knock-out ESCs could not survive after differentiation induced by LIF removal or retinoic acid because of the induction of apoptosis, indicating that Cdyl2 is important for normal differentiation of ESCs. ESC expressing exogenous Cdyl2 showed incomplete down-regulation of Oct-4 and Nanog by retinoic acid, and generated teratomas with an abnormal composition of three germ layers, showing perturbation of differentiation ability. Pathologically, aberrant expression of human CDYL2 was observed in breast cancer cell lines and primary breast cancers. Two breast cancer cell lines (MDA-MB-231 and MDA-MB-468) expressing exogenous CDYL2 showed enhanced attachment ability along with the up-regulation of integrin alpha-6 and integrin beta-1. The population of cancer stem cells, defined as ALDH positive cells, were increased in CDYL2-expressing MDA-MB-468 cells, showing that human CDYL2 is involved in proliferation of cancer stem cells. From these data, we conclude that, between self-renewal and differentiation of stem cells, mouse and human Cdyl2/CDYL2 is necessary for the implementation of the initial step of differentiation. Citation Format: Naoko Hattori, Kana Kimura, Jumpei Taguchi, Toshio Imai, Yasuhiro Yamada, Toshikazu Ushijima. Cdyl2 is a chromodomain protein involved in the maintenance of pluripotency of stem 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 921. doi:10.1158/1538-7445.AM2017-921
Abstract 4159:In vitrodrug response (IVDR) and tumor-associated biomarker (BM) expression profiles in lung carcinoma (LC)
Authors: Ricardo J. Parker, Patric M. Schiltz, Michael P. Myers
Journal: Cancer Research (2017)

Abstract Assessing IVDR to Chemo and BM expression in tumors of patients (Pts) before treatment can stratify therapy and improve outcome. Historical IVDR and BM data were analyzed retrospectively on 582 human LC specimens including 311 adenocarcinomas (ADCA), 131 non-small cell lung carcinomas (NSCLC), and 140 squamous cell carcinomas (SQCC) resected from Pts diagnosed with primary (PD), recurrent (RD) or metastatic disease (MD), and tested at a single clinical reference lab between March 2004 and July 2006. Pt and specimen information were unlinked directly and anonymized. IVDR was determined in prepared aliquots of Pts’ viable tumor cell suspensions after 5-day exposures to single physiologic doses of Chemo (CARBO, CPLAT, GMCB, NVBL, TAXOL, TXTR, VP16, TOPO). IVDR was bifurcated into extreme resistance (ER, non-response) or low resistance (LR, response). Standard immunohistochemistry (IHC) was performed on the same Pts’ paraffin-embedded LC sections to detect BMs mutant-p53 (mp53; n=322), EGFR (n=250), and BCL-2 (n=270), and results showed 57% overexpressed mp53, 91% overexpressed EGFR, and 32% expressed BCL-2. IVDR profiles for ADAC and NSCLC were similar, while SQCC was comparatively less resistant. IVDR profiles for PD, RD and MD of a given histology were relatively dissimilar. In ADCA, RD was more resistant than PD and MD. In NSCLC and SQCC, MD was more resistant. Significant portions of LCs showed prevalent ER to CARBO, TAXOL, TXTR, and VP16; and cross resistance to combinations, suggesting no clinical benefit from toxic ineffective Chemo. In such settings, disease progression may negatively impact a Pt’s tolerance to further Chemo. Pre-assessment of IVDR and BMs may identify ER factors, stratify treatment, and potentially improve clinical outcomes. Citation Format: Ricardo J. Parker, Patric M. Schiltz, Michael P. Myers. In vitro drug response (IVDR) and tumor-associated biomarker (BM) expression profiles in lung carcinoma (LC) [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 4159. doi:10.1158/1538-7445.AM2017-4159
A Single Arm, Phase II Study of Eltrombopag to Enhance Platelet Count Recovery in Older Patients with Acute Myeloid Leukemia (AML) Undergoing Remission Induction Therapy
Authors: Sudipto Mukherjee, Hong Li, Brian P. Hobbs, Aaron T. Gerds, Anjali S. Advani, Hetty E. Carraway, Aziz Nazha, Samjhana Bogati, Eric Parsons, Benjamin Pannell, Matt Kalaycio, Yogenthiran Saunthararajah, Jaroslaw P. Maciejewski, Mikkael A. Sekeres
Journal: Blood (2019)
Abstract 2328: Race specific hyper-activation of CCR9-mediated survival signals and its impact on efficacy of docetaxel in prostate cancer
Authors: Neeraj Kapur, Hina Mir, Guru Sonpavde, Shailesh Singh
Journal: Cancer Research (2017)

Abstract Current approaches to treat and manage prostate cancer (PCa) have failed to reduce racial disparity primarily due to undefined molecular mechanism. We have shown higher expression of chemokine receptor-9 in PCa cells and CCR9 expression was higher in PCa cells (MDA-PCa-2b) derived from African American (AA) patient compared to PCa cells derived form European American (EA) patients (LNCaP and PC3). Using antibody microarray we observed hyper activation of survival molecules and down-regulation of apoptotic molecules in AA PCa cells compared to EA PCa cell lines, following CCL25 stimulation. Comparative heat map analysis showed significant increase (~2-3 fold) in phosphorylation of pro-survival proteins in AA cells compared to EA cells treated with CCL25, which was further confirmed by western blot analysis. Furthermore, CCL25 treated PCa cells showed decreased expression of pro-apoptotic proteins (Bim, Bid, Bak), which was significantly abrogated by CCR9 shRNA. This effect was more pronounced in AA cells compared to EA cells. Efficacy of docetaxel (DTX) was higher after CCR9 blockade in presence of CCL25 compared to cells treated with CCL25 without blocking CCR9. Improvement in efficacy of DTX was due to inhibition of cell survival and activation of pro-apoptotic signals following CCR9 blockade. These observations suggest potential involvement of CCR9 mediated molecular pathways in disparity associated with outcome of PCa. Citation Format: Neeraj Kapur, Hina Mir, Guru Sonpavde, Shailesh Singh. Race specific hyper-activation of CCR9-mediated survival signals and its impact on efficacy of docetaxel in 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 2328. doi:10.1158/1538-7445.AM2017-2328
Abstract 634: RNAi-mediated β-catenin inhibition promotes T-cell infiltration and anti-tumor activity in combination with immune checkpoint blockade
Authors: Shanthi Ganesh, Serena Shui, Weimin Wang, Bob D. Brown, Marc Abrams
Journal: Cancer Research (2017)

Abstract Recent research strongly suggests an important role for Wnt/β-catenin signaling in mediating cancer immune evasion and resistance to immune checkpoint therapy, including anti-PD-1, anti-PD-L1, and anti CTLA-4 antibodies. The mechanism by which Wnt/β-catenin signaling causes checkpoint resistance is believed to involve blocking of specific cytokines which trigger immune cell recruitment to the tumor, resulting in the phenomenon of T-cell exclusion and rendering the tumor to a non-inflamed state. Inhibition of β-catenin may be an effective strategy for increasing the low response rate to these effective medicines in numerous cancer populations. DCR-BCAT is a potent and specific chemically-optimized RNA interference (RNAi) trigger targeting CTNNB1, the gene which encodes β-catenin, formulated in a tumor-selective EnCore lipid nanoparticle. In syngeneic mouse tumor models, β-catenin inhibition promoted T-cell infiltration and significantly improved the sensitivity of the tumors to checkpoint inhibition. The combination of DCR-BCAT and IO therapy yielded significant tumor growth inhibition compared to monotherapy in B16F10 melanoma, 4T1 mammary carcinoma, Neuro2A neuroblastoma and Renca renal adenocarcinoma. Importantly, a significant increase in CD8+ T-cells after DCR-BCAT monotherapy was observed in all models evaluated, including genetically-driven spontaneous MMTV-Wnt1 tumors. These data support clinical development of these combination approaches for this first-in-class RNAi therapeutic. Citation Format: Shanthi Ganesh, Serena Shui, Weimin Wang, Bob D. Brown, Marc Abrams. RNAi-mediated β-catenin inhibition promotes T-cell infiltration and anti-tumor activity in combination with immune checkpoint blockade [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 634. doi:10.1158/1538-7445.AM2017-634
Abstract 4054: Development of dual function small molecules as therapeutic agents for cancer treatment
Authors: Scott Grindrod, Alfredo Velena, Mira Jung
Journal: Cancer Research (2017)

Abstract Inhibitors of histone deactylases (HDACs) are emerging as potent anti-cancer agents for treatment of patients with hematopoietic and solid tumors. However, most of these compounds exhibit limitations, including off-targets and toxicity. To improve the efficacy and target specificity of drugs, we developed the compound, SP-1-161 conferring HDAC inhibition activity and ataxia-telangiectasia mutated (ATM) activation. The purpose of this study is to develop a therapy that optimizes the protective effects of ATM activation in normal tissue with the sensitizing effects of HDAC inhibition in cancerous tissue into a single molecule. The compound SP-1-161 was rationally designed by optimizing ATM activation by the cap domain of a hydroximic acid, screened against a panel of Class I and Class II HDAC enzymes, and identified as a pan-HDAC inhibitor with nanomolar potency (IC50 = 8 nM). Western analysis confirms that SP-1-161 increases acetylated histone H3/H4 and α-tubulin and ATM activation in MCF7 cells. Phosphorylated ATM was gradually increased within 1 - 4 hrs in a time-dependent manner. SP-1-161 was then tested in normal breast epithelial (184A1) and breast cancer (MCF7) cell lines to determine its cytotoxicity and effect on radiation clonogenic survival in combination with graded radiation exposure. The data showed that the cytotoxicity values (IC50) were low micro-molar ranges. Furthermore, SP-1-161 protected 184A1 cells (from D0 = 1 Gy to D0 = 1.4 Gy) while increasing sensitivity of MCF7 cells to IR (from D0=1.6 Gy to D0=1.12 Gy). Together, our results demonstrate that SP-1-161 is an unprecedented radio-chemo therapeutic agent for treatment of cancers while protecting normal cells. Citation Format: Scott Grindrod, Alfredo Velena, Mira Jung. Development of dual function small molecules as therapeutic agents for cancer treatment [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 4054. doi:10.1158/1538-7445.AM2017-4054
Abstract 674: HPV16 was the preponderant type of HPV infection in cutaneous squamous cell carcinoma
Authors: Gang Shi, Anne C. Fischer, Jonathan M. Zenilman, Patti E. Gravitt, Max Fischer, Inbal B. Sander, Jonathan D. Cuda, Janis M. Taube, Mohammed Lilo, W P Andrew Lee, Anthony P. Tufaro
Journal: Cancer Research (2017)

Abstract Purpose: Human papillomavirus (HPV) has been well established as a causative factor in mucosal oropharyngeal cancer and anogenital surface malignancies. However, its etiological role in cutaneous squamous cell carcinoma (cSCC) is still debated. The aim of this study is to identify the presence of HPV types in cSCC and identify their associations with cSCC. Methods: 77 cSCC blocks from 54 patients underwent DNA isolation and a broad spectrum of HPV PCR tests to detect the presence of HPV genotypes by the use of a universal primer pair GP5+/GP6+. The resultant PCR products were cloned to T Vectors and subsequently underwent DNA sequencing and Nucleotide BLAST search to identify the HPV types in cSCC. To ensure the accuracy of the HPV PCR test, 16 blocks from 10 head and neck SCC (oropharyngeal) patients were also included in the HPV presence and type analyses. Cutaneous SCC patients’ demographics, pathology and clinical parameters were compared and analyzed statistically in conjunction with the HPV test results. Results: HPV DNA was found in 37 of 77 (48.1%) blocks representing 32 of 54 (59.3%) cSCC patients. HPV16 was the preponderant type of HPV Infection, accounting for 28 of 32 (87.5%) and 30 of 37 (81.08%) HPV positive patients and blocks. Other HPV genotypes found included HPV18, 57, 10, 2, accounting for 4 of 32 (12.5%), 2 of 32 (6.25%), 2 of 32 (6.25%), 2 of 32 (6.25%) of the HPV positive patients and 4 of 37 (10.81%), 2 of 37 (5.41%), 2 of 37 (5.41%), 2 of 37 (5.41%) of the HPV positive blocks, respectively. HPV infection was significantly associated with the cSCC tumor size in this cohort of patients. Tumors with a size of ≤20mm were more frequently associated with HPV. Moreover, the average tumor size of the HPV positive group was also significantly smaller than that of the HPV negative group. Conclusions: HPV infection is very commonly found in cSCC patients and HPV16 is the major type of HPV involved in cSCC oncogenesis, accounting for &amp;gt;80% of HPV infections. HPV is a contributing factor, which appears to be contributing to a smaller size of cSCC, which may improve the prognostic classification of patients to provide a new insight into tumorigenesis. Citation Format: Gang Shi, Anne C. Fischer, Jonathan M. Zenilman, Patti E. Gravitt, Max Fischer, Inbal B. Sander, Jonathan D. Cuda, Janis M. Taube, Mohammed Lilo, W P Andrew Lee, Anthony P. Tufaro. HPV16 was the preponderant type of HPV infection in cutaneous squamous cell 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 674. doi:10.1158/1538-7445.AM2017-674
Abstract 759: Highly-sensitive detection of EGFR mutation in non-small cell lung cancer using mutant-enrichment method
Authors: Hung-Chi Chien
Journal: Cancer Research (2017)

Abstract Detection of mutations in EGFR in non-small cell lung cancer is important for the clinical decision-making process of molecularly targeted therapies, including Iressa®, Tarceva®, and Tagrisso®. In this study we developed an assay allowing the detection of EGFR gene mutations being conducted in the routine diagnostic procedure and its analytic and clinical performance were evaluated using different types of specimens. The EGFR mutation assay in this study allows for detecting EGFR exon 19 deletion (Del), exon 20 insertion (Ins), and mutation in T790M, L858R, S768I and L861Q of rare amounts in a normal genetic background. Enhancement of detection sensitivity was achieved with the developed mutant enrichment method which combines mutation-specific primers and 3'-phosphorylation oligonucleotides as blockers for inhibiting wild-type gene from DNA amplification. Analytic performance for each mutant was assessed using the control plasmids containing the mutant genes of known amounts as well as the genomic DNA extracted from mutant cell lines and Horizon FFPE samples. The assay performance were also evaluated using clinical samples in parallel with the FDA-approval companion diagnostic product therascreen® EGFR RGQ PCR Kit . The sensitivity of the assay evaluated using control plasmids for Del, T790M , L858R, S768I, L861Q mutation and Ins was 5%, 0.5%, 1%, 0.5%, 0.1% and 0.5% respectively, and was 1%, 0.5%, 0.5%, 0.5%, 0.1% and 0.5% respectively when applying on HDx reference standards. Diagnostic results for the 116 clinical samples for identifying mutations of del, T790M, L858R, S768I, L861Q and Ins was 92.2%, 100%, 99.1%, 100%, 97.4% and 100% respectively concordance with the therascreen® EGFR RGQ PCR Kit, including 17 cases of multiple mutations. The overall diagnostic results for all mutations evaluated with PPA (positive percent agreement), NPA (negative percentage agreement) and OPA (overall percentage agreement) were 83.3%, 98.2% and 90.5%, respectively. The three samples firstly diagnostic as false positive were retested and confirmed to be Exon 19 del by DNA sequencing. The assay demonstrated good sensitivity when compared with commercial product. More clinical studies are being performed to establish relationship between drug efficacy and different mutation combinations. Citation Format: Hung-Chi Chien. Highly-sensitive detection of EGFR mutation in non-small cell lung cancer using mutant-enrichment method [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 759. doi:10.1158/1538-7445.AM2017-759
Treatment of Latent Tuberculosis Infection
Authors: Dominik Zenner, Netta Beer, Ross J. Harris, Marc C. Lipman, Helen R. Stagg, Marieke J. van der Werf
Journal: Annals of Internal Medicine (2017)

Treatment of latent tuberculosis infection (LTBI) is an important component of tuberculosis (TB) control, and this study updates a previous network meta-analysis of the best LTBI treatment options to inform public health action and programmatic management of LTBI.To evaluate the comparative efficacy and harms of LTBI treatment regimens aimed at preventing active TB among adults and children.PubMed, Embase, and Web of Science from indexing to 8 May 2017; clinical trial registries; and conference abstracts. No language restrictions were applied.Randomized controlled trials that evaluated human LTBI treatments and recorded at least 1 of 2 prespecified end points (hepatotoxicity and prevention of active TB).2 investigators independently extracted data from eligible studies and assessed study quality according to a standard protocol.The network meta-analysis of 8 new and 53 previously included studies showed that isoniazid regimens of 6 months (odds ratio [OR], 0.65 [95% credible interval {CrI}, 0.50 to 0.83]) or 12 to 72 months (OR, 0.50 [CrI, 0.41 to 0.62]), rifampicin-only regimens (OR, 0.41 [CrI, 0.19 to 0.85]), rifampicin-isoniazid regimens of 3 to 4 months (OR, 0.53 [CrI, 0.36 to 0.78]), rifampicin-isoniazid-pyrazinamide regimens (OR, 0.35 [CrI, 0.19 to 0.61]), and rifampicin-pyrazinamide regimens (OR, 0.53 [CrI, 0.33 to 0.84]) were efficacious compared with placebo. Evidence existed for efficacy of weekly rifapentine-isoniazid regimens compared with no treatment (OR, 0.36 [CrI, 0.18 to 0.73]). No conclusive evidence showed that HIV status altered treatment efficacy.Evidence was sparse for many comparisons and hepatotoxicity outcomes, and risk of bias was high or unknown for many studies.Evidence exists for the efficacy and safety of 6-month isoniazid monotherapy, rifampicin monotherapy, and combination therapies with 3 to 4 months of isoniazid and rifampicin.U.K. National Institute for Health Research. (PROSPERO: CRD42016037871).
Abstract 4024: Physiologically relevant target engagement using the cellular thermal shift assay (CETSA)
Authors: Jakob Karen, Catrine Sioberg, Nancy Dekki Shalaly, Daniel Martinez Molina
Journal: Cancer Research (2017)

Abstract Targeted therapies are dependent on adequate occupancy and target engagement to reach their efficacy measure. Yet, more than half of novel candidate drugs entering clinical trial stage fail before proof of concept is achieved. Inadequate target engagement is often at the root cause of these failures. Therefore, we have developed a versatile label-free method to quantify the target engagement of drugs on their native physiological relevant targets. The method is validated in multiple sample matrices, using different technical platforms to allow studies of target engagement from bench to bedside: in living cells and tissue from rodents and man. CETSA(®) is a patented biophysical method measuring the thermal stability of drug target proteins and the shift induced by their ligands. By quantifying the melting temperature and shift induced by the ligand we can quantify the potency of target engagement. This potency determination allows filtering of candidate drugs by their ability to engage the target in its physiologically relevant form, in relevant sample formats such as intact cells or tissue. We present several applications of the method and the utility in preclinical in vitro studies and translation to in vivo systems. In addition, new powerful detection formats are being evaluated and will be presented. The utility and value of the CETSA(®) method enabling preclinical development of novel drugs is substantiated by the examples included here. We show the value of the method both for compound/drug profiling, for target profiling and for unbiased drug profiling on whole proteomes in response to drug treatments. Such datasets can be generated from in vitro systems to clinical samples and may reduce the high attrition rate in proof of concept studies by facilitating the discovery, development and evaluation of novel drugs. Citation Format: Jakob Karen, Catrine Sioberg, Nancy Dekki Shalaly, Daniel Martinez Molina. Physiologically relevant target engagement using the cellular thermal shift assay (CETSA) [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 4024. doi:10.1158/1538-7445.AM2017-4024