tbuckley/cabot-search huggingface dataset:
Abstract 6281: Differential response of irradiated breast carcinoma cells to DNA-PK inhibition: Spheroid response is governed by cell adhesion effects rather than changes in radiosensitivity
Authors: Jing Yu, Ryan Lu, Jessie Nedrow, George Sgouros
Journal: Cancer Research (2020)

Abstract Agents that increase tumor radiosensitivity are of interest in improving outcomes in radiotherapy (XRT). DNA-PKcs inhibitors lead to radiosensitization and also to alterations in cell adhesion proteins. Using a HER2 positive mammary carcinoma cell line, NT2.5, we investigated the impact of Nu7441, a potent and selective DNA-PKcs inhibitor together with external beam irradiation in both 2D monolayer and 3D spheroid cell culture systems. Colony formation assays were performed for cells irradiated as monolayers and also for cells disaggregated from spheroids. Cells grown in monolayer culture and as spheroids were incubated with Nu7441 (5 µM) for 24 h after different doses of external beam irradiation. In monolayer culture cells, α/β increased from 3.0 ± 0.2 Gy (XRT alone) to 6.9 ± 0.2 Gy when XRT was followed by Nu7441 incubation. Corresponding α/β values for cells obtained by disaggregating treated spheroids were 3.6 ± 0.7 Gy (XRT alone) and 3.5 ± 0.2 Gy (XRT+Nu7441). In contrast to the minimal change in α/β, spheroids survival was highly sensitive to Nu7441 incubation. 21 days after 0, 2, 4, 6, 8, or 10 Gy XRT alone 100, 83, 75, 63, 56, and 31%, respectively, of the irradiated spheroids remained intact; when Nu7441 treatment was involved, 56% remained intact at 2 Gy and 13% at 4 Gy, no spheroids survived to 3 weeks at 6 Gy or more. We also found a progressive increase in fragmentation for spheroids exposed only to Nu7441 (0 Gy): 3/24, 9/24 and 17/24 fragmented after 14, 21 and 28 days of incubation, respectively. The discrepancy between the minimal change in α/β from cells derived from spheroids and the spheroid growth response was not related to poor penetration of Nu7441 since the colony formation assay results for different sizes of spheroids (180 to 400 µm) treated with 4 Gy with or without Nu7441were not significantly different. The results suggest that spheroid response to DNA-PKcs inhibitors is driven by their known inhibition of cell-cell adhesion pathways and potentially less so by radiosensitization. Citation Format: Jing Yu, Ryan Lu, Jessie Nedrow, George Sgouros. Differential response of irradiated breast carcinoma cells to DNA-PK inhibition: Spheroid response is governed by cell adhesion effects rather than changes in radiosensitivity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6281.
Abstract 4614: Genome-wide association analysis of pro-inflammatory cytokines and gene-lifestyle interaction for invasive breast cancer risk: The WHI Database for Genotypes and Phenotypes Study
Authors: Su Yon Jung, Peter Scott, Sihao Han, Matteo Pellegrini, Jeanette Papp, Eric Sobel, Herbert Yu, Zuo-Feng Zhang
Journal: Cancer Research (2020)

Abstract Purpose: Pro-inflammatory biomarkers and their genetic variants may interact with obesity and obesity-related lifestyle factors, influencing breast cancer risk in postmenopausal women, but the interrelated metabolic pathways are incompletely understood. Methods: We used data from the Women's Health Initiative Database for Genotypes and Phenotypes Study including 16,088 postmenopausal women, a population highly susceptible to obesity and increased risk for breast cancer. We conducted a genome-wide association (GWA) analysis in two steps: 1) with six GWA substudies, GWA meta-analysis of pro-inflammatory cytokines (Interleukin-6 [IL-6] and C-reactive protein [CRP]) for their gene-lifestyle interactions and 2) test for the association between identified single-nucleotide polymorphisms (SNPs) at the genome-wide level and breast cancer risk. Results: In women overall and stratified by obesity status (body mass index, waist circumference, and waist-to-hip circumference) and obesity-related lifestyle factors (physical activity and high fat-diet), 88 loci were associated with pro-inflammatory phenotypes at genome-wide significance: 3 associated with IL-6 (1 index SNP in MAPK1 and 1 independent SNP in DEC1); 85 with CRP (3 index SNPs in CRP/CRPP1/HNF1A and 2 SNPs in APOE/APOC1, independently). Of those, 27 loci had significantly increased risk for breast cancer. Conclusions: We found a number of novel genetic markers in relation to pro-inflammatory phenotypes, which interacted with obesity and related lifestyle factors. A substantial proportion of those SNPs' susceptibility influences breast cancer risk in the identical subgroup populations. Our findings may contribute to improved prediction accuracy for cancer and suggest intervention strategies for women who carry the risk genotypes, eventually reducing breast cancer risk. Citation Format: Su Yon Jung, Peter Scott, Sihao Han, Matteo Pellegrini, Jeanette Papp, Eric Sobel, Herbert Yu, Zuo-Feng Zhang. Genome-wide association analysis of pro-inflammatory cytokines and gene-lifestyle interaction for invasive breast cancer risk: The WHI Database for Genotypes and Phenotypes Study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4614.
TCT-748 Nurse Led Sedation: The Clinical and Echocardiographic Outcomes of the 7-Year Emory Experience
Authors: John Lisko, Patricia Keegan, Norihiko Kamioka, Samuel Maidman, Jose Binongo, Peter Block, Adam Greenbaum, Robert Guyton, Vasilis Babaliaros
Journal: Journal of the American College of Cardiology (2019)
Abstract 5817: Anti-tropomyosin drugs prevent the rescue of vincristine-induced mitotic spindle defects
Authors: Peter Gunning, Yao Wang, Jeff H. Stear, Ashleigh Swain, Xing Xu, Nicole Bryce, Irina B. Alieva, Vera B. Dugina, Timothy Cripe, Justine Stehn, Edna C. Hardeman
Journal: Cancer Research (2020)

Abstract Drugs targeting a major component of the actin filaments of cancer cells, tropomyosin Tpm3.1, synergize with anti-microtubule drugs in neuroblastoma and lung cancer models both in vitro and in vivo and a wide range of other cancer types in vitro. We have determined the mechanism of synergy in HeLa cells to gain insight into the potential interaction of actin filaments and microtubules in the survival and proliferation of cancer cells. HeLa cells exhibit a strong synergistic response to the combined treatment of vincristine (VCR) and anti-Tpm3.1 compounds, marked by an enhanced reduction in cell viability, apoptosis induction and mitotic cell cycle arrest. Tpm3.1 localizes to the cell cortex during mitosis, potentially associating with the microtubule network, particularly the dynein/dynactin complexes responsible for mediating cortical pulling forces during spindle assembly. VCR alone causes supernumerary NuMA organized acentrosomal microtubule organizing centers upon nuclear envelope breakdown, which can be resolved via a clustering mechanism to achieve bipolar cell division. The addition of anti-Tpm3.1 compounds inhibits NuMA-associated clustering in VCR-treated cells, leading to irreparable defects during spindle assembly and thus a largely increased number of cells with multi-polar spindles undergoing mitotic delay and catastrophe. We conclude that actin/Tpm3.1 filaments contribute to the formation of the bipolar spindle and play a critical role in the clustering of acentrosomal microtubule asters. Citation Format: Peter Gunning, Yao Wang, Jeff H. Stear, Ashleigh Swain, Xing Xu, Nicole Bryce, Irina B. Alieva, Vera B. Dugina, Timothy Cripe, Justine Stehn, Edna C. Hardeman. Anti-tropomyosin drugs prevent the rescue of vincristine-induced mitotic spindle defects [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5817.
Abstract 3904: The novel combination of PAC-1 and ONC201 circumvent H3K27M-driven pro-survival gene expression to induce DIPG cell death
Authors: Ashlyn Parkhurst, Youngran Park, Antje Arnold, Michael Koldobskiy, Charles Eberhart, Eric Raabe, Jeffery Rubens
Journal: Cancer Research (2020)

Abstract Diffuse Intrinsic Pontine Gliomas (DIPGs) are universally fatal tumors, resistant to the cytotoxic effects of all known therapies. We aim to better understand the mechanisms contributing to this resistance to design new combination therapies that will improve DIPG survival. DIPG's aggressive phenotype is driven by the H3K27M oncohistone mutation that leads to global genomic DNA hypomethylation and abnormal gene expression. To identify patterns of gene expression driven by the H3K27M mutation, we introduced the H3K27M mutation into murine neural stem cells and performed whole genome bisulfite sequencing (WGBS) to evaluate for genes with the greatest differential methylation in their promoter region. These studies identified an abundance of pro-survival genes such a BCL-2, BCL-xL, MCL-1, Caspase-3, and XIAP. Western blot confirmed elevated expression of these pro-survival factors and RNA-Seq of primary human DIPG confirmed increased expression compared to normal brain. PAC-1 is a compound that cleaves protective zinc bonds to activate procaspase-3, directly inducing cell death. ONC201 is a small molecule that inhibits the anti-apoptotic protein XIAP, which prevents activated caspase-3 from translocating to the nucleus to induce apoptosis. We hypothesized that PAC-1 combined with ONC201 will circumvent these protective abnormalities in the DIPG apoptotic signaling cascade to induce tumor cell death. PAC-1 induces high rates of apoptosis in DIPG (25µM concentrations increases the percent of cells undergoing apoptosis; cleaved caspase 3 immunofluorescence assay 5% to 30% (t-test p&amp;lt;0.05), ANNEXIN V Cell sorting assay 11% to 40% (t-test p&amp;lt;0.05), and western blot for cPARP.) PAC-1 synergizes with ONC201 to further induce apoptosis in DIPG. Combination therapy decreases the percent of viable cells by &amp;gt;40% compared to DMSO control (ANOVA p&amp;lt;0.05 compared to each medication alone and DMSO control). Combination therapy also increases the induction of cPARP compared to each medication alone (western blot). These studies identified H3K27M-mediated expression of pro-survival genes in DIPG. The novel combination of PAC-1 and ONC201 therapy synergize to circumvent this abnormal apoptotic signaling cascade to induce cell death. Our data support future clinical trials combining PAC-1 with ONC201 to extend survival in DIPG. Citation Format: Ashlyn Parkhurst, Youngran Park, Antje Arnold, Michael Koldobskiy, Charles Eberhart, Eric Raabe, Jeffery Rubens. The novel combination of PAC-1 and ONC201 circumvent H3K27M-driven pro-survival gene expression to induce DIPG cell death [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3904.
Abstract 5415: Profiling cancer testis antigens in osteosarcomas
Authors: Zhongting Zhang, Yifei Wang, Wendong Zhang, Zhaohui Xu, Xin Zhou, Michael Roth, Jonathan Gill, Douglas Harrison, Pooja Hingorani, Sylvester Jusu, Sankar Kannan, Xiangjun Tian, Jing Wang, Rossana N Segura Lazcano, Alexander Lazar, Richard Gorlick
Journal: Cancer Research (2020)

Abstract Cancer testis antigens (CTA) are reported to have restricted expression in placenta and testis, but they are also known to be expressed in some malignant tumors. Immunotherapy targeting CTAs in melanomas and certain types of soft tissue sarcomas have shown potential therapeutic value. However, the expression pattern of CTAs in osteosarcoma (OS) has not been fully elucidated. To characterize the CTA landscape of OS, we compared RNA sequencing data from 40 high-risk OS patients treated at MD Anderson Cancer Center and 111 OS patients available through a public online database. All of these tumor data are subsequently compared with testis/placenta and other normal tissue RNA-sequencing data from the NIH Genotype-Tissue Expression (GTEx) database as well as an online dataset which includes normal bone tissue. 53 genes that are significantly highly expressed in OS and testis/placenta (log fold change tumor versus normal &amp;gt;1.0 for each tissue, p &amp;lt; 0.01) are selected. Of those, 11 genes have been annotated in the Cancer Testis Database (CTdatabase) such as MAGEA3/A6 and LY6K. We also identified 42 genes that are not annotated in the CTdatabase. The co-expression pattern of CTAs in OS was also investigated by unsupervised hierarchical cluster analysis. The expression of selected CTAs was validated by IHC staining with an OS tissue microarray from 100 patients, and western blot using PDX models and patient-derived cell lines. Interestingly, the results demonstrated that multiple CTAs such as MAGEA3, LY6K and PAGE5 are also highly expressed in normal bone tissue. The current results suggest further development of immunotherapy approaches targeting CTAs in OS. Citation Format: Zhongting Zhang, Yifei Wang, Wendong Zhang, Zhaohui Xu, Xin Zhou, Michael Roth, Jonathan Gill, Douglas Harrison, Pooja Hingorani, Sylvester Jusu, Sankar Kannan, Xiangjun Tian, Jing Wang, Rossana N Segura Lazcano, Alexander Lazar, Richard Gorlick. Profiling cancer testis antigens in osteosarcomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5415.
Abstract 4178: ETH-155008, a dual inhibitor of CDK and Pim in preclinical treatment of human B-cell lymphoma xenografts
Authors: Changnian Liu, Zuopeng Sun, Chunping Xu, Pan Zhang, Bin Ji, James Zhang, Laura Liu, Chengzhi Yu
Journal: Cancer Research (2020)

Abstract Non-Hodgkin lymphomas (NHLs) are the most common hematologic malignancies. The treatment of lymphoma presents a challenge in clinical oncology. Despite significant therapeutic efficacy achieved with combination of chemotherapy and new targeted agents, a large number of patients eventually relapse. Cyclin-dependent kinases (CDKs) are therapeutic targets frequently deregulated in various cancers including solid tumors and hematopoietic malignances. It was also reported that Moloney murine leukemia virus (PIM) kinases are overexpressed in several hematopoietic and solid tumors, especially in B-cell lymphomas. We evaluated the inhibition of kinases' activities and cell proliferation in vitro, and antitumor activities in vivo of ETH-155008, a dual inhibitor of CDK4/6 and PIM in preclinical treatment of human B-cell lymphoma xenografts. ETH-155008 was found to have strong inhibitory activities against key target enzymes with IC50s for CDK4/D1 at 0.8nM, CDK6/D1 at 1.4nM, PIM-1 at 13.3 nM, and PIM-3 at 0.9 nM. ETH-155008 showed to have highly potent antiproliferative activities against cultured human B-cell lymphoma cells of WSU-DLCL2 (diffuse large B-cell lymphoma) and JeKo-1 (mantle cell lymphoma) with IC50s at 1.7nM and 20 nM, respectively. The in vivo antitumor activities of ETH-155008 were evaluated and compared with abemaciclib (CDK4/6 inhibitor) and Imbruvica (Bruton tyrosine kinase inhibitor) in the treatment of the two lymphoma models, respectively. Treatment with ETH-155008 (40 mg/kg/daily x 14-21 days) almost completely eradicated the tumor xenografts and some of the tumor-bearing mice were cured; while as control drugs abemaciclib produced a tumor growth inhibition (TGI) of 56-60% and ibrutinib with a TGI of 60-67% in the two xenograft models. ETH-155008 treatment showed very little toxicity (only 2-4% body weight loss) which were well below the maximum tolerated dose. ETH-155008 represents a novel dual inhibitor that may yet fulfill the promise of effective B-cell lymphoma therapy through dual targeting of CDK4/6 and PIM3. These preclinical results supported the safety and efficacy observed in the preclinical studies and worthy of further clinical evaluation. Citation Format: Changnian Liu, Zuopeng Sun, Chunping Xu, Pan Zhang, Bin Ji, James Zhang, Laura Liu, Chengzhi Yu. ETH-155008, a dual inhibitor of CDK and Pim in preclinical treatment of human B-cell lymphoma xenografts [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4178.
Impact of SARS-CoV-2 Pandemic on Colorectal Cancer Screening Delay: Effect on Stage Shift and Increased Mortality
Authors: Luigi Ricciardiello, Clarissa Ferrari, Michela Cameletti, Federica Gaianill, Francesco Buttitta, Franco Bazzoli, Gian Luigi de’Angelis, Alberto Malesci, Luigi Laghi
Journal: Clinical Gastroenterology and Hepatology (2020)

The SARS-CoV-2 pandemic had a sudden, dramatic impact on healthcare. In Italy, since the beginning of the pandemic, colorectal cancer (CRC) screening programs have been forcefully suspended. We aimed to evaluate whether screening procedure delays can affect the outcomes of CRC screening.
Abstract 6268: Use of the anti-viral drug ribavirin as a radiosensitizing agent in nasopharyngeal carcinoma
Authors: Sakibul Huq, Joshua Casaos, Riccardo Serra, Michael Peters, Yuanxuan Xia, Andy Ding, Jeffrey Ehresman, Jayanidhi Kedda, Manuel Morales, Noah Gorelick, Tianna Zhao, Wataru Ishida, Alexander Perdomo-Pantoja, Arba Cecia, Chenchen Ji, Ian Suk, David Sidransky, Mariana Brait, Henry Brem, Nicolas Skuli, Betty Tyler
Journal: Cancer Research (2020)

Abstract Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma with a propensity for metastasis, leading many patients to fail available treatments and/or present with advanced-stage disease. There is currently a scarcity of targeted therapies for NPC, despite working knowledge of several proteins with key roles in NPC cancer biology. These include EZH2, Snail, eIF4E, and IMPDH, which are all overexpressed in NPC and correlated with poor patient prognosis. These proteins are known to be targeted by ribavirin, a well-characterized anti-viral drug that has recently been repurposed as an anti-cancer agent in several solid and hematologic malignancies. In the present study, we investigated the potential of ribavirin as a targeted therapy and radiosensitizing agent in five human NPC cell lines. We show in vitro, using cellular growth assays, flow cytometry, BrdU cell proliferation assays, scratch wound assays, and invasion assays, that ribavirin decreases NPC cellular proliferation, migration, and invasion and promotes cell cycle arrest and cell death. Modulation of EZH2, Snail, eIF4E, IMPDH, and mTOR were observed in western blots and enzymatic activity assays in response to ribavirin treatment. In vivo, monotherapy with ribavirin reduced flank tumor growth in multiple NPC xenograft models. Given that radiation therapy is a mainstay of NPC treatment, we next investigated the effects of combining ribavirin with radiation. Using clonogenic assays and flow cytometry, we demonstrate that ribavirin enhanced the cytotoxic effects of radiation on NPC cells in vitro. Most importantly, using a flank tumor xenograft model, we show that pre-treatment with ribavirin potentiated the effects of radiation therapy in vivo. Our work suggests that NPC responds to ribavirin-mediated EZH2, Snail, eIF4E, IMPDH, and mTOR modulation and positions ribavirin for clinical evaluation as a targeted therapy and radiosensitizing agent in this cancer. Citation Format: Sakibul Huq, Joshua Casaos, Riccardo Serra, Michael Peters, Yuanxuan Xia, Andy Ding, Jeffrey Ehresman, Jayanidhi Kedda, Manuel Morales, Noah Gorelick, Tianna Zhao, Wataru Ishida, Alexander Perdomo-Pantoja, Arba Cecia, Chenchen Ji, Ian Suk, David Sidransky, Mariana Brait, Henry Brem, Nicolas Skuli, Betty Tyler. Use of the anti-viral drug ribavirin as a radiosensitizing agent in nasopharyngeal carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6268.
Abstract 1086: Downstream kinase signaling is dictated by specific KRAS mutations
Authors: Konstantin Budagyan, Jonathan Chernoff
Journal: Cancer Research (2020)

Abstract Oncogenic KRAS mutations are common in colorectal cancer (CRC), found in ~50% of tumors, and are associated with poor prognosis and resistance to therapy. There is substantial diversity of KRAS alleles observed in CRC. Importantly, emerging clinical and experimental analysis of relatively common KRAS mutations at amino acids G12, G13, A146, and Q61 suggest that each mutation differently influences the clinical properties of a disease and response to therapy. For example, KRAS G12 mutations confer resistance to EGFR-targeted therapy, while G13D mutations do not. Although there is clinical evidence to suggest biological differences between mutant KRAS alleles, it is not yet known what drives these differences and whether they can be exploited for allele-specific therapy. We hypothesized that different KRAS mutants elicit variable alterations in downstream signaling pathways. To investigate this hypothesis, we created a novel system by which we can model KRAS mutants in isogenic mouse colon epithelial cell lines. To generate the cell lines, we developed an assay using fluorescent co-selection for CRISPR-driven genome editing. This assay involves simultaneous introduction of single-guide RNAs (sgRNAs) to two different endogenous loci resulting in double-editing events. We first introduced Cas9 and blue fluorescent protein (BFP) into mouse colon epithelial cell line containing heterozygous KRAS G12D mutation. We then used sgRNAs targeting BFP and the mutant G12D KRAS allele along with homology-directed repair (HDR) templates for a GFP gene and a KRAS mutant allele of our choice. Cells that successfully undergo HDR are GFP-positive and contain the desired KRAS mutation. Therefore, selection for GFP-positive cells allows us to identify those with phenotypically silent KRAS edits. Ultimately, this method allows us to toggle between different mutant alleles while preserving the wild-type allele, all in an isogenic background. Using this method, we have generated cell lines with endogenous heterozygous KRAS mutations commonly seen in CRC (G12D, G12V, G12C, G12R, G13D). In order to elucidate cellular signaling pathway differences between the KRAS mutants, we screened the mutated cell lines using a small-molecule library of ~160 protein kinase inhibitors. We found that there are mutation-specific differences in drug sensitivity profiles. These observations suggest that KRAS mutants drive specific cellular signaling pathways, and that further exploration of these pathways may prove to be valuable for identification of novel therapeutic opportunities in CRC. Citation Format: Konstantin Budagyan, Jonathan Chernoff. Downstream kinase signaling is dictated by specific KRAS mutations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1086.