tbuckley/cabot-search huggingface dataset:
Abstract 1664: Inhibition of 4T1 mammary tumor growth in BALB/c mice by subcutaneous and intraperitoneal injection of a 4T1 whole cell vaccine containing IL-2 and GM-CSF as adjuvants
Authors: Jonathan F. Head, Jeffrey T. Phillips, Xianpeng Jiang, Robert L. Elliott
Journal: Cancer Research (2017)

Abstract Developing animal tumor models for human cancer vaccines creates a tool to investigate the mechanism of action, variations in formulation, dosing schedules, and combinations with other forms of cancer therapy. In this study we developed a mouse whole cell mammary cancer vaccine model with both subcutaneous and intraperitoneal injection of the vaccine. The vaccine, containing 4T1 mouse mammary cancer cells (1,000,000 cells), IL-2 (0.2 µg) and GM-CSF (0.1 µg) in a total volume of 150 µl, was injected either subcutaneously into the backs of BALB/c mice or intraperitoneally. There were six injections of the vaccine (weeks 1, 2, 3, 7, 11, 15) and one week after the last injection 100,000 4T1 cells from cell culture in a volume of 100 µl were injected into the scapular region of the mice. At 22 days post 4T1 tumor transplantation there was a 37% inhibition of the growth of the 4T1 tumor in the mice receiving the subcutaneous injection of the vaccine and a 42% inhibition of the growth of the 4T1 tumor in the mice receiving the intraperitoneal injection of the vaccine. The inhibition of 4T1 mammary tumor growth in this mouse model with subcutaneous injection of a whole cell vaccine gives further support for the previously reported efficacy in a Phase 1/2 clinical trial of our therapeutic breast cancer vaccine containing autologous and allogeneic breast cancer cells in the adjuvant setting. The inhibition of 4T1 tumor growth with intraperitoneal injection suggests a delivery method that may be applicable to ovarian cancer and cancer patients with malignant ascites. Citation Format: Jonathan F. Head, Jeffrey T. Phillips, Xianpeng Jiang, Robert L. Elliott. Inhibition of 4T1 mammary tumor growth in BALB/c mice by subcutaneous and intraperitoneal injection of a 4T1 whole cell vaccine containing IL-2 and GM-CSF as adjuvants [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 1664. doi:10.1158/1538-7445.AM2017-1664
Abstract 3028: Reactive oxygen species induced nuclear translocation of c-MET via INTERNET mechanism
Authors: Mei-Kuang Chen, Yi Du, Yu-Yi Chu, Mien-Chie Hung
Journal: Cancer Research (2017)

Abstract c-MET is one of the receptor tyrosine kinases (RTKs) that are overexpressed in malignant cancer types including breast cancer. c-MET is traditionally known for its role in signaling transduction from the cell surface, our recent publication provided evidence that c-MET can be translocated into the nucleus and phosphorylate PARP1 in response to reactive oxygen species (ROS) stimulation (Du et al. Nat Med 2016). Oxidative stress is a common phenomenon in cancer cells due to alteration of metabolism, and constitutive oxidative stress related to ROS has been observed in breast cancer cells. In this study, we demonstrated that hepatocyte growth factor (HGF) as well as hydrogen peroxide (H2O2) can induce retrograde translocation of c-MET holoreceptor via a membrane-bound vesicle transport mechanism and translocate into the nucleus through INTERNET (integral trafficking from the ER to the nuclear envelope transport pathway) (Wang et al. J Biol Chem 2012) in breast cancer cells. While c-MET nuclear transportation increases dramatically under H2O2 treatment, our findings provide a putative mechanism by which breast cancer cells adapt to oxidative stress and suggest that INTERNET might be a general nuclear translocation mechanism shared among RTKs. Citation Format: Mei-Kuang Chen, Yi Du, Yu-Yi Chu, Mien-Chie Hung. Reactive oxygen species induced nuclear translocation of c-MET via INTERNET mechanism [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 3028. doi:10.1158/1538-7445.AM2017-3028
Abstract 5211: <i>Hormophysa triquerta</i> polyphenol, an elixir that deters CXCR4- and COX2-dependent dissemination destiny of treatment-resistant pancreatic cancer cells
Authors: Sheeja Aravindan, Sathish Kumar Ramraj, Dinesh Babu Somasundaram, Kathiresan Kandasamy, Somasundaram S. Thirugnanasambandan, Terence Herman, Natarajan Aravindan
Journal: Cancer Research (2017)

Abstract Therapy resistant pancreatic cancer (PC) cells play a crucial role in tumor relapse, recurrence, and metastasis. Recently, we showed the anti-PC potential of an array of seaweed polyphenols and identified efficient drug deliverables. Herein, we investigated the benefit of one such deliverable, Hormophysa triquerta polyphenol (HT-EA), in regulating the dissemination physiognomy of therapy resistant PC cells in vitro, and residual PC in vivo. Human PC cells exposed to clinical radiation (FIR), with/without HT-EA pretreatment were examined for the alterations in the tumor invasion/metastasis (TIM) transcriptome (93 genes, QPCR-profiling). Utilizing a mouse model of residual PC, we investigated the benefit of HT-EA in the translation regulation of crucial TIM targets (TMA-IHC). Radiation activated 30, 50, 15, and 38 TIM molecules in surviving Panc-1, Panc-3.27, BxPC3, and MiaPaCa-2 cells. Of these, 15, 44, 12, and 26 molecules were suppressed with HT-EA pretreatment. CXCR4 and COX2 exhibited cell line-independent increases after FIR, and was completely suppressed with HT-EA, across all PC cells. HT-EA treatment resulted in translational repression of FIR-induced CXCR4, COX2, β-catenin, MMP9, Ki-67, BAPX, PhPT-1, MEGF10, and GRB10 in residual PC. Muting CXCR4 or COX2 regulated the migration/invasion potential of IR-surviving cells, while forced expression of CXCR4 or COX2 significantly increased migration/invasion capabilities of PC cells. Further, treatment with HT-EA significantly inhibited IR-induced and, CXCR4/COX2 forced expression-induced PC cell migration/invasion. This study (i) documents the TIM blueprint in radiotherapy-resistant PC cells, (ii) defines the role of CXCR4 and COX2 in induced metastatic potential, and (iii) recognizes the potential of HT-EA in deterring the CXCR4/COX2-dependent dissemination destiny of therapy resistant residual PC cells. Citation Format: Sheeja Aravindan, Sathish Kumar Ramraj, Dinesh Babu Somasundaram, Kathiresan Kandasamy, Somasundaram S. Thirugnanasambandan, Terence Herman, Natarajan Aravindan. Hormophysa triquerta polyphenol, an elixir that deters CXCR4- and COX2-dependent dissemination destiny of treatment-resistant pancreatic cancer 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 5211. doi:10.1158/1538-7445.AM2017-5211
Abstract 5332: ISG15 knockdown inhibits growth of pancreatic cancer
Authors: Julian Burks, Jill Smith
Journal: Cancer Research (2017)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease driven by mutated KRAS with an average survival of only 3-6 months from the time of diagnosis. Interferon-Stimulated Gene 15 (ISG15) is a 15 kDa protein induced by Type I interferons (IFN-α and IFN-β) and is a member of the ubiquitin-like superfamily of proteins. The ISG15 pathway is highly elevated in various malignancies where it has been shown to stabilize KRAS protein expression. However, very little is known about the role of the ISG15 pathway in PDAC. The purpose of this project is to investigate the expression and proliferative effects of the ISG15 pathway in PDAC. Methods: The ISG15 knockdown cells were created using the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) gene editing system. ISG15 was stably knocked-down in murine Panc02 pancreatic cancer cells by transfection with an ISG15 CRISPR construct from Genscript (pSpCas9 BB-2A-Puro (PX459)) and treated with media containing puromycin (2 μg/ml) for selection. Knockdown was confirmed by RT-PCR. The effect of ISG15 knockdown on PDAC cell growth in vitro was determined by comparing viable cell counts on wild-type and ISG15 knockdown Panc02 cells 48 hours after plating. The effect of ISG15 knockdown on pancreatic tumorigenesis was determined by subcutaneous inoculation of syngeneic immune competent C57BL/6 mice with 1x106 Panc02 wild-type or ISG15 knockdown cells. Tumor volumes were measured weekly and after 3 weeks the mice were euthanized, tumors dissected and weighed. Results: ISG15 CRISPR treated cells had a 50% reduction in ISG15 mRNA expression as compared to wild-type cells. ISG15 knockdown in Panc02 PDAC cells significantly reduced cell growth as compared to wild-type cells (p=0.030). Tumors formed from ISG15 knockdown Panc02 cells significantly had a 74% reduction in tumor volume (p=0.031) and 78% reduction in tumor weight (p=0.029) as compared to wild-type cells. Conclusion: The ISG15 pathway contributes to PDAC by increasing cell growth and the tumorigenic potential of pancreatic cancer cells. Ultimately, strategies to target the ISG15 pathway may lead to improved survival for patients diagnosed with PDAC. Supported by: NIH T32CA00968 grant Citation Format: Julian Burks, Jill Smith. ISG15 knockdown inhibits growth of pancreatic 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 5332. doi:10.1158/1538-7445.AM2017-5332
Abstract 2723: MET exon 14 skipping mutations in advanced non-small cell lung cancer (NSCLC) are not associated with MET amplification and overexpression
Authors: Ana Gimenez-Capitan, Cristina Teixidó, Cristina Aguado, Sonia Rodríguez, Jordi Bertran-Alamillo, Josep Castellví, Zaira Yeste, Ana Pérez, Rafael Rosell, Miguel Angel Molina-Vila
Journal: Cancer Research (2017)

Abstract Background: Activating alterations of the mesenchymal epithelial transition (MET) oncogene in NSCLC are potentially actionable with targeted MET inhibitors. MET exon 14 skipping mutations have been described in 3% of patients (p) in NSCLC,.Fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) are currently used for detecting MET amplification and overexpression, respectively, but are not useful to detect MET splicing variants. On the other hand, the reverse transcription-polymerase chain reaction (RT-PCR) technique has the potential to detect this actionable alteration. Methods: We designed and validated a custom set of 5´and 3´ primers to detect the MET exon 14 splicing variant by RT-PCR. RNA isolation from FFPE samples was performed with Roche High Pure FFPET RNA isolation kit and M-MLV Reverse Transcriptase enzyme was used in the RT-PCR. A panel of cell lines was initially employed to assess the performance of the technique. Subsequently, a total of 232 formalin-fixed paraffin-embedded (FFPE) samples from advanced NSCLC patients were analyzed. Of them, 15 were positive by RT-PCR (n=209) for the MET exon 14 variant. The bands corresponding to the splicing variant were submitted to Sanger sequencing. Results were compared with FISH (ZytoVision Dual Color probe Z-2087-200) and IHC (Ventana CONFIRM anti-Total c-MET (SP44)). Results: A total of 232 EGFR-wt advanced NSCLC p were analyzed by IHC and 42 (18.1%) were considered as positive (cut-off 3+≥ 50%). Regarding FISH, MET amplification was detected in 13 out of 58 p (22.4%) evaluable while the MET exon 14 skipping variant was detected in 15 (7.2%) out of 209 p . Unexpectedly, only three (21.4%) of the positive MET exon 14 skipping p by RT-PCR were positive for IHC. Finally, of the 15 MET exon 14 positive p, 5 were evaluable for FISH and none of them were positive for MET amplification. Conclusion: In our cohort of 232 EGFR-wt, advanced NSCLC p, the MET exon 14 skipping mutation had an incidence of 7.2% No correlation was found between the presence of the MET exon 14 variant by RT-PCR and MET overexpression or amplification. Detection of MET exon 14 alterations poses a challenge for diagnostic testing. Citation Format: Ana Gimenez-Capitan, Cristina Teixidó, Cristina Aguado, Sonia Rodríguez, Jordi Bertran-Alamillo, Josep Castellví, Zaira Yeste, Ana Pérez, Rafael Rosell, Miguel Angel Molina-Vila. MET exon 14 skipping mutations in advanced non-small cell lung cancer (NSCLC) are not associated with MET amplification and overexpression [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 2723. doi:10.1158/1538-7445.AM2017-2723
Abstract 2740: High-throughput and sensitive quantification of circulating tumor DNA
Authors: Yinghui Guan, Oleg Mayba, Shan Lu, Thomas Sandmann, Younjeong Choi, Walter Darbonne, Vincent Leveque, Lisa Ryner, Eric Humke, Nga W. Tam, Sundari Sujathasarma, Anna Cheung, Richard Bourgon, Yulei Wang
Journal: Cancer Research (2017)

Abstract Circulating tumor DNA (ctDNA) has a great potential to serve as non-invasive biomarkers for monitoring disease progression and treatment response. However, its broad clinical applications have been hindered by sensitivity, throughput and complexity of existing ctDNA detection methods. Here we report an adaptation of a multiplex PCR pre-amplification (PreAmp) into the microfluidic multiplex PCR (MMP-Seq) technology for high-throughput and sensitive quantitation of ctDNA. We have demonstrated that PreAmp MMP-Seq enabled sensitive (down to 0.6% allele frequency), reproducible (R2=0.97), accurate and quantitative mutation detection from as low as 1.6 ng DNA input. An Empirical Bayesian Model has been established to estimate background error rates for every base of amplicons in the ctDNA panel using data from 43 normal plasmas. 0.1-0.3% of median error rates were observed across all positions. 149 longitudinal plasma samples from 12 ovarian and 10 pancreatic cancer patients of PhI DMUC5754A anti-MUC16 ADC trials were then profiled using PreAmp MMP-Seq. 79% (11/14) driver mutations found in tissue samples were also identified in matching baseline plasma samples at frequencies well above estimated error rates. Moreover, we found that changes of corresponding ctDNA concentration in post-treatment plasma samples were correlated with changes in tumor burdens and circulating protein marker levels. In conclusion, the MMP-seq PreAmp workflow provides an inexpensive, reproducible and flexible solution for mutation detection in plasma DNA samples. Citation Format: Yinghui Guan, Oleg Mayba, Shan Lu, Thomas Sandmann, Younjeong Choi, Walter Darbonne, Vincent Leveque, Lisa Ryner, Eric Humke, Nga W. Tam, Sundari Sujathasarma, Anna Cheung, Richard Bourgon, Yulei Wang. High-throughput and sensitive quantification of circulating tumor DNA [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 2740. doi:10.1158/1538-7445.AM2017-2740
The new allergic rhinitis therapy (MP29-02) effectively treats patients with seasonal allergic rhinitis regardless of their predominant symptom
Authors: Claus Bachert, Phil Lieberman, Glenis Scadding, Paul Ratner, Ullrich Munzel, Jean Bousquet
Journal: Allergy (2013)

MP29-02 (a novel intranasal formulation of azelastine hydrochloride [AZE] and fluticasone propionate [FP]) is more effective than commercially-available AZE or FP in controlling both nasal and ocular allergic rhinitis (AR) symptoms in patients with moderate-to-severe AR.1 Although significance over placebo (PLA) and active parameters is an essential proof of efficacy, clinical relevance is harder to judge, and is influenced by many patient-related factors such as predominant symptom. In clinical practice, patients frequently present with a predominant symptom. To mimic patient clinical presenting patterns, patients included in an MP29-02 clinical trial1 were categorized into four ‘types’ according to their predominant symptoms at baseline (i.e. congestion, itching, rhinorrhoea or sneezing predominants). Nasal congestion is frequently cited as the most bothersome nasal symptom,2 and is often difficult to control. It is associated with sleep-disordered breathing, which negatively impacts on patient quality of life, impairs productivity and increases daytime sleepiness causing tiredness and irritability and even anxiety and depression.3,4
Abstract 3946: Chromosome instability drives phenotypic switching to metastasis
Authors: Chong-Feng Gao, Yanli Su, Julie Koeman, Curt Essenberg, Karl Dykema, Eric Hudson, Sok Kean Khoo, George Vande Woude
Journal: Cancer Research (2017)

Abstract Chromosome instability (CIN) is the most striking feature of human cancers. However, how CIN drives tumor progression to metastasis remains elusive. Here we studied the role of chromosome content changes in generating the phenotypic dynamics that is required for metastasis. We isolated epithelial (E) and mesenchymal (M) clones from human carcinoma cell lines and showed that the E clones were able to generate mesenchymal variants, which had the potential to further produce epithelial revertants autonomously. The successive acquisition of invasive mesenchymal and then epithelial phenotypes recapitulated the steps in tumor progression to metastasis. Importantly, the generation of mesenchymal variants from clonal epithelial populations was associated with subtle changes in chromosome content, which altered the chromosome transcriptome and influenced the expression of genes encoding intercellular junction (IJ) proteins, while the loss of chromosome 10p, which harbors the ZEB1 gene, was frequently detected in epithelial variants generated from M clones. Knocking down these IJ genes in E cells induced a mesenchymal phenotype, while knocking down the ZEB1 gene in M cells induced an epithelial phenotype, demonstrating a causal role of chromosome content changes in phenotypic determination. Thus, our studies suggest a novel paradigm of tumor metastasis: primary epithelial carcinoma cells that lose chromosomes harboring IJ genes acquire an invasive mesenchymal phenotype, and subsequent chromosome content changes such as loss of 10p in disseminated mesenchymal cells generate epithelial variants, which can be selected for to generate epithelial tumors during metastatic colonization. Citation Format: Chong-Feng Gao, Yanli Su, Julie Koeman, Curt Essenberg, Karl Dykema, Eric Hudson, Sok Kean Khoo, George Vande Woude. Chromosome instability drives phenotypic switching to metastasis [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 3946. doi:10.1158/1538-7445.AM2017-3946
Abstract 4533: <i>In silico</i> analysis of enhanced radiosensitivity in radiation treatment combined with androgen deprivation therapy for prostate cancer
Authors: Mengdi Qian, Alexandru Almasan, Evren Gürkan-Çavusoglu
Journal: Cancer Research (2017)

Abstract The purpose of this study is to quantitatively analyze the improved radiosensitivity of prostate cancer cells to ionizing radiation (IR) when radiation treatment is combined with androgen deprivation therapy (ADT). The double strand breaks (DSBs) induced by ionizing radiation are repaired primarily by non-homologous end joining (NHEJ). It is reported in the literature that NHEJ is impaired after ADT, which then results in increased radiosensitivity and better IR treatment outcomes in prostate cancer. In this study, we have used our models for NHEJ repair of DSBs under IR treatment and IR + ADT combination treatment conditions to determine how the combination treatment results in better outcomes. We have modeled the effect of multiple doses of IR that are delivered 24 hours apart to mimic the conventional, fractionated radiation treatment. The analysis results showed that the DSBs accumulate more in the case of combined treatment with ADT compared to faster and more efficient repair when only IR is applied. We have used the experimental data on relative cell numbers and relative sub-G1 cell numbers from the literature to determine the difference in the levels of DSBs that lead to cell death differences between the two treatment strategies. The literature data also shows that there is patient response variability to ADT in terms of the reduction in the levels of Ku70/80, which is the first NHEJ protein complex that is recruited to DSBs. We have modeled this patient variability in our models by introducing variability to Ku70/80 protein concentrations used in the simulations. Our simulation results agree with the observation from clinical data that lower concentration levels of Ku70/80 lead to better radiosensitization. The amount of IR can be adjusted with respect to the level of radiosensitization after ADT on a patient specific level to achieve a desired level of DSBs that will lead to maximum cell death; this dose optimization effort will be the next step in our quantitative analysis. Citation Format: Mengdi Qian, Alexandru Almasan, Evren Gürkan-Çavusoglu. In silico analysis of enhanced radiosensitivity in radiation treatment combined with androgen deprivation therapy 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 4533. doi:10.1158/1538-7445.AM2017-4533