tbuckley/cabot-search huggingface dataset:
Abstract 2581: VGLL4 suppresses the human breast cancer progression through the inhibition of YAP oncogenic function
Authors: Jianmin Zhang
Journal: Cancer Research (2017)

Abstract VGLL4 is a Vestigial-like (VGLL) protein that is deregulated in various types of cancer. However, the functions of VGLL4 in breast cancer remain largely unknown. Here, we demonstrate that VGLL4 expression positively correlates with survival for breast cancer patients. The overexpression of VGLL4 in breast cancer cells reduced cell proliferation, colony formation, cell migration and invasion in vitro and inhibited tumor growth in vivo. We found that the 2nd TEAD-interacting domain (TDU2) of VGLL4 is involved in interactions between VGLL4 and the transcription factor TEAD and that the deletion of this domain completely abolished the phenotype induced by VGLL4 overexpression. Interestingly, RNAseq analysis indicated that VGLL4 overexpression not only inhibits YAP targets but also activates the TGF-β and Notch signaling pathways. Our study provides evidence of the tumor-suppressive effects of VGLL4 on breast cancer progression and suggests that VGLL4 and its TDU2 domain may become promising and efficient therapeutic targets for delaying the development of breast cancer and improving patient survival. Citation Format: Jianmin Zhang. VGLL4 suppresses the human breast cancer progression through the inhibition of YAP oncogenic function [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 2581. doi:10.1158/1538-7445.AM2017-2581
Abstract 5715: Gene body methylation and expression of <i>SHOX2</i> gene are potent prognostic markers for survival in intermediate grade gliomas and renal cancers
Authors: Yu-An Zhang, Yunyun Zhou, Xin Luo, Guanghua Xiao, Adi F. Gazdar
Journal: Cancer Research (2017)

Abstract Background: Previous data indicated that low level of promoter methylation of the SHOX2 gene was a prognostic marker for worse progression-free survival for non-small cell lung cancer. Purpose: (a) to determine the relationship between SHOX2 gene methylation and expression; b) to determine whether SHOX2 gene methylation and expression were prognostic markers for other cancers. Methods: We examined multiple methylation and expression datasets available from The Cancer Genome Atlas (TCGA) and other previously published studies. Data from a total of more than 1000 intermediate grade gliomas and 1100 renal cancer cases were examined, along with smaller number of corresponding non-malignant tissues. We performed Kaplan-Meier survival analyses and univariate and multivariate Cox regression model analyses. Results: SHOX2 gene contains three CpG islands encompassing the promoter region and body. Methylation of various regions of SHOX2 gene body was significantly positively correlated with its expression in gliomas and renal cancer. Aberrantly high methylation and expression of SHOX2 gene, which were significantly higher than the corresponding nonmalignant tissues, were identified in subsets of gliomas and renal cancers. Survival analysis of patients indicated that the methylation and expression of SHOX2 gene in gliomas and renal cancer (both clear cell and papillary cell carcinomas) were highly potent markers for poor survival. We further investigated the combination of SHOX2 with other known clinically relevant glioma markers (IDH genotype status, TERT expression, 1p/19q chromosome co-deletion, MGMT methylation, ATRX mutation and NES expression). When combined with SHOX2 expression, we identified subsets of glioma patients with significantly favorable survival outcomes, especially in the subgroup (i.e., IDH wild-type) associated with worse prognosis for each individual marker. Multivariate analysis demonstrated that SHOX2 was a potent independent survival marker for gliomas. Conclusion: Gene body methylation and expression of SHOX2 gene are tightly positively correlated and are potent new markers for overall survival prognosis for intermediate grade gliomas and renal cancer. The combination of IDH or other relevant prognostic markers with SHOX2 identified intermediate grade glioma subsets with improved survival outcomes. Citation Format: Yu-An Zhang, Yunyun Zhou, Xin Luo, Guanghua Xiao, Adi F. Gazdar. Gene body methylation and expression of SHOX2 gene are potent prognostic markers for survival in intermediate grade gliomas and renal cancers [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 5715. doi:10.1158/1538-7445.AM2017-5715
Abstract 4179: Potent and selective TRK inhibitor CH7057288
Authors: Hiroshi Tanaka, Hitoshi Sase, Toshiyuki Tsukaguchi, Hiromi Tanimura, Masami Hasegawa, Kiyoshi Hasegawa, Yoshiyuki Ono, Nobuhiro Oikawa, Hiroshi Sakamoto, Toshiyuki Mio
Journal: Cancer Research (2017)

Abstract TRK receptor tyrosine kinases are expressed as fusion proteins encoded by various fusion genes across a wide variety of cancer types, including lung and colorectal cancer. These fusion proteins have potent oncogenic activity and are thought to be an attractive therapeutic target. In a kinase inhibitor screening we identified CH7057288, a potent and selective TRK inhibitor belonging to a novel chemical class. Our inhibitor showed selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppressed proliferation of TRK fusion-positive cell lines, but not that of TRK-negative cell lines. In subcutaneously implanted xenograft models of TRK fusion-positive cells, strong tumor growth inhibition was observed. Furthermore, CH7057288 induced regression of intracranial tumors and greatly improved event-free survival in an intracranial implantation model mimicking brain metastasis. Recently, resistant mutations in TRK have been reported in patients showing disease progression after treatment with a TRK inhibitor under clinical development. Our compound maintained similar levels of in vitro and in vivo activity against some of the resistant mutants as it did to wild-type TRK. In summary, CH7057288 could be a promising therapeutic agent for TRK fusion-positive cancer. Citation Format: Hiroshi Tanaka, Hitoshi Sase, Toshiyuki Tsukaguchi, Hiromi Tanimura, Masami Hasegawa, Kiyoshi Hasegawa, Yoshiyuki Ono, Nobuhiro Oikawa, Hiroshi Sakamoto, Toshiyuki Mio. Potent and selective TRK inhibitor CH7057288 [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 4179. doi:10.1158/1538-7445.AM2017-4179
mTORC1 Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression
Authors: Nahid A. Khan, Joni Nikkanen, Shuichi Yatsuga, Christopher Jackson, Liya Wang, Swagat Pradhan, Riikka Kivelä, Alberto Pessia, Vidya Velagapudi, Anu Suomalainen
Journal: Cell Metabolism (2017)
Abstract 1391: The epigenetic regulator, G9a, is a KRAS-inducible protein and its inactivation inhibits PanIN formation by this oncogene
Authors: Angela Mathison, Ann Salmonson, Brooke Paradise, Mckenna Missfeldt, Juan Iovanna, Daniel Billadeau, Raul Urrutia, Gwen Lomberk
Journal: Cancer Research (2017)

Abstract Pancreatic ductular adenocarcinoma (PDAC) ranks fourth as a cause of cancer death in the USA and is almost universally fatal, with the annual number of deaths equivalent to the number of newly diagnosed cases. Valuable research in the field has revealed genetic aberrations that contribute to PDAC development and progression, with KRAS being one of the most frequent mutations in more than 90% of patient samples. However, to date, any efforts to directly target KRAS have failed in the clinic. Thus, there is indisputably an urgent need to further improve our understanding of molecular mechanisms underlying PDAC development as to identify novel therapeutic targets, including druggable important downstream targets and nodes orchestrated by oncogenic KRAS. In particular, we are interested in epigenetic pathways involved in PDAC development and progression due to the potential reversibility of any alteration, unlike genetic mutation. In the current study, using a cell model that allows inducible expression of mutant KRASG12D, we find that protein levels of the dimethyl-K9H3 histone methyl transferase (HMT), G9a, and its complex partners are increased in response to activation of the oncogenic Kras pathway. Furthermore, the activation of this oncogenic pathway results in the formation of the G9a-GLP-Wiz trimer complex, as determined by affinity protein purification, combined with mass spectrometry. In vivo experiments involving the cross of the Pdx1-CRE/LSL-KRASG12D mice with G9afl/fl animals demonstrate that a loss of the H3K9Me2 mark in the nucleus of exocrine cells is accompanied by a significantly reduced number of PanIN lesions. RNA-Seq experiments from these animals reveal that these mice have reduced levels of typical molecular markers of PanINs. In addition, these experiments show changes in the levels in several genes, which have been previously been shown to synergize with Kras to mediate pancreatic cancer initiation. Congruently, pharmacological inhibition of G9a using BRD4770 displays an inhibitory effect on KRASG12D-induced cell proliferation. Combined, these data provide evidence for a key role of the meK9H3-G9a pathway as a mediator of the oncogenic Kras response and defines a novel point of potential therapeutic intervention for PDAC. Citation Format: Angela Mathison, Ann Salmonson, Brooke Paradise, Mckenna Missfeldt, Juan Iovanna, Daniel Billadeau, Raul Urrutia, Gwen Lomberk. The epigenetic regulator, G9a, is a KRAS-inducible protein and its inactivation inhibits PanIN formation by this oncogene [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 1391. doi:10.1158/1538-7445.AM2017-1391
Abstract 2667: In vitro properties and pre-clinical activity of PF-06801591, a high-affinity engineered anti-human PD-1
Authors: Sawsan Youssef, Yasmina Abdiche, HoangKim Nguyen, Joyce Chou, Sherman Michael Chin, Cris Kamperschroer, Patricia A. Schneider, Eugenia Kraynov, Heike I. Krupka, Arvind Rajpal, John Lin
Journal: Cancer Research (2017)

Abstract Monoclonal-antibody-based therapies targeting the immune checkpoint receptors have become the new standard of care in many cancers. Antibodies that specifically target programmed death receptor-1 (PD-1) or its cognate ligand, programmed death receptor ligand-1 (PD-L1), alone or in combination, have yielded clinical benefits and durable responses in patient subsets with various cancers (including metastatic melanoma, NSCLC, RCC, urothelial cancer, cHL and others). Here we report on the biophysical characteristics and non-clinical antagonistic activities of PF-06801591. PF-06801591 is a humanized anti-PD-1 antibody of human IgG4 isotype, that binds selectively and with similar potency to human and cynomolgus monkey PD-1 receptor (EC50 ~50 pM) and blocks its interaction with its cognate ligands PD-L1 and PD-L2 (IC50 &amp;lt; 1 nM) with no detectable Fc effector function. The interaction of PF-06801591 to PD-1 rescues T cell suppression and exhaustion that translates into NFAT activation, IL-2 and IFN-gamma secretion and T cell proliferation both in vitro cultures and in vivo using an acute xeno GvHD model with human PBMC transfer. Binding of PF-068001591 to human and cynomolgus PD-1 is characterized by the formation of a very stable complex (T1/2 = 2 h) as measured by SPR at 37 C, resulting in high affinity (KD ~20 pM) as measured in solution by KinExA at 23 C. In addition, we explored therapeutic potential of anti-PD-1 in combination with other immunotherapy agents using surrogate antibodies in non-clinical tumor models. The data presented here support future development of PF-06801591 as a single agent or in combination with other immunotherapies. Citation Format: Sawsan Youssef, Yasmina Abdiche, HoangKim Nguyen, Joyce Chou, Sherman Michael Chin, Cris Kamperschroer, Patricia A. Schneider, Eugenia Kraynov, Heike I. Krupka, Arvind Rajpal, John Lin. In vitro properties and pre-clinical activity of PF-06801591, a high-affinity engineered anti-human PD-1 [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 2667. doi:10.1158/1538-7445.AM2017-2667
Abstract 4611: A 3D <i>in vitro</i> culture-based method to visualize and quantify effects of immuno-modulatory drugs
Authors: Lidia Daszkiewicz, Kuan Yan, Maarten Klop, Leo Price
Journal: Cancer Research (2017)

Abstract BACKGROUNDUnleashing the full potential of cancer immunotherapy is hampered by a lack of effective in vitro testing methods. 2D cultured cells poorly reflect the in vivo situation and lack the tumour microenvironment whereas humanized animal models are slow, have low throughput and are expensive. 3D cultures, on the other hand, more faithfully reproduce the organization of a tissue, recapitulating the cell-cell connections and cellular heterogeneity found in the tumour and allow for a cost-efficient testing of drug candidates. To address the unmet need of immunotherapy cancer drug developers for robust assays that incorporate the human immune system, with functional read-outs in a high throughput (384well plate) format, we developed an in vitro platform based on 3D co-cultures of cancer tumoroids and immune cells. This assay is designed to test the capacity of small molecules, bi-specific antibodies, checkpoint modulators, vaccines and combinations of thereof to enhance anti-cancer immune responses. METHODSCancer cells of different sources were grown in a hydrogel to form tumoroids and then HLA-matched PBMCs pre-conditioned via different protocols to achieve activated or exhausted T cells, were added in the presence or absence of immune-modulatory drugs. T cell infiltration and subsequent tumoroid killing was quantified using 3D high-content imaging. After ‘optical sectioning’ 3D image stacks were reconstituted and morphometric analysis was performed with OMiner software. RESULTS AND CONCLUSIONS Addition of immune checkpoint inhibitors, pembrolizumab and ipilimumab, led to enhanced T cell infiltration and cytotoxicity of exhausted T cells. These results showed that automated 3D image and data analysis enables discrimination of immune-tumour cell interactions depending on activation status of T cells and permits the visualization of T cell re-gain of function in the presence of checkpoint modulators. A 3D environment allows the different cell types to engage in a more realistic setting than when cells are grow in a monolayer and enables the quantification of spatially resolved information, which is of an utmost importance when studying tumor-immune cell relationships. This new and innovative platform empowers immunotherapy drug developers with a powerful tool to evaluate drug performance. Furthermore, drug combinations can be studied to determine synergistic effects with other checkpoint inhibitors of standard of care compounds in an efficient manner. Citation Format: Lidia Daszkiewicz, Kuan Yan, Maarten Klop, Leo Price. A 3D in vitro culture-based method to visualize and quantify effects of immuno-modulatory drugs [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 4611. doi:10.1158/1538-7445.AM2017-4611
Abstract 188: Preventive effect of aerosolized bexarotene in three major subtypes of lung cancer: adenocarcinoma, squamous cell carcinoma and small cell lung cancer in mice
Authors: Qi Zhang, Jing Pan, Marker S. Miller, Ronald A. Lubet, Yian Wang, Ming You
Journal: Cancer Research (2017)

Abstract Lung cancer is the leading cause of cancer-related deaths in the United States. The 5 year survival rate for lung cancer patients has remained a dismal 15% for 3 decades. Thus, the development of chemopreventive agents that could prevent lung cancer could potentially reduce the incidence and mortality of pulmonary neoplasms. Bexarotene has exhibited inhibitory effects in preclinical in vivo models of mammary and lung tumorigenesis, has been approved for clinical use in the treatment of cutaneous T-cell lymphoma, and has shown efficacy in phase I/II trials of non-small cell lung cancer (NSCLC). Preclinical studies have demonstrated that it is highly effective in the prevention of all three major subtypes of lung cancer in mouse models: adenocarcinoma (AD), squamous cell carcinoma (SCC), and small cell lung cancer (SCLC). The major side effects of bexarotene when administered orally to rodents or human patients have been hypertriglyceridemia and hypercholesterolemia. Previous studies in a mouse model of lung AD have demonstrated that aerosol delivery of bexarotene through nasal inhalation exhibited potent chemopreventive activity similar to that observed following oral administration (59 to74% reductions in lung tumor multiplicity). The significant decreases in tumor multiplicity and tumor load were achieved without hypertriglycerides that accompany oral bexarotene administration. In this study, aerosolized delivery of 10-30 mg/ml bexarotene showed a significant chemopreventive effect in all three major subtypes. In the N-nitroso-tris-chloroethylurea (NTCU) induced mouse SCC model, 1 week after the first dose of NTCU a dose dependent decrease in tumor formation was observed, with the highest dose causing 75% (p&amp;lt;0.001) and 42% (p&amp;lt;0.01) decreases in SCC tumor burden and the percentage of SCC tumors, respectively. Tumor load was decreased by 73% in A/Jp53 mouse AD model and by 41% in A/Jp53Rb mouse SCLC model. Aerosol delivery of bexarotene had no effect on animal body weight and other signs of toxicity, and no effect on triglyceride and cholesterol level. Aerosolized bexarotene formulation was effective against all 3 major lung cancer cell types and would be a major advance achieving significant reductions in preventing lung cancer incidence in persons at high risk of lung cancer e.g. former or present smokers. Citation Format: Qi Zhang, Jing Pan, Marker S. Miller, Ronald A. Lubet, Yian Wang, Ming You. Preventive effect of aerosolized bexarotene in three major subtypes of lung cancer: adenocarcinoma, squamous cell carcinoma and small cell lung cancer in mice [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 188. doi:10.1158/1538-7445.AM2017-188
Abstract LB-266: DAXX promotes de novo lipogenesis in triple-negative breast cancer
Authors: Iqbal Mahmud, Timothy J. Garrett, Daiqing Liao
Journal: Cancer Research (2017)

Abstract Triple-negative breast cancers (TNBCs), defined by the absence of ER and PR expression and the lack of HER2 amplification, have no targeted treatment options, are highly aggressive, and exhibit poor prognosis. Identification of drivers and associated signaling pathways, particularly for TNBCs, is needed to assist the development of targeted therapies, to prolong disease-free survival, and to improve clinical outcome for cancer patients. Using high-throughput microarray-based global transcriptome profiling, we found that transcriptional regulator DAXX depletion strikingly impaired while DAXX overexpression enhanced the expression of genes in the de novo lipogenesis pathways in TNBCs cell line. Consistently, unbiased global metabolomics and lipidomics profiling by Ultra-High performance Liquid Chromatography coupled High-Resolution Mass Spectrometry (UHPLC-HRMS) also revealed that DAXX promotes de novo lipogenesis in both TNBC cell line as well as in corresponding xenograft tumors. In analyzing large number of genomic datasets including The Cancer Genome Atlas (TCGA), MolEcular Taxonomy of BReast cancer International Consortium (METABRIC), and The Cancer Cell Line Encyclopedia (CCLE) dataset, we found that DAXX expression is significantly higher in TNBC tumor samples and cell lines, and also DAXX gene expression positively correlates with that of key lipogenesis enzymes. The role of DAXX in cancer metabolism is previously unknown. Our integrated OMICs data analysis thus indicates that DAXX promotes de novo lipogenesis in TNBC. The mechanism through which DAXX regulates lipid metabolism is being investigated in our laboratory. Overall, our study identifies a potentially important pathway driving TNBC progression and suggests potential therapeutic targets for treating this aggressive form of breast cancer that still lacks curative treatment options. Citation Format: Iqbal Mahmud, Timothy J. Garrett, Daiqing Liao. DAXX promotes de novo lipogenesis in triple-negative 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 LB-266. doi:10.1158/1538-7445.AM2017-LB-266
Abstract 4692: Local adjuvant treatment of clinical stage I-II melanoma with low dose CpG-B and/or GM-CSF: Long-term follow-up of three randomized controlled phase II trials
Authors: Bas D. Koster, Mari F. van den Hout, Berbel J. Sluijter, Barbara G. Molenkamp, Ronald J. Vuylsteke, Arnold Baars, Paul A. van Leeuwen, Rik J. Scheper, Monique P. van den Tol, Alfons J. van den Eertwegh, Tanja D. de Gruijl
Journal: Cancer Research (2017)

Abstract Introduction: Currently, there is no widely used adjuvant treatment available to improve survival after surgical excision of localized melanoma. Here, we present the clinical outcome of patients who participated in three randomized phase-II trials and received low-dose local immunotherapy, which was shown to be safe and to boost loco-regional and systemic anti-melanoma T cell immunity. Patients and Methods: In three single-center, single-blinded, randomized and placebo (saline) controlled phase-II clinical trials, patients with early stage melanoma were treated with 1) Granulocyte/Macrophage-Colony Stimulating Factor (GM-CSF), 2) unmethylated CpG type-B oligodeoxynucleotide CpG7909 (CpG-B), and 3) CpG-B, alone or combined with GM-CSF, through 1-4 intradermal injections at the site of the primary melanoma excision scar, within 7 days preceding re-excision and sentinel lymph node (SLN) biopsy. For clinical follow-up analysis, all treated patients were grouped together (treated group n=36) as were the patients who received saline (saline group n=28). Results: 10-year recurrence-free survival rate in the treated group was 94% (95% CI 78-98) versus 48% (95% CI 21-71) in the saline group (P=0.005), hazard ratio (HR) for recurrence was 0.15 (95% CI 0.06-0.60) for the treated group. This apparent antitumor efficacy was in line with the observation upon pathological examination of less tumor positive SLN in the treated group (P=0.05). The 10-year distant recurrence-free survival rate in treated patients was also higher (94%, 78-98 versus 59%, 28-81, HR 0.22, 0.07-0.93; P=0.04). Conclusion: Local low-dose immunotherapy in patients with early-stage melanoma may offer durable protection against distant recurrences. These findings warrant further clinical exploration of this local non-toxic immune potentiating regimen. Citation Format: Bas D. Koster, Mari F. van den Hout, Berbel J. Sluijter, Barbara G. Molenkamp, Ronald J. Vuylsteke, Arnold Baars, Paul A. van Leeuwen, Rik J. Scheper, Monique P. van den Tol, Alfons J. van den Eertwegh, Tanja D. de Gruijl. Local adjuvant treatment of clinical stage I-II melanoma with low dose CpG-B and/or GM-CSF: Long-term follow-up of three randomized controlled phase II trials [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 4692. doi:10.1158/1538-7445.AM2017-4692