tbuckley/cabot-search huggingface dataset:
Abstract 1237: PDGF induces cell growth and changes in glucose metabolism in colon cancer in the absence of PDGF receptors
Authors: Romana Moench, Tanja Grimmig, Christoph-Thomas Germer, Ana Maria Waaga-Gasser, Martin Gasser
Journal: Cancer Research (2017)

Abstract Background: The Platelet derived growth factor (PDGF) and its receptors play a major role in inducing proliferation, migration, and angiogenesis by activating intracellular PI3K/Akt/mTOR signaling events in different solid tumors and therefore represent attractive targets in tumor therapy. Recently we showed a PDGF-induced activation of metabolism and proliferation in HT29 colon cancer cells in the absence of specific PDGF receptors. The aim of this study was to analyze PDGFR and VEGFR expression and possible alternative PDGF binding partners in colorectal cancer (CRC). Methods: Human HT29 colon cancer cells were cultured and stimulated with PDGF in a time-dependent manner. Additionally, VEGFR2 and EGFR inhibition was performed to analyze alternative PDGF signaling events. Whole cell or RNA extracts were analyzed by Western Blot and RT-q-PCR for receptors and PI3K/Akt/mTOR signaling. To investigate the effects of specific receptor inhibition on proliferation, MTS proliferation assays were performed. Moreover, mRNA levels of PDGFR and VEGFR in tumors from patients with CRC were analyzed by RT-qPCR. Results: Human UICC stage I-IV tumors exhibited a significantly increased PDGFRβ and VEGFR1,2 gene expression. As observed previously, HT29 colon cancer cells showed only positivity for VEGFR1,2, but no PDGFR protein expression. Despite that, stimulation with PDGF resulted in increased proliferation and metabolic changes. In contrast, Caco-2 and SW480 colon cancer cells showed PDGFR and VEGFR expression on protein level. Interestingly, PDGF stimulation increased VEGFR1 and 2 gene expression in HT29 colon cancer cells and secondly inhibition of VEGFR2 and EGFR showed alterations in proliferation and Akt signaling in PDGF stimulated cancer cells. Conclusion: Despite the absence of PDGF receptors in HT29 colon cancer cells, PDGF induced proliferating and metabolic effects in the tumor cells, suggesting an alternative binding partner on the tumor cell surface. Further investigation of the alternative PDGF binding partners could be of clinical relevance in CRC. Note: This abstract was not presented at the meeting. Citation Format: Romana Moench, Tanja Grimmig, Christoph-Thomas Germer, Ana Maria Waaga-Gasser, Martin Gasser. PDGF induces cell growth and changes in glucose metabolism in colon cancer in the absence of PDGF receptors [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 1237. doi:10.1158/1538-7445.AM2017-1237
Abstract 4413: Targeting glutamine metabolism in MUC1 expressing triple negative breast cancer
Authors: Gennifer D. Goode, Venugopal Gunda, Pankaj Singh
Journal: Cancer Research (2017)

Abstract Breast cancer, the second leading cause of cancer deaths in women, accounts for nearly 1 in 3 cancer cases diagnosed in the U.S. women. Triple negative breast cancer (TNBC) accounts for approximately 15-25% of all breast cancer cases and has an increased incidence of metastasis, high recurrence within 1-3 years and a high mortality rate. Therefore, identifying factors that facilitate tumor growth and metastasis have the potential to serve as novel molecular targets for breast cancer therapy. Mucin1 (MUC1), a glycoprotein associated with chemoresistance, is aberrantly overexpressed in TNBC and facilitates growth and metastasis of TNBC cells. Recent studies suggest a role for MUC1 in modulating cancer cell metabolism to support tumor growth. In the present study we examined the role that MUC1 plays in TNBC tumor metabolism; thus facilitating tumor growth. Our results indicate that MUC1 expression facilitates glutamine metabolism. A correlation between MUC1 expression, glutamine dependency, and amino-oxyacetate (AOA) sensitivity was established. These alterations can be attributed in part to alterations in the expression of genes regulating glutamine metabolism. Collectively, these findings suggest that MUC1 serves as a metabolic regulator in TNBC, facilitating metabolic reprogramming of glutamine that influences growth of TNBC. Additionally, the findings with AOA’s effectiveness provide evidence for potential therapeutic utility, particularly for MUC1 overexpressing TNBC. Citation Format: Gennifer D. Goode, Venugopal Gunda, Pankaj Singh. Targeting glutamine metabolism in MUC1 expressing 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 4413. doi:10.1158/1538-7445.AM2017-4413
Abstract 4013: A novel multifunctional protein tag enables simple and sensitive bioluminescent quantification of tagged proteins
Authors: Christopher Eggers, Braeden Butler, Robin Hurst, Mary Hall, Brock Binkowski, Lance Encell, Marie Schwinn, Thomas Machleidt, Keith Wood, Frank Fan
Journal: Cancer Research (2017)

Abstract Dysregulation of protein expression is a key mechanism of tumorigenesis. The most commonly used approach to monitor changes in expression is to perform SDS-PAGE, followed by immunoblotting, a labor-intensive process that requires high-quality antibodies to detect proteins at endogenous levels of expression. We have developed a novel protein tag utilizing NanoLuc Binary Technology (NanoBiT), a binary complementation system based on NanoLuc luciferase. The tag, designated High BiT (HiBiT), is only 11 amino acids in length, which minimizes potential interference with protein function. The amount of HiBiT-tagged protein is measured using a lytic detection reagent containing Large BiT (LgBiT), which binds with high affinity to HiBiT (KD~1 nM) to reconstitute a bright, luminescent enzyme. HiBiT-tagged proteins can be quantified in cell lysates over 7 orders of magnitude of linear dynamic range with a limit of detection of less than 10-19 moles (3 fg of 30 kDa protein). The simple add-mix-read assay protocol can be completed in minutes, providing an assay that is compatible with high-throughput applications. The sensitivity of the assay allows quantification of expression at endogenous levels, and the small tag size is ideal for CRISPR-mediated genome editing. HiBiT-tagged proteins separated by SDS-PAGE can be detected on blots at sub-picogram levels with a detection reagent containing LgBiT. By eliminating the multiple steps of blocking, binding, and washing of traditional blotting techniques, the protocol takes minutes instead of hours. Additionally, the cell surface expression, internalization, or secretion of HiBiT-tagged proteins can be measured in minutes using a non-lytic detection reagent containing the cell-impermeable LgBiT protein. HiBiT represents a next-generation protein tag that allows simple quantification of proteins of interest in their cellular context or following SDS-PAGE. Citation Format: Christopher Eggers, Braeden Butler, Robin Hurst, Mary Hall, Brock Binkowski, Lance Encell, Marie Schwinn, Thomas Machleidt, Keith Wood, Frank Fan. A novel multifunctional protein tag enables simple and sensitive bioluminescent quantification of tagged proteins [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 4013. doi:10.1158/1538-7445.AM2017-4013
Abstract 3751: Allogeneic EGFRvIII chimeric antigen receptor T cells for treatment of glioblastoma
Authors: Oi Kwan Wong, Mathilde Dusseaux, Jing-Tyan Ma, Melinda Au, Sophie Leduc, Joyce Chou, Jessica M. Yu, Marjorie Bateman, Thomas Pertel, Kevin C. Lindquist, Julianne Smith, Barbra Sasu, Shu-Hui Liu
Journal: Cancer Research (2017)

Abstract Glioblastoma multiforme (GBM) is a highly aggressive form of brain tumors with a 5-year survival rate of less than 10%. Standard-of-care combining radiation therapy with temozolomide only yields a median survival of 14.6 months and more effective therapeutic options to extend patient lives are urgently needed. EGFR variant III (EGFRvIII) is a tumor specific mutant of EGFR found in 25-30% of GBM but not expressed in healthy tissues. EGFRvIII is formed by an in-frame deletion of exons 2-7 of the wild-type EGFR which leads to removal of 267 amino acids in the extracellular domain of the receptor. The truncated receptor loses its ability to bind ligands but acquires constitutive kinase activity. The lack of normal tissue expression makes EGFRvIII an ideal target for developing CAR T therapy. Most CAR T therapies in clinical development use the patients’ own T cells for CAR T manufacturing. Our approach is to develop an “off-the-shelf” CAR-T treatment for GBM using healthy donor T cells with the TCR (T-cell receptor) disrupted to prevent graft-versus-host disease. This allogeneic approach could circumvent challenges faced by some patients due to limited availability and quality of their own T cells and rapid progress of their diseases, and has the potential to reduce the high cost associated with autologous CART therapy. Using phage panning and hybridoma approaches, we generated a series of humanized and fully human EGFRvIII antibodies with a wide range of affinities. Recombinant EGFRvIII protein binding by Biacore and FACS assays using EGFRvIII and EGFR wild-type expressing cells demonstrated that these antibodies are highly specific for EGFRvIII. The antibodies were converted to ScFvs and cloned into a CAR vector. Subsequently, EGFRvIII CARs were transduced into primary human T cells for functional studies. We developed a series of assays to evaluate CAR expression, degranulation activity and target dependent cytotoxicity. Our goal is to select CAR candidate that is safe, persistent and has potent target dependent cytotoxicity. Citation Format: Oi Kwan Wong, Mathilde Dusseaux, Jing-Tyan Ma, Melinda Au, Sophie Leduc, Joyce Chou, Jessica M. Yu, Marjorie Bateman, Thomas Pertel, Kevin C. Lindquist, Julianne Smith, Barbra Sasu, Shu-Hui Liu. Allogeneic EGFRvIII chimeric antigen receptor T cells for treatment of glioblastoma [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 3751. doi:10.1158/1538-7445.AM2017-3751
Biodegradable Hollow Mesoporous Silica Nanoparticles for Regulating Tumor Microenvironment and Enhancing Antitumor Efficiency
Authors: Miao Kong, Jiamin Tang, Qi Qiao, Tingting Wu, Yan Qi, Songwei Tan, Xueqin Gao, Zhiping Zhang
Journal: Theranostics (2017)

There is accumulating evidence that regulating tumor microenvironment plays a vital role in improving antitumor efficiency.Herein, to remodel tumor immune microenvironment and elicit synergistic antitumor effects, lipid-coated biodegradable hollow mesoporous silica nanoparticle (dHMLB) was constructed with co-encapsulation of all-trans retinoic acid (ATRA), doxorubicin (DOX) and interleukin-2 (IL-2) for chemo-immunotherapy.The nanoparticle-mediated combinational therapy provided a benign regulation on tumor microenvironment through activation of tumor infiltrating T lymphocytes and natural killer cells, promotion of cytokines secretion of IFN-γ and IL-12, and down-regulation of immunosuppressive myeloid-derived suppressor cells, cytokine IL-10 and TGF-β.ATRA/DOX/IL-2 co-loaded dHMLB demonstrated significant tumor growth and metastasis inhibition, and also exhibited favorable biodegradability and safety.This nanoplatform has great potential in developing a feasible strategy to remodel tumor immune microenvironment and achieve enhanced antitumor effect.
Abstract 3928: Association of calcium sensing receptor polymorphisms at rs1801725 with circulating calcium in breast cancer patients
Authors: Diva Whalen, Li Wang, Sarrah Widatalla, Josiah Ochieng, Ann Richmond, Amos Sakwe
Journal: Cancer Research (2017)

Abstract Patients with metastatic or end-stage breast cancer (BC) inevitably develop hypercalcemia, while up to 30% of BC patients develop cancer-induced hypercalcemia (CIH) in the absence of metastases or bone diseases. The commonly diagnosed mild increase in circulating calcium activates the calcium sensing receptor (CaSR) and has been shown to be associated with larger and more aggressive breast tumors in postmenopausal and premenopausal patients respectively. Whether differences in circulating calcium and/or specific inactivating CaSR variants play any role in disparities in BC outcomes remains unclear. DESIGN METHODS: We identified 199 BC cases and 384 age and genetic ancestry-matched controls with calcium assay and genotyping data from the Vanderbilt University DNA biorepository (BioVU) linked to de-identified electronic medical records. The linear mixed effects and codominant models were used to assess the relationship between inactivating CaSR mutations at rs1801725 (codon 986) and rs1801726 (codon 1011) and either circulating calcium levels or risk of high calcium-driven aggressive BC outcomes. RESULTS: We observed that circulating calcium levels were significantly higher in BC cases compared to control subjects (p=0.001) and interestingly, in subjects of African ancestry compared to Caucasians (p=0.001). The A986S mutant CaSR is common among Caucasians while the Q1011E mutant receptor is common among African Americans. However, only inactivating mutations at rs1801725 locus were significantly associated with higher calcium levels (p=0.006) and a higher (69%) risk of high calcium-driven aggressive BC outcomes compared to the wild type receptor. We also demonstrate that invasive BC cells are tolerant to sustained high calcium and that their adaptation to high calcium occurs via up-regulation of calcium-activated early response and malignancy-associated genes. CONCLUSION: These data suggest that inactivating CaSR polymorphisms at rs1801725 predispose BC patients to hypercalcemia and that high circulating calcium-driven aggressive disease outcomes occur via calcium modulated malignancy-associated genes such as MAGEC2/CT10. Citation Format: Diva Whalen, Li Wang, Sarrah Widatalla, Josiah Ochieng, Ann Richmond, Amos Sakwe. Association of calcium sensing receptor polymorphisms at rs1801725 with circulating calcium in breast cancer patients [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 3928. doi:10.1158/1538-7445.AM2017-3928
Abstract 5734: The influence of body mass index on overall survival following surgical resection of non-small cell lung cancer
Authors: Xi Liu, Boris Sepesi, Kathryn A. Gold, Arlene M. Correa, John V. Heymach, Ara A. Vaporciyan, Jason Roszik, Ethan Dmitrovsky
Journal: Cancer Research (2017)

Abstract Prior work implicated an association between increased body mass index (BMI) and lower risk of mortality from lung cancer. The aim of our study was to comprehensively evaluate the influence of BMI on long-term overall survival in surgical patients with non-small cell lung cancer. This study investigated 1935 patients who underwent surgical resection for lung cancer at MD Anderson Cancer Center (from 2000 - 2014). Study variables included both patient and treatment related characteristics. Univariate and multivariate Cox regression analyses were performed to identify variables associated with overall survival. By univariate analysis, significant predictors of better survival were higher BMI, pathologic tumor stage (stage I versus stages II, III, or IV), type of surgery (lobectomy/pneumonectomy versus wedge resection/segmentectomy), younger age, female gender, and adenocarcinoma histology (versus squamous) (all p &amp;lt; 0.05). Patients considered morbidly obese (BMI ≥ 35) had a trend towards better outcomes than those classified as obese (BMI ≥ 30 and &amp;lt;35) (p = 0.05), overweight (BMI ≥25 and &amp;lt;30) (p = 0.13), or healthy weight (BMI &amp;lt; 25) (p = 0.37) (HR 0.727, 0.848, 0.926, and 1, respectively). By multivariate analysis, BMI remained an independent predictor of survival (p = 0.02). Propensity matching analysis showed significantly better overall survival (p = 0.008) in patients with BMI ≥ 30 as compared to BMI &amp;lt; 25. For exploratory analysis of expressed mRNAs associated with obesity in lung cancer, the association between obesity-related species (LEP, LEPR, PCSK1, POMC, MC4R, BMIQ1, BMIQ2, BMIQ3, UCP2, BMIQ5, BMIQ6, INSIG2, FTO, TMEM18, GNPDA2, NEGR1, BDNF, KCTD15, SH2B1, MTCH2 and NPC1) and survival was explored using The Cancer Genome Atlas (TCGA). Kaplan Meier analyses demonstrated significantly improved overall survival in lung cancer patients with higher Uncoupling Protein 2 (UCP2) expression, as will be presented. In summary, this large, single center series, after controlling for disease stage and other variables found higher BMI was associated with improved overall survival following surgical resection of non-small cell lung cancer. Studies are underway to elucidate the underlying mechanisms responsible for this association between BMI and lung cancer survival. Citation Format: Xi Liu, Boris Sepesi, Kathryn A. Gold, Arlene M. Correa, John V. Heymach, Ara A. Vaporciyan, Jason Roszik, Ethan Dmitrovsky. The influence of body mass index on overall survival following surgical resection of non-small cell lung 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 5734. doi:10.1158/1538-7445.AM2017-5734
Abstract 1525: Chemically induced degradation of the oncogenic transcription factor BCL6
Authors: Nina Kerres, Steffen Steurer, Stefanie Schlager, Gerd Bader, Helmut Berger, Sophia Blake, Maureen Caligiuri, John Engen, Peter Ettmayer, Thomas Gerstberger, Daniel Gerlach, Roxana Jacob, Simon Lucas, Moriz Mayer, Mischerikow Nikolai, Rumpel Klaus, Scharn Dirk, Schnitzer Renate, Tilman Voss, Zoephel Andreas, Norbert Kraut, Darryl McConnell, Pearson Mark, Manfred Koegl
Journal: Cancer Research (2017)

Abstract The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B-cell lymphoma (DLBCL). It is a DNA-binding protein that represses gene transcription through the recruitment of co-repressor proteins via its BTB domain. Disruption of the interaction of BCL6 with co-repressor proteins interferes with the physiological and oncogenic functions of BCL6. We have used structure-based drug desgin to develop potent compounds that block this interaction with half maximal inhibitory concentration values (IC50s) below 3 nM. In addition to inhibiting co-repressor binding, a subset of the identified inhibitors also caused rapid disappearance of BCL6 protein in cells. This effect was mediated by compound-induced multi-ubiquitylation of BCL6 and degradation by the proteasome and was dependent on the presence of a functional DNA binding domain on BCL6. Compounds that induced BCL6 degradation displayed significantly stronger induction of expression of BCL6-repressed genes than compounds that merely inhibited co-repressor interaction. BCL6-degrading inhibitors had anti-proliferative effects in several DLBCL cell lines, while non-degrading BCL6 inhibitors only had minor effects on proliferation. The fact that the magnitude of effects elicited by this novel class of BCL6 degrading compounds greatly exceeds that of our equipotent classical co-repressor interaction inhibitors offers exciting new opportunities for the development of BCL6-based lymphoma therapeutics. Citation Format: Nina Kerres, Steffen Steurer, Stefanie Schlager, Gerd Bader, Helmut Berger, Sophia Blake, Maureen Caligiuri, John Engen, Peter Ettmayer, Thomas Gerstberger, Daniel Gerlach, Roxana Jacob, Simon Lucas, Moriz Mayer, Mischerikow Nikolai, Rumpel Klaus, Scharn Dirk, Schnitzer Renate, Tilman Voss, Zoephel Andreas, Norbert Kraut, Darryl McConnell, Pearson Mark, Manfred Koegl. Chemically induced degradation of the oncogenic transcription factor BCL6 [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 1525. doi:10.1158/1538-7445.AM2017-1525
Abstract 4522: Hypoxia-induced alteration of mitochondrial dynamics is linked to chemoresistance in ovarian cancer
Authors: Youngjin Han, Boyun Kim, Yong Sang Song
Journal: Cancer Research (2017)

Abstract Hypoxia, commonly observed in the tumor microenvironment, has been shown to be related to the cancer hallmarks. Hypoxia generates reactive oxygen species (ROS), inducing changes in mitochondrial function and structure in various diseases. Mitochondria, dynamic intracellular organelles, go through incessant processes of fission and fusion for efficient generation of energy. We investigated alterations in mitochondrial networks under hypoxic conditions (&amp;lt; 1 % O2) and subsequent effects of the mitochondrial alteration on drug response in ovarian cancer cells. Mitochondrial fission was prevalent in cancer cells under hypoxic conditions. Translocation of phospho-Drp1 (Ser616), a biochemically active mitochondrial fission protein, to mitochondria was enhanced under hypoxic conditions. An increase in ROS production was accompanied under hypoxic conditions. ROS scavenging reversed the hypoxia-elicited mitochondrial fission, while exogenous H2O2 treatment promoted mitochondrial fission. These results strongly implicate that ROS are important modulators of mitochondrial dynamics under hypoxia. Interestingly, hypoxia-induced mitochondrial fission altered the response of cancer cells to cisplatin (CDDP). Ovarian cancer cells in hypoxic and normoxic conditions were differentially affected by CDDP when mitochondrial fission was inhibited. Taken together, the alteration of mitochondrial dynamics, a cellular adaptation to hypoxia, is associated with chemoresistance. Mitochondria adapted to the hypoxic tumor microenvironment could be a potential target for anti-cancer therapy. Citation Format: Youngjin Han, Boyun Kim, Yong Sang Song. Hypoxia-induced alteration of mitochondrial dynamics is linked to chemoresistance in ovarian 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 4522. doi:10.1158/1538-7445.AM2017-4522