tbuckley/cabot-search huggingface dataset:
Abstract 5337: USP26 regulates TGF-β signaling by deubiquitinating and stabilizing SMAD7
Authors: Pieter J.A. Eichhorn, Sarah Lui, Prasanna Iyengar, Patrick Jaynes
Journal: Cancer Research (2017)

Abstract The amplitude of transforming growth factor-β (TGF-β) signal is tightly regulated to ensure appropriate physiological responses. As part of negative feedback loop SMAD7, a direct transcriptional target of downstream TGF-β signaling, acts as a scaffold to recruit the E3 ligase SMURF2 to target the TGF-β receptor complex for ubiquitin mediated degradation. Here we identify the deubiquitinating enzyme USP26 as a novel integral component of this negative feedback loop. We demonstrate that TGF-β rapidly enhances the expression of USP26 and reinforces SMAD7 stability by limiting the ubiquitin mediated turnover of SMAD7. Conversely, knockdown of USP26 rapidly degrades SMAD7 resulting in TGF-β receptor stabilization and enhanced levels of p-SMAD2. Clinically, loss of USP26 correlates with high TGF-β activity and confers poor prognosis in glioblastoma. Our data identify USP26 as a novel negative regulator of the TGF-β pathway and suggests that loss of USP26 expression may be an important factor in glioblastoma pathogenesis. Citation Format: Pieter J.A. Eichhorn, Sarah Lui, Prasanna Iyengar, Patrick Jaynes. USP26 regulates TGF-β signaling by deubiquitinating and stabilizing SMAD7 [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 5337. doi:10.1158/1538-7445.AM2017-5337
Abstract 1615: C-Reactive protein and radiotherapy-induced skin toxicity in breast cancer
Authors: Jennifer J. Hu, Doug Case, Mark O. Lively, Eunkyung Lee, Cristiane Takita, James J. Urbanic, Glenn J. Lesser, Edward G. Shaw
Journal: Cancer Research (2017)

Abstract Background: Post-surgery adjuvant radiotherapy (RT) for breast cancer significantly reduced the local recurrence rate. However, many patients develop early adverse skin reactions (EASRs) that impact quality of life. Methods: In a large prospective study of 1,000 breast cancer patients undergoing RT, we evaluated an inflammatory biomarker, C-reactive protein (CRP) in predicting RT-induced EASRs. In each patient, we measured pre- and post-RT plasma CRP levels using a highly-sensitive ELISA CRP assay. RT-induced EASRs were assessed using the Oncology Nursing Society Skin Toxicity Criteria. Association between EASRs and CRP were assessed using logistic regression models after adjusting for potential confounders. Results: The study population includes 405 non-Hispanic White, 280 African Americans, 218 Hispanic Whites, 52 Asians, and 45 others. RT-induced grade 3+ and 4+ skin toxicity at the end of RT were observed in 42% and 15% patients, respectively. CRP levels differ significantly by race/ethnicity at baseline and at the end of RT. RT-induced grade 4+ skin toxicity was significantly associated with: obesity and pre-RT CRP &amp;gt; 2mg/L (OR=3.27; 95%CI=1.88, 5.68), obesity and post-RT CRP &amp;gt; 2mg/L (OR=4.42; 95%CI=2.38, 8.23), or obesity and change of CRP &amp;gt; 1mg/L (OR=3.58; 95%CI=2.00, 6.39). Conclusion: The current data validate our previous findings that the inflammatory biomarker CRP is associated with RT-induced EASRs, particularly combined with obesity. Impact: Our current findings support the discovery and development of anti-inflammatory agents to protect normal tissue from RT-induced EASRs and improve quality of life in breast cancer patients undergoing RT. Citation Format: Jennifer J. Hu, Doug Case, Mark O. Lively, Eunkyung Lee, Cristiane Takita, James J. Urbanic, Glenn J. Lesser, Edward G. Shaw. C-Reactive protein and radiotherapy-induced skin toxicity in 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 1615. doi:10.1158/1538-7445.AM2017-1615
Abstract 1656: Comprehensive evaluation of human immune system reconstitution in NSGTM and NSGTM-SGM3 toward the development of a novel Onco-HuTM xenograft model
Authors: Aaron J. Middlebrook, Eileen Snowden, Warren Porter, Friedrich Hahn, Mitchell Ferguson, Brian Soper, James Keck, Joan Malcolm, Shannon Dillmore, Smita Ghanekar, Rainer Blaesius
Journal: Cancer Research (2017)

Abstract The recent successes of immunotherapeutic approaches to the treatment of melanoma and the promise of similar treatments in a variety of other cancers underscore the importance of the immune system in cancer. Indeed, effective therapeutic design and evaluation require a comprehensive understanding of the interplay between the immune compartment and the proliferating tumor cells that comprise the tumor microenvironment. A humanized mouse strain engrafted with cancerous tissue from a patient derived xenograft (PDX) tumor provides researchers with a highly sophisticated tool, ideally suited to facilitate the design of treatment strategies that prevent tumor evasion of immune cells and that improve cytotoxic responses. Severely combined immunodeficient mice such as NOD scid gamma (NSGTM) and triple transgenic NSG mice expressing human cytokines KITLG, CSF2, and IL-3 (NSGTM-SGM3) are proven hosts for the engraftment of human tumors and establishment of human immune system components following hematopoietic stem cell (CD34+) transplantation. The endogenous expression of cytokines that support the development of myeloid lineages and regulatory T cells potentially represents a substantial improvement over standard NSG mice. Here we employ four 14-color flow cytometry panels to perform a comprehensive and detailed analysis of the entire immune system. The four panels are designed to fully characterize specific branches of the immune system: 1) T cells 2) NK cells/dendritic cells/B cells 3) myeloid lineages, and 4) immune checkpoint markers. Blood, spleen, and bone marrow tissue from both NSG and NSG-SGM3 mice were evaluated at 9, 16, 21, and 31 weeks of age using each of the four phenotyping panels. Our results indicate that the triple transgenic NSG-SGM3 mice exhibit a more completely humanized immune system compared to NSG mice, with specific improvements in the distribution of T-cell subsets and overall representation of the myeloid lineage. NSG mice engrafted with allogeneic human tumors represent a valuable preclinical testing platform for immuno-oncology. Citation Format: Aaron J. Middlebrook, Eileen Snowden, Warren Porter, Friedrich Hahn, Mitchell Ferguson, Brian Soper, James Keck, Joan Malcolm, Shannon Dillmore, Smita Ghanekar, Rainer Blaesius. Comprehensive evaluation of human immune system reconstitution in NSGTM and NSGTM-SGM3 toward the development of a novel Onco-HuTM xenograft model [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 1656. doi:10.1158/1538-7445.AM2017-1656
Abstract 1141: Evaluation of GABRP as a novel therapeutic target in triple negative breast cancer
Authors: Vikram B. Wali, Gauri A. Patwardhan, Christos Hatzis, Lajos Pusztai
Journal: Cancer Research (2017)

Abstract Triple Negative breast cancers (TNBC) represent nearly 20% of all breast cancers but do not have any targeted therapies available due to lack of amplification of HER2 and expression of estrogen and progesterone receptors. To identify potentially druggable targets for TNBC, we compared TNBC to non-TNBC tumors in large independent gene expression clinical datasets to identify highly expressed genes in TNBC that encode for proteins expressed on the cell surface. We found gamma-aminobutyric acid type A receptor pi (GABRP) to be the most overexpressed receptor protein gene in TNBC, while its expression in normal tissues was low and comparable to that of proteins targeted by drugs or therapeutic antibodies already in clinical testing. We compared GABRP mRNA and protein expression across panel of breast cancer cell lines and found it to be particularly elevated in HCC1143 and MDA-MB-468 TNBC cells. Knockdown of GABRP using siRNA suppressed TNBC cell growth and stable GABRP knock-down by shRNA suppressed growth of MDA-MB-468 xenografts in nude mice. Sub-cellular fractionation of TNBC cells and subsequent Western blot analysis confirmed that GABRP is located predominantly in the cell membrane. GABRP protein expression on cell surface was also detected by flowcytometry. Interestingly, treatment with 5-100μg/ml of anti-GABRP antibody that binds to the extracellular domain (ECD) itself inhibited growth of TNBC cell lines expressing higher GABRP, while the same doses of a control antibody had no effect in these cells in culture. Our goal is to generate an antibody drug conjugate (ADC) for TNBC by conjugating anti-GABRP antibody with a maytansinoid such as DM1, which has proven cytotoxicity in breast cancer cells. Together, our results suggest that GABRP is a potential therapeutic target for triple-negative breast cancers. Citation Format: Vikram B. Wali, Gauri A. Patwardhan, Christos Hatzis, Lajos Pusztai. Evaluation of GABRP as a novel therapeutic target 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 1141. doi:10.1158/1538-7445.AM2017-1141
Abstract 1877: Coordination of Rac1 and Cdc42 by centrosomal microtubules in focal adhesion dynamics and directed cell migration
Authors: Jean-Cheng Kuo
Journal: Cancer Research (2017)

Abstract Cancer metastasis causes the increase of mortality in most cancer patients, and abnormal cell migration contributes to this disease progression. To control cell migration, the dynamical control of a protein complex within focal adhesions has to be regulated appropriately. It is known that focal adhesions can be regulated dynamically by microtubules. To examine the effects of centrosomal microtubules and non-centrosomal microtubules in regulating focal adhesion dynamics and directed cell migration, we first generated centrosome-deficient cells. We find that centrosomal microtubules and non-centrosomal microtubules control focal adhesion dynamics through modulating focal adhesion composition, which dynamically control the activity of small GTPases Rac1 and Cdc42. Deficiency of centrosomal microtubules significantly disrupts the balance of Rac1 and Cdc42, thereby inhibiting directed cell migration. This study reveals the effects of centrosome in focal adhesions, and indicates an important role for Rac1 and Cdc42 activation that controls actin polymerization, cell polarization and directed cell migration. Citation Format: Jean-Cheng Kuo. Coordination of Rac1 and Cdc42 by centrosomal microtubules in focal adhesion dynamics and directed cell migration [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 1877. doi:10.1158/1538-7445.AM2017-1877
Investigating biological associations of dasatinib drug sensitivity using molecular concepts analysis
Authors: Matt Anstett
Journal: Clinical Cancer Research (2007)

A40  Dasatinib (BMS-354825, Bristol-Myers Squibb), a multi-tyrosine kinase inhibitor, was recently approved for the treatment of imatinib refractory CML and BCR-ABL positive ALL. Because dasatinib is a promising therapeutic agent for preventing growth and metastasis of various malignancies, identifying additional tumor types and optimal patient sub-populations is critical.Recent molecular profiling work (Huang et al, Cancer Res 2007; 67:2226-2238) defined a gene expression signature associated with sensitivity to Dasatinib in vitro. Here, using the Oncomine Concepts Map, we analyzed this sensitivity signature in the context of thousands of gene sets associated with pathways, mechanisms, diseases and drugs. Our analysis demonstrated significant associations with biological functions that may underlie sensitivity and specific tumor types and subpopulations that show coordinate over-expression of the sensitivity signature. Our analysis confirmed a link to basal-type breast cancer and correctly linked dasatinib sensitivity with BCR-ABL positive leukemia. Importantly, novel tumor populations were linked to dasatinib sensitivity, suggesting additional indications for consideration.
Abstract 4792: Prmt6 promotes lung tumor growth via modulation of Ilf2 expression
Authors: Sreedevi Avasarala, Pei-Ying Wu, Michelle Van Scoyk, Abinaya Baskaran, Yanlin Su, Odile David, Robert A. Winn, Kamesh Bikkavilli
Journal: Cancer Research (2017)

Abstract Lung cancer kills more people in the US than any other malignancy. High mortalities are in part due to the diagnosis at an advanced inoperable stage where the 5-year survival is only 4%. Therefore improving survival will require increased knowledge of genes that drive the complex mechanisms of lung cancer initiation and progression. Emerging data implicate novel roles for protein arginine methylation in lung cancers. In protein arginine methylation, nitrogen/s of arginine can be post-translationally modified via the addition of a methyl group, catalyzed by a class of enzymes, protein arginine methyl transferases (PRMTs). Protein arginine methyl transferase 6 (PRMT6) is a methyl transferase that modifies histone tails, and its expression is upregulated in lung cancers, correlating with a worse overall patient survival. However, the in vivo role of PRMT6 has never been examined. In this study, we show that targeted over-expression of PRMT6 in the mouse lungs (PRMT6 gain-of-function mouse model) results in an increased chemical carcinogen-induced lung tumorigenesis. We also performed proteomics on PRMT6-associated proteins from the mouse lung and identified Interleukin-enhancer binding protein 2 (ILF2) a.k.a. nuclear factor 45 (NF45) as a novel PRMT6 interacting protein. By using a battery of cell-based assays, we show that PRMT6 plays an essential role in the regulation of the pro-proliferative functions of ILF2. Therefore, targeting PRMT6/ILF2 axis might open new possibilities for the therapeutic intervention of lung cancer. Citation Format: Sreedevi Avasarala, Pei-Ying Wu, Michelle Van Scoyk, Abinaya Baskaran, Yanlin Su, Odile David, Robert A. Winn, Kamesh Bikkavilli. Prmt6 promotes lung tumor growth via modulation of Ilf2 expression [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 4792. doi:10.1158/1538-7445.AM2017-4792
Abstract 2333: Modulation of Bax and mTOR for cancer therapeutics
Authors: Rui Li, Chunyong Ding, Jun Zhang, Maohua Xie, Dongkyoo Park, Ye Ding, Guo Chen, Guojing Zhang, Melissa Gilbert-Ross, Wei Zhou, Adam Marcus, Shi-Yong Sun, Zhuo Chen, Gabriel Sica, Suresh Ramalingam, Andrew Magis, Haian Fu, Fadlo Khuri, Walter Curran, Taofeek Owonikoko, Dong Shin, Jia Zhou, Xingming Deng
Journal: Cancer Research (2017)

Abstract Pharmacologic manipulation of the serine (S)184 phosphorylation site of Bax protein to functionally regulate its proapoptotic activity is an attractive anticancer strategy. We recently identified three small molecule Bax agonists. SMBA1 was selected as the lead compound based on its chemical structure and its drug-like properties, from which a more effective analog, CYD-2-11, was generated. CYD-2-11 targets the structural pocket around S184 in the C-terminal tail of Bax, directly activating its proapoptotic activity via 6A7 conformational change and formation of Bax homo-oligomers in mitochondrial membranes. CYD-2-11 suppresses tumor growth in SCLC, NSCLC and patient-derived lung cancer xenografts as well as the genetically engineered mutant KRAS-driven lung cancer model with no significant normal tissue toxicity. Inhibition of mTOR by RAD001 enhances S184 Bax phosphorylation in lung cancer cell lines and tumor tissues from lung cancer patients treated with RAD001, which inactivates the propaoptotic function of Bax, contributing to rapalog-resistance. Combined CYD-2-11 and RAD001 treatment not only displays strong synergistic activity against lung cancer but also overcomes rapalog-resistance in vitro and in vivo. Therefore, a mechanism-driven combination of Bax agonist and mTOR inhibitor represents a highly attractive therapeutic strategy to improve lung cancer patient outcomes. Citation Format: Rui Li, Chunyong Ding, Jun Zhang, Maohua Xie, Dongkyoo Park, Ye Ding, Guo Chen, Guojing Zhang, Melissa Gilbert-Ross, Wei Zhou, Adam Marcus, Shi-Yong Sun, Zhuo Chen, Gabriel Sica, Suresh Ramalingam, Andrew Magis, Haian Fu, Fadlo Khuri, Walter Curran, Taofeek Owonikoko, Dong Shin, Jia Zhou, Xingming Deng. Modulation of Bax and mTOR for cancer therapeutics [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 2333. doi:10.1158/1538-7445.AM2017-2333
Abstract 2240: “Smart” selenium compound ISC-4 inhibits androgen receptor signaling and induces ROS- and p53-dependent apoptosis in LNCaP prostate cancer cells
Authors: Wei Wu, Kartick Pramanik, Cheng Jiang, Shantu Amin, Arun K. Sharma, Junxuan Lu
Journal: Cancer Research (2017)

Abstract “Smart” selenium compound phenylbutyl isoselenocyanate (ISC-4) was developed by substituting sulfur in cancer chemopreventive compound phenylbutyl isothiocyanate (PBITC) with selenium, resulting in increased anti-cancer activity in several melanoma and colon cancer cell lines. The in vivo anticancer beneficial effects of ISC-4 have been reported in both melanoma and colon cancer mouse models as well. To explore the potential chemopreventive attributes of ISC-4 against prostate carcinogenesis, we selected LNCaP cells (with wild type p53 and functional androgen receptor (AR) signaling) to examine the growth suppression and apoptosis responses in cell culture and interrogated signaling mechanisms through pharmacological and siRNA knockdown approaches. Results show that when compared with PBITC, ISC-4 was more potent at suppressing cell growth and inducing apoptotic cell death in LNCaP cells. ISC-4 induced caspase-mediated apoptosis (as evidenced by cleavage of PARP) in dose- and time-dependent manners in association with decreased AR and its best known target prostate specific antigen (PSA) protein abundance and upregulation of p53-DNA damage response (DDR) protein expression levels: p53, its canonical target p21, and p-H2AX that marks DNA double-strand break sites. Similar to the rapid induction of reactive oxygen species (ROS) by isothiocyanates, ISC-4 exposure resulted in increased dihydroethidium-detectable ROS in a concentration-dependent manner. Preincubation with the ROS scavenger N-Acetyl-L-cysteine (NAC, 10 µM to 2 mM), markedly reduced ISC-4-induced cell death and attenuated p53, p21 and p-H2AX. Moreover, siRNA knockdown of p53 did not suppress ROS production, but decreased ISC-4-induced Annexin V-positive apoptosis, PARP cleavage and the DDR proteins. Taken together, these data suggest that ISC-4 inhibits LNCaP cell growth and survival with concomitant suppression of AR signaling and induction of ROS-p53-DDR mediated apoptosis. Given the pivotal significance of AR signaling in prostate epithelial survival, cancer genesis and progression, and the preservation of wild type p53 in precancerous lesions and early stage prostate cancer, our findings suggest attractive chemopreventive potential of ISC-4 against prostate carcinogenesis. Citation Format: Wei Wu, Kartick Pramanik, Cheng Jiang, Shantu Amin, Arun K. Sharma, Junxuan Lu. “Smart” selenium compound ISC-4 inhibits androgen receptor signaling and induces ROS- and p53-dependent apoptosis in LNCaP prostate 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 2240. doi:10.1158/1538-7445.AM2017-2240
Abstract 5166: Sensitivity of melanoma cells to a novel class of Ras inhibitors
Authors: Kate M. Saville, Kevin Lee, Tyler E. Mattox, Xi Chen, Jacob Valiyaveettil, Kristy Berry, Veronica Ramírez-Alcántara, Bing Zhu, Adam Keeton, Michael Boyd, Gary Piazza, Ashley S. Lindsey
Journal: Cancer Research (2017)

Abstract A high percentage of human cancers arise from mutations in the ras gene that encodes an abnormal Ras protein locked in a constitutively active GTP-bound state that promotes tumor cell proliferation, survival, and metastasis. These gain-in-function mutations in the ras gene or constitutive activation of tyrosine kinase receptors upstream of the Ras protein drive tumor cell growth by activating Raf/MAPK and PI3K/AKT signaling pathways. Ras has been an elusive drug target for which no inhibitors are available to treat Ras-driven cancers. Screening a library of indene derivatives in a differential phenotypic assay identified a novel compound class displaying high potency and selectivity to inhibit the growth of tumor cells harboring mutant Ras relative to tumor cells with wild type (WT) Ras. Lead optimization resulted in a drug development candidate (DC070-547) and several back-up analogs (e.g. ADT-006) with IC50 values in the low nanomolar range and selectivity indices of 100 fold or greater to inhibit the growth of tumor cells with constitutively activated Ras relative to tumor cells with low levels of activated Ras. Sensitivity among a large panel of tumor cell lines to this compound class strongly correlated with levels of activated Ras, but did not appear to be limited to a specific ras gene mutation or Ras protein isoform. Here, we report that DC070-547 and ADT-006 potently and selectively inhibit the growth of the human melanoma cell line, SK-MEL-2, harboring a mutation in the ras gene that encodes the constitutively active N-Ras protein with IC50 values of 7 and 25 nM, respectively. In addition, both compounds potently inhibited the growth of the murine melanoma cell line, B16-F10 with WT ras, but harboring a mutation in a tyrosine kinase receptor upstream of Ras, specifically PDGFRα, which results in high levels of active, GTP-bound Ras as confirmed by Ras-RBD pull-down assays. To determine if treatment can disrupt Ras signaling, B16-F10 cells were incubated with the compounds before being subjected to Western blotting for phosphorylated signaling molecules downstream of Ras. Treatment reduced levels of phosphorylated c-Raf and MEK at concentrations that inhibit tumor cell growth. These findings support further investigation of this novel class of Ras inhibitors for the treatment of Ras-driven melanoma. Citation Format: Kate M. Saville, Kevin Lee, Tyler E. Mattox, Xi Chen, Jacob Valiyaveettil, Kristy Berry, Veronica Ramírez-Alcántara, Bing Zhu, Adam Keeton, Michael Boyd, Gary Piazza, Ashley S. Lindsey. Sensitivity of melanoma cells to a novel class of Ras inhibitors [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 5166. doi:10.1158/1538-7445.AM2017-5166