tbuckley/cabot-search huggingface dataset:
Expression of survivin in canine mammary tumor
Authors: Teshome E. Yehualaeshet, Leonard H. Billups
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

792 

Canine mammary tumor is the commonest tumor in female dogs and a good animal model of human breast cancer. It is challenging for clinicians and pathologists because of complex histological classification and unpredictable biological behavior. Basic and translational researchers in cancer biology have converged on survivin , member of the inhibitor of apoptosis (IAP), as a pivotal cancer gene, not simply for its sharp expression in tumors and not in normal tissues, but also for the potential exploitation of this pathway in cancer diagnosis and therapy. The objective of this study was to elucidate the expression of survivin in canine mammary tumors. Histological examination and classification of spontaneous mammary tumors from dogs (190 female and 1 male) was performed on H&E-stained sections according to WHO guidelines. In this study, we have analyzed the expression of survivin, α-SMA, vimentin and cytokeratin AE1/AE3 in formalin-fixed, paraffin-embedded tissue samples of mammary tumors of the dog by using the avidin-biotin-peroxidase complex immunohistochemical technique. The immunohistochemical finding implicate the expression of survivin in canine mammary tumor and interestingly, this is the first report to show the expression of survivin in canine mammary tumor. The deposition of α-SMA occurs within the stroma and myoepithelial cells of a majority of mammary tumor types. Our results demonstrate the distinct expression and localization of survivin may render further hints to diagnosis, evaluate the stages of the tumor and therapy.
Phase II study of irinotecan and carboplatin followed by maintenance sunitinib in the first-line treatment of extensive-stage small cell lung cancer.
Authors: E. T. Lubiner, D. R. Spigel, F. A. Greco, M. S. Rubin, D. Shipley, D. S. Thompson, J. F. Eakle, R. H. Brown, H. A. Burris, J. D. Hainsworth
Journal: Journal of Clinical Oncology (2010)

7049 Background: Angiogenesis contributes to tumor growth in small-cell lung cancer (SCLC). Inhibiting angiogenesis may be one strategy to delay disease progression in patients who have received initial platinum-doublet chemotherapy. This phase II study investigated the use of maintenance sunitinib following first-line irinotecan and carboplatin in patients with extensive stage SCLC. Methods: Eligible patients were aged > 18 years, had previously untreated extensive-stage SCLC, ECOG PS 0 or 1; adequate organ function; and no active brain metastasis. Patients received up to 6 cycles of irinotecan 60 mg/m2 on days 1, 8, and 15, and carboplatin AUC=4 on day 1; cycles were repeated every 28 days. Patients were reevaluated for response every 8 weeks. All patients without progression or intolerable toxicity continued on single- agent sunitinib 25 mg orally daily until progression. The primary endpoint was 1-year overall survival. Results: 34 patients were enrolled between 2/09 and 10/09. Baseline characteristics included: median age 65 years (range, 41-80); male, 53%; and ECOG 0, 44%. A median of 3 cycles of irinotecan/carboplatin were given; 4 patients (12%) received maintenance sunitinib for a median of 4 weeks (range: 4-8+). After a median follow-up of 25 weeks (range: 9–42), 31 patients remain alive, and 4 are continuing sunitinib. The objective response rate with chemotherapy was 47% (95% CI 30-65), and an additional 38% had stable disease. The median time-to- progression (TTP) was 7.6 months. The 6-month overall survival was 91% (additional time is required before 1 year OS can be assessed). No grade 3/4 toxicities have been observed in the 4 patients who have received sunitinib. Conclusions: In this phase II trial, maintenance sunitinib was well-tolerated following platinum doublet chemotherapy as first-line treatment for extensive-stage SCLC. Early assessment of activity is encouraging, however additional follow-up is required. No significant financial relationships to disclose.
Abstract 3078: GSK-3 inhibitor 9ING41 potentiates the antitumor effects of CPT-11 in human breast cancer
Authors: Andrey Ugolkov, Irina Gaisina, Kevin White, Alan Kozikowski, Thomas O’Halloran, Andrew Mazar
Journal: Cancer Research (2016)

Abstract Glycogen Synthase Kinase-3beta (GSK-3beta), a serine/threonine protein kinase, has been demonstrated to be potential therapeutic target in human breast cancer. Our objective was to evaluate novel GSK-3 inhibitors alone and in combination with chemotherapeutic drugs for the targeted therapy of breast cancer. Using a short-term treatment, we found that the GSK-3 inhibitor 9ING41 significantly potentiates the antitumor effects of CPT-11, cisplatin and 5-FU to inhibit breast cancer cell growth. We established hormone-refractory BC-1 and BC-2 patient-derived xenograft (PDX) tumor models from metastatic pleural effusions that were obtained from breast cancer patients. We considered BC-1 and BC-2 PDX tumors as chemoresistant, because metastatic disease progressed in both cases in despite of the fact that patients received many cycles of chemotherapy. Although we found that BC-1 and BC-2 PDX tumors express estrogen receptor (ER), both PDX tumors carried activating mutations in ESR1. These mutations confer ligand-independent activity of the ER in tamoxifen-resistant breast tumors. We found that BC-1 and BC-2 PDX tumors grew without estradiol supplementation in immunodeficient mice, which suggests a hormone-refractory nature of these tumors. We found that GSK-3 inhibitor 9ING41 potentiates the effects of chemotherapeutic drug CPT-11, and leads to the regression of BC-1 and BC-2 breast PDX tumors. Our results demonstrate inhibition of GSK-3 as a promising therapeutic approach to overcome breast cancer chemoresistance, and identify GSK-3 inhibitor 9ING41 as a drug candidate for the targeted therapy of human breast cancer. Citation Format: Andrey Ugolkov, Irina Gaisina, Kevin White, Alan Kozikowski, Thomas O’Halloran, Andrew Mazar. GSK-3 inhibitor 9ING41 potentiates the antitumor effects of CPT-11 in human breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3078.
Front-Line Therapy of Acute Myeloid Leukemia in Elderly Patients. Safety and Efficacy of Two Different Schedules of Fludarabine-Based Regimens.
Authors: Stefano Rocco, Giancarla Pricolo, Luca Pezzullo, Antonella Prudenzano, Olimpia Finizio, Francesco Casulli, Lucia Bene, Carlo De Rosa, Vincenzo Mettivier, Patrizio Mazza
Journal: Blood (2005)
Prevention of base excision repair by TRC102 (methoxyamine) potentiates the anti-tumor activity of pemetrexed in vitro and in vivo
Authors: L. Liu, A. Bulgar, J. Donze, B. J. Adams, C. P. Theuer, S. L. Gerson
Journal: Journal of Clinical Oncology (2007)

13005 Background: TRC102 (methoxyamine) reverses resistance to alkylating agents by inhibiting base excision repair (BER; a mechanism of DNA repair), thereby increasing DNA strand breaks and potentiating the anti-tumor activity of alkylating agents without additional toxicity, Based on these data, TRC102 is currently being studied in combination with temozolomide in a phase 1 trial. We hypothesized that inhibition of BER by TRC102 would also increase DNA strand breaks and improve the anti-tumor activity of anti-metabolite chemotherapeutics, including pemetrexed, because these agents also produce AP sites that are recognized and repaired by BER. Methods: Pemetrexed- induced AP sites and BER inhibition was quantified using an apurinic/apyrimidinic (AP) site assay in vitro. Single and double DNA strand breaks were quantified by the Comet assay in vitro and anti-tumor activity was assessed in an in vivo xenograft study of subcutaneously implanted H460 human lung cancer cells. Results: Pemetrexed induced and TRC102 reduced the number of available AP sites in pemetrexed- treated H460 cells (by 60–80%), indicating successful inhibition of BER. TRC102 treatment increased DNA strand breaks in pemetrexed-treated H460 cells (2 fold increase versus treatment with pemetrexed alone). Premetrexed treatment alone and in combination with TRC 102 delayed tumor growth in vivo (tumor growth delay of 4.7 days in the 150 mg/m 2 pemetrexed alone group, 5.7 days in the 150 mg/m 2 pemetrexed + 2 mg/m 2 TRC102 group and 6.9 days in the 150 mg/m 2 pemetrexed + 4 mg/m 2 TRC102 group); in vivo systemic toxicity was not increased. TRC102 alone had no effect in vitro or in vivo. Conclusions: TRC102 effectively inhibits BER in lung cancer cells treated with pemetrexed. Inhibition of DNA repair by TRC102 results in an increase in DNA strand breaks and improved anti-tumor activity versus treatment with pemetrexed alone. Given its preclinical efficacy and safety profile, study of TRC102 combined with pemetrexed in a phase 1 trial is warranted. No significant financial relationships to disclose.
Abstract 1287: The dual IAP antagonist, ASTX660, increases the anti-tumor activity of paclitaxel in preclinical models of triple-negative breast cancer in vivo
Authors: Tomoko Smyth, Yoko Nakatsuru, Ryoto Fujita, George Ward, Luke Bevan, Jon Lewis, Nicola Wallis, John Lyons
Journal: Cancer Research (2016)

Abstract Background: Paclitaxel-mediated secretion of inflammatory mediators, including TNFα, potentially creates paracrine and autocrine signaling loops that can reduce paclitaxel-induced apoptosis with resultant cancer cell survival (paclitaxel resistance). One mechanism of cancer cell survival is the expression of inhibitor of apoptosis proteins (IAPs): Cellular IAP (cIAP) is involved in inflammatory pro-survival NF-κB activation, blocking the activation of effector caspases 3 and 7, while X-linked IAP (XIAP) directly binds the effector caspases 3, 7 and 9, inhibiting the full activation of the apoptotic pathway. Antagonism of IAPs in the setting of paclitaxel treatment may enhance the cancer cell death by switching the chemotherapy-induced inflammatory TNFα signaling from pro-survival to apoptosis. ASTX660 is an orally bioavailable dual antagonist of cIAP and XIAP, currently being investigated in a single-agent Phase 1/2 clinical trial in patients with advanced solid tumors and lymphomas (NCT02503423). Here, we characterize the activity of ASTX660 in triple-negative breast cancer (TNBC) preclinical models as a single agent and in combination with paclitaxel. Results: We first investigated the viability of 21 TNBC cell lines treated with ASTX660 in vitro and found that 43% were sensitive either to ASTX660 alone (MDA-MB-231 and HCC38) or in the presence of exogenous TNFα (HCC1806, Hs578T, BT549, HCC1395, DU4475, MDA-MB-453 and mouse EMT6). In HCC1806 xenografts in mice, both ASTX660 (daily oral treatment) and paclitaxel (weekly intravenous treatment) as single agents caused moderate tumor growth inhibition but not regression. ASTX660 and paclitaxel combination treatment, however, caused regression and all tumors achieved a partial response by Day 19 of treatment. An increase in circulating acute-phase-proteins in animals was also observed on paclitaxel treatment. Conclusions: Our study suggests that paclitaxel treatment causes an inflammatory response which could qualitatively change the tumor environment. Inhibition of IAPs in such inflammatory environment induced by paclitaxel may lead to rapid apoptotic cell death. Thus, addition of IAP antagonist may be a promising approach to enhance the TNBC response to paclitaxel therapy. Citation Format: Tomoko Smyth, Yoko Nakatsuru, Ryoto Fujita, George Ward, Luke Bevan, Jon Lewis, Nicola Wallis, John Lyons. The dual IAP antagonist, ASTX660, increases the anti-tumor activity of paclitaxel in preclinical models of triple-negative breast cancer in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1287.
Abstract 2340: PD-1 blockade suppresses gastric cancer development by promoting antitumor immunity in mice
Authors: Woosook Kim, Yoku Hayakawa, James G. Fox, Timothy C. Wang
Journal: Cancer Research (2016)

Abstract Since advanced gastric cancer is difficult to cure with chemo and/or radiation therapy, new therapeutic approaches are clearly needed. Targeting immune checkpoints such as CTLA-4 and PD-1/PD-L1 has shown promising antitumor immunity in many malignancies by modulating T cell activity. PD-L1 and to a lesser extent of PD-L2 are expressed in human gastric cancer and expression of PD-L1 is associated with poor prognosis. Therefore, developing immunotherapies is an attractive strategy for the treatment of gastric cancer. We evaluated the efficacy of anti-PD-1 therapy in a mouse model of gastric cancer. Gastrin-deficient (GAS-KO) mice have been shown to develop large antral tumors with the combination of N-methyl-N-nitrosourea (MNU) and Helicobacter felis (H. felis) infection. Tumors developed in GAS-KO mice exhibited increased expression of PD-L1 and higher mutation rates than those in wild-type mice. To study the effect of anti-PD-1 antibody in tumor initiation or an early stage of progression, GAS-KO mice were induced with H.felis/MNU to develop tumors, one week later (10 weeks post-MNU) treated with anti-PD-1 antibody or isotype control (10 mg/kg IP qw) and sacrificed at 30 weeks post-MNU. We confirmed that GAS-KO mice treated with isotype control had moderate tumor burdens. Of interest, however, less and much smaller tumors were observed in mice treated with anti-PD-1. To compare immune cell populations in spleen tissue and peripheral blood from each group of mice, flow cytometric analysis was performed. Anti-PD-1-treated mice showed an increase in T cells including cytotoxic CD8+ T cells and a decrease in regulatory T cells and myeloid-derived suppressor cell (MDSC) populations compared with controls. In accordance with this, CD3-positive T lymphocytes were more frequently found in gastric tumors of anti-PD-1-treated mice than controls. Furthermore, qRT-PCR analysis revealed differential cytokine gene expression profiles including Il6, Il1b, and Il23 following anti-PD-1 treatment. Together, these data implicate that PD-1 blockade promotes immune infiltrates and therefore potentiates antitumor immune responses, suggesting targeting PD-1 as a potential new anticancer strategy in gastric cancer. Understanding anti-PD-1 therapy at the cellular and molecular level could provide new strategies for developing highly efficacious combination therapies. Citation Format: Woosook Kim, Yoku Hayakawa, James G. Fox, Timothy C. Wang. PD-1 blockade suppresses gastric cancer development by promoting antitumor immunity in mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2340.
Abstract 1108: MicroRNA-211 enhances the oncogenicity of oral carcinoma through targeting TCF12 and up-regulating FAM213A expression
Authors: Yi-Fen Chen, Kuo-Wei Chang, Shu-Chun Lin
Journal: Cancer Research (2016)

Abstract To address the oncogenic roles of miR-211, we generated K14-EGFP-miR-211 transgenic mouse lines. Upon the 4-nitroquinoline 1-oxide (4NQO) induction, the transgenic mice exhibited more extensive and severe tumorigenesis in tongue compared to the controls. 4NQO up-regulated miR-211 expression in oral squamous cell carcinoma (OSCC) cells. miR-211 directly targeted transcription factor 12 (TCF12), which mediated suppressor activities and was drastically down-regulated in OSCC tumors. GeneChip analysis, bioinformatic algorithm, reporter assay and ChIP assay pinpointed that Family with Sequence Similarity 213, Member A (FAM213A), an anti-oxidative molecule, was transcriptionally repressed by TCF12. Knockdown of FAM213A decreased oncogenic activity and ALDH1-positive cell population, and increased oxygen stress in OSCC cells. The expression of TCF12 and FAM213A was inversely correlated in head and neck carcinoma samples according to The Cancer Genome Atlas. OSCC patients carrying tumors with high FAM213A expression tended to have worse survival. Furthermore, 4NQO treatment down-regulated TCF12 and up-regulated FAM213A through modulating miR-211. The transgenic mouse model recaptures the molecular and histopathological changes as seen in human OSCC pathogenesis. This study highlights that miR-211 responds to oncogenic stimuli to promote the neoplastic process of OSCC by targeting TCF12 and up-regulating FAM213A. Citation Format: Yi-Fen Chen, Kuo-Wei Chang, Shu-Chun Lin. MicroRNA-211 enhances the oncogenicity of oral carcinoma through targeting TCF12 and up-regulating FAM213A expression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1108.
Abstract 5136: HER2 or EGFR inhibition interacts with tumor microenvironment by downregulation of PD-L1 and chemokines
Authors: Jin Won Kim, Ji Hea Sung, Mi Hyun Kang, Ji-Won Kim, Se-Hyun Kim, Keun-Wook Lee, Hye Seung Lee, Jee Hyun Kim
Journal: Cancer Research (2016)

Abstract Background: Agents targeting HER2 or EGFR have been applied in several cancer types. Tumor microenvironment including tumor-infiltrating lymphocytes could be a predictive marker in HER2- or EGFR- targeted therapy, although there are some controversies. However, the effects of HER2 and EGFR inhibition on tumor microenvironment are unclear. Method: We screened HER2, EGFR, and PD-L1 expression in gastric cancer cell lines by western blot (SNU216, SNU668, SNU719, AGS, N87, YCC3, and YCC10). HER2 and EGFR was inhibited by using dual inhibitor (afatinib, lapatinib). After HER2 and EGFR inhibition, the change of PD-L1 expression was evaluated in HER2 overexpressed cell lines (SNU216, N87, SKBR3) at western blot, FACS, PCR, and qPCR. Selective blockade for down-steam molecules of HER2 and EGFR was conducted by using pictilisib (PI3K inhibitor) and trametinib (MEK inhibitor). The change of chemokines such as CXCL1, CCL2, and CCL21 was evaluated after HER2 and EGFR inhibition by PCR. In clinical data, PD-L1 expression and HER2 expression in resected gastric cancer were also evaluated by immunohistochemistry analysis. Results: EGFR-overexpressed or HER2-overexpressed gastric cancer cell lines (SNU216, SNU668, N87) showed higher protein expression of PD-L1. PD-L1 expression decreased with dose-dependent manner in afatinib- or lapatinib- treated cell lines (SNU216, N87, SKBR3). In pictilisib-treated cell lines, PD-L1 was also down-regulated. However, trametinib-treated cell lines did not show down-regulation of PD-L1. After lapatinib treatment in HER2 overexpressed cell lines, CXCL1, CCL21, and CCL2 decreased with dose-dependent manner. In 289 patients with resected gastric cancer, there was a significant association between HER2 and PD-L1 expression (p = 0.03). Conclusions: PD-L1 is associated with HER2 and EGFR expression. PD-L1 is regulated by inhibition of PI3K pathway. Therefore, HER2 or EGFR inhibition could interact with tumor microenvironment by down-regulation of expression of PD-L1 and chemokines. Citation Format: Jin Won Kim, Ji Hea Sung, Mi Hyun Kang, Ji-Won Kim, Se-Hyun Kim, Keun-Wook Lee, Hye Seung Lee, Jee Hyun Kim. HER2 or EGFR inhibition interacts with tumor microenvironment by downregulation of PD-L1 and chemokines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5136.
Abstract 5165: ADAM17: a common effector for RAS and MET-driven transformation of primary keratinocytes
Authors: Christophe Cataisson, Mary Klosterman, Kelly Shibuya, Glenn Merlino, Stuart H. Yuspa
Journal: Cancer Research (2016)

Abstract The purpose of the current study is to determine the contribution of the metalloproteinase ADAM17 (a disintegrin and metalloprotease 17) to the transformation driven by activated MET or oncogenic RAS in primary keratinocytes. Transgenic keratinocytes overexpressing HGF (MT-HGF) to activate MET and keratinocytes transduced with an oncogenic RAS share identical phenotypic and biochemical features of transformation and produce squamous tumors in vivo. In both keratinocyte populations, these common features arise from autocrine activation of EGFR through elevated expression and release of EGFR ligands. Amphiregulin (AREG) blockade in MT-HGF keratinocytes decreases MET-mediated EGFR transactivation. Inhibition of EGFR ablates the initiated signature of MT-HGF keratinocytes in vitro and causes regression of tumors from MT-HGF keratinocytes tranplanted in vivo. Deletion or knock-down of ADAM17 decreases EGFR activation in both RAS and MT-HGF keratinocytes and reverses the transformation associated gene signature in RAS keratinocytes. Using AREG release as an indicator of ADAM17 activity, we determined that knock-down of either the SRC kinase or inactive Rhomboid 2 (iRhom2) reduces the ability of keratinocytes to release AREG upon HGF stimulation. Collectively our data suggest that MET-mediated transformation of keratinocytes occurs through EGFR transactivation and that ADAM17 is a necessary effector for RAS and MET-driven transformation. Citation Format: Christophe Cataisson, Mary Klosterman, Kelly Shibuya, Glenn Merlino, Stuart H. Yuspa. ADAM17: a common effector for RAS and MET-driven transformation of primary keratinocytes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5165.
Treatment of Hypertension in Patients With Coronary Artery Disease
Authors: Clive Rosendorff, Daniel T. Lackland, Matthew Allison, Wilbert S. Aronow, Henry R. Black, Roger S. Blumenthal, Christopher P. Cannon, James A. de Lemos, William J. Elliott, Laura Findeiss, Bernard J. Gersh, Joel M. Gore, Daniel Levy, Janet B. Long, Christopher M. O’Connor, Patrick T. O’Gara, Gbenga Ogedegbe, Suzanne Oparil, William B. White
Journal: Circulation (2015)
ZNStress: a high-throughput drug screening protocol for identification of compounds modulating neuronal stress in the transgenic mutant sod1G93R zebrafish model of amyotrophic lateral sclerosis
Authors: Alexander McGown, Dame Pamela J. Shaw, Tennore Ramesh
Journal: Molecular Neurodegeneration (2016)

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease with death on average within 2–3 years of symptom onset. Mutations in superoxide dismutase 1 (SOD1) have been identified to cause ALS. Riluzole, the only neuroprotective drug for ALS provides life extension of only 3 months on average. Thishighlights the need for compound screening in disease models to identify new neuroprotective therapies for this disease. Zebrafish is an emerging model system that is well suited for the study of diseasepathophysiology and also for high throughput (HT) drug screening. The mutant sod1 zebrafish model of ALS mimics the hallmark features of ALS. Using a fluorescence based readout of neuronal stress, we developed a high throughput (HT) screen to identify neuroprotective compounds. Here we show that the zebrafish screen is a robust system that can be used to rapidly screen thousands ofcompounds and also demonstrate that riluzole is capable of reducing neuronal stress in this model system. The screen shows optimal quality control, maintaining a high sensitivity and specificity withoutcompromising throughput. Most importantly, we demonstrate that many compounds previously failed in human clinical trials, showed no stress reducing activity in the zebrafish assay. We conclude that HT drug screening using a mutant sod1 zebrafish is a reliable model system which supplemented with secondary assays would be useful in identifying drugs with potential for neuroprotective efficacy in ALS.