tbuckley/cabot-search huggingface dataset:
Abstract 1092: PF562271, a Pyk2 inhibitor, reduces glioma tumor growth and invasion in C57Bl6-Gl261 mouse glioma model
Authors: Jescelica Ortiz-Rivera, Kimberleve Rolón-Reyes, Alejandro Albors, Luis Cubano, Lilia Kucheryavykh
Journal: Cancer Research (2017)

Abstract Glioblastoma is an extraordinarily aggressive type of brain cancer due to its invasive and proliferative nature. The tumor microenvironment, with microglia as a critical player, has an important role in tumor progression. Microglia infiltrate majority of gliomas and release factors, which favor tumor growth and invasion. Previously we demonstrated that microglia residing within the tumor stimulate glioma cell invasion through the proline rich tyrosine kinase 2 (Pyk2) signaling cascade. We hypothesize that the use of pharmacological inhibitors of Pyk2 together with currently applied chemotherapy can significantly reduce invasiveness of glioblastoma tumor and improve the outcome of the treatment. Using C57Bl/6-Gl261 mouse glioma implantation model we investigated the effect of the combined treatment for glioblastoma with temozolomide (TMZ, 50 mg/kg, once/day, orally) together with a Pyk2 inhibitor PF562271 (twice/daily, 25 mg/kg, orally) vs. TMZ monotherapy. Treatment was provided during 14 days, beginning the 5th day after glioma implantation. For the assessment of the effectiveness of treatment animals’ survival, tumor size, and invasion area were evaluated. Western blot were used for the evaluation of the level of Pyk2 phosphorylation in tumor cells. For the purification of glioma cells from total tumor tissue Percol gradients were used. The study revealed that treatment with PF562271 reduced invasion of glioma cells at the tumor edge, while TMZ reduced the tumor growth. Combined treatment showed significantly more prominent effect on reduction of tumors growth compared to TMZ monotherapy and additionally reduced invasiveness of tumors similar to PF562271 monotherapy. In both PF562271 monotherapy and combined treatments the downregulation of Pyk2 phosphorylation in glioma cells has been recorded. Survival analysis demonstrated a significance increase of survival of animals received combined treatment compare to TMZ monotherapy. In conclusion, we can state that combined treatment with TMZ together with PF562271 reduced Pyk2-related tumor growth and invasiveness and increased animal survival. This research was made possible by NIH grant numbers: 1SC2GM102040, G12MD007583, R25GM110513, Puerto Rico Science, Technology, and Research Trust grant number 2016-00157, and US Department of Education Grant number P031S130068. Citation Format: Jescelica Ortiz-Rivera, Kimberleve Rolón-Reyes, Alejandro Albors, Luis Cubano, Lilia Kucheryavykh. PF562271, a Pyk2 inhibitor, reduces glioma tumor growth and invasion in C57Bl6-Gl261 mouse glioma 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 1092. doi:10.1158/1538-7445.AM2017-1092
Abstract LB-155: Effects of alcohol consumption, cigarette smoking, betel quid chewing in upper digestive disease: A large cross-sectional study in Taiwan and meta-analysis
Authors: Yun-Shiuan Chuang, Meng-Chieh Wu, Pi-i Lin, Fang-Run Yu, Yao-Kuang Wang, Deng-Chyang Wu, I-Chen Wu, Ming-Tsang Wu
Journal: Cancer Research (2017)

Abstract Alcohol drinking and cigarette smoking are well-known risk factors of upper digestive diseases, especially esophageal cancer. In Taiwan, betel quid chewing is another common risk factor. This study investigated the association between use of these three substances and upper digestive diseases. We collected data from 9,275 patients (&amp;gt;20 years) receiving esophagogastroduodenoscopy at four hospitals starting in 2008. Multiple imputation was used to handle missing questionnaire data and polynomial regressions were used to analyze the association between risk factors and clinical stage in the esophagus, stomach and duodenum. A random effects model was used to perform a meta-analysis and arrive at overall odds ratio and 95% confidence intervals. Participants who habitually smoked cigarettes, drank alcohol and chewed betel areca simultaneously had a 16.32-fold risk of esophageal cancer (95% CI =7.13-37.36), 2.93-fold risk of Barrette’s esophagus (95% CI =1.99-4.30), 1.59-fold risk of grade A-B erosive esophagitis (95% CI = 1.27-1.98), 1.97-fold risk of gastric ulcer (95% CI =1.50-2.59), 2.10-fold risk of duodenitis (95% CI =1.54-2.87) and 1.27-fold risk of duodenal ulcer (95% CI =1.00-2.69). Using more substances concurrently was associated with a significant trend at higher risk to develop those diseases. Meta-analysis also revealed the use of three substances came with a high risk of esophageal diseases. Our data concluded that cigarette smoking, alcohol drinking and betel quid chewing were associated with upper digestive tract disease. People who habitually used all three substances in Taiwan were at significantly higher risk of developing Barrette’s esophagus and esophageal cancer. This extremely high elevated risk of esophageal cancer alarms the clinical community and proper public health measures must be implemented in the clinical setting when identifying patients with exposure to the three risk factors. Citation Format: Yun-Shiuan Chuang, Meng-Chieh Wu, Pi-i Lin, Fang-Run Yu, Yao-Kuang Wang, Deng-Chyang Wu, I-Chen Wu, Ming-Tsang Wu. Effects of alcohol consumption, cigarette smoking, betel quid chewing in upper digestive disease: A large cross-sectional study in Taiwan and meta-analysis [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-155. doi:10.1158/1538-7445.AM2017-LB-155
Abstract 3345: Selective killing of SMARCA2- and SMARCA4-deficient tumors by inhibition of EZH2: <i>In vitro</i> and <i>in vivo</i> preclinical models
Authors: Elayne Chan-Penebre, Kelli Armstrong, Allison Drew, Alexandra R. Grassian, Igor Feldman, Maria Roche, Peter Ho, Dorothy Brach, Alejandra Raimondi, Robert A. Copeland, Richard Chesworth, Jesse J. Smith, Scott A. Ribich
Journal: Cancer Research (2017)

Abstract The histone methyltransferase EZH2 is the enzymatic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the methylation of H3K27 thereby repressing target gene transcription. EZH2 is amplified, overexpressed, or mutated in multiple cancer types, most notably Follicular Lymphoma (FL) and germinal center Diffuse Large B-cell Lymphoma (GCB-DLBCL). We previously reported that preclinical models of malignant rhabdoid tumors, which are deficient in the SWI/SNF core component INI1 (SNF5, SMARCB1), are selectively killed by potent and selective inhibitors of EZH2. Here we report another class of SWI/SNF-altered cancers named small cell carcinoma of the ovary hypercalcemic type (SCCOHT) that is dependent on EZH2 activity. SCCOHT is a very aggressive form of cancer that responds poorly to conventional therapy with a one-year overall survival rate of only 50%. Very few novel agents have been approved for this indication; thus there is a need for targeted therapeutics in SCCOHT. SMARCA4 and SMARCA2 are co-inactivated in this tumor type that has many rhabdoid features. We demonstrate that tazemetostat, an EZH2 inhibitor currently in phase 2 clinical trials, induces potent and selective killing in SMARCA2 and SMARCA4-deficient ovarian cell lines. In addition to small molecule inhibitor data, we conducted functional genomics studies with CRISPR pooled screening, and confirmed that SCCOHT is also sensitive to CRISPR-mediated EZH2 gene ablation. Dose-dependent anti-tumor effects were observed upon tazemetostat treatment in SCCOHT xenografts deficient in both SMARCA2 and SMARCA4. We also report on additional non-ovarian tumor types with dual SMARCA2/SMARCA4 loss including NSCLC that exhibit EZH2 dependence representing additional potential therapeutic indications for tazemetostat treatment. Citation Format: Elayne Chan-Penebre, Kelli Armstrong, Allison Drew, Alexandra R. Grassian, Igor Feldman, Maria Roche, Peter Ho, Dorothy Brach, Alejandra Raimondi, Robert A. Copeland, Richard Chesworth, Jesse J. Smith, Scott A. Ribich. Selective killing of SMARCA2- and SMARCA4-deficient tumors by inhibition of EZH2: In vitro and in vivo preclinical models [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 3345. doi:10.1158/1538-7445.AM2017-3345
Abstract 053: Carbaprostacyclin Promotes Vascular Growth in Mouse Hindlimb Ischemia
Authors: Qi Liu, Toya Terry, Su Pan, Zhongwei Yang, James T Willerson, Richard A Dixon
Journal: Circulation Research (2013)

Background: Prostacyclin and its stable analogues are vascular protective agents that have been used clinically to reduce blood vessel constriction. Recent studies indicate they stimulate angiogenesis in response to tissue ischemia, but their role in arteriolar growth remains unclear. In the current study, we test the hypothesis that the prostacyclin stable analogue carbaprostacyclin (cPGI2) facilitates arteriolar growth in ischemic hindlimbs. Methods and Results: Catheters were attached to osmotic pumps in order to continuously deliver either cPGI2 or saline (control) locally into ischemic mouse hindlimbs for 7 and 14 days (n=5/group). At 7 days of cPGI2 delivery, live microscopic images showed more distinct structural remodeling at the arteriolar level in the cPGI2 group than in the saline group, including tortuosity of arteriolar-to-arteriolar connections and increased intersecting of adjacent arterioles. Vascular casting with a silicone radiopaque agent into the distal region of the infrarenal abdominal aorta revealed a more pronounced arterial anastomoses in the cPGI2 treated versus the saline treated ischemic legs. After immunofluorescence staining, laser scanning confocal microscopic analysis found more transmembrane proteoglycan NG2 positive vessels in cross sections of anterior thigh muscles in cPGI2-treated mice than in saline-treated mice. At 14 days, quantitative micro-computed tomography analysis indicated cPGI2-treated legs had markedly increased vascular volume (41.28 ± 2.22 vs 27.11 ± 2.85 mm3), significantly more blood vessels (0.16 ± 0.014 vs 0.09± 0.011 1/mm) and less distance between vessels (6.60 ± 0.52 vs 10.15 ±1.14 mm) than did saline-treated legs. To further verify the pro-arteriogenic effect of cPGI2, a quantitative histogram was generated and exhibited that cPGI2-treated ischemic legs have a significant increase in small vessels, with vessel diameter bins ranging from 40-60 microns. We similarly evaluated contralateral nonischemic legs and found no significant differences in vessel distribution in the cPGI2 and saline groups. Conclusion: Multi-imaging technical analyses indicated that local delivery of carbaprostacylin promotes arteriolar growth in mouse hindlimb ischemia.
Abstract 4901: Urokinase-derived peptide UP-7 effectively inhibits metastatic growth of breast cancer through suppression of FAK activation
Authors: Young Ae Joe, Hyun-Kyung Kim, Purevjargal Naidansuren, Seung Woo Lee, Rae-Kwon Kim, Su-Jae Lee, Suk Keun Lee, Yong-Kil Hong
Journal: Cancer Research (2017)

Abstract The recombinant kringle domain of urokinase-type plasminogen activator (UK1) has been shown to inhibit angiogenesis in vitro and in vivo and suppress brain tumor in vivo. To avoid limitations in application due to mass production of recombinant proteins, we dissected UK1 sequences to seven peptides based on structure and amino acid characteristics, and examined the anti-angiogenic activities for the constructed peptides. UP-7 peptide derived from ß-sheets region of UK1 was the most potent inhibitor of the proliferation and migration of endothelial cells (ECs) in vitro, and it also inhibited in vivo angiogenesis in the mouse matrigel plug assay. Such anti-angiogenic activities were not exerted by the scrambled peptide. At molecular level, UP-7 inhibited the VEGF or bFGF-induced phosphorylation of FAK and ERK1/2 and suppressed formation of stress fibers and focal adhesions. It also inhibited the attachment and spreading of ECs onto immobilized fibronectin. In a lung cancer animal model xenografted with UP-7-non-sensitive NCI H460, systemic treatment of UP-7 effectively suppressed tumor growth through inhibition of angiogenesis. Interestingly, breast cancer cells such as MDA-MB231 were sensitive to UP-7 in proliferation differently from other cancer cells. It inhibited the migration and invasion of LM-2-MDA-MD231 and suppressed the phosphorylation of FAK. Accordingly, UP-7 potently inhibited lung metastatic growth of LM2-MDA-MB-231 in experimental metastasis model. Taken together, these results suggest that novel UK1-derived peptide, UP-7 can be effectively used for treatment of the metastatic growth of breast cancer. (NRF-2012R1A1A2007175, NRF-2012R1A5A2051476) Citation Format: Young Ae Joe, Hyun-Kyung Kim, Purevjargal Naidansuren, Seung Woo Lee, Rae-Kwon Kim, Su-Jae Lee, Suk Keun Lee, Yong-Kil Hong. Urokinase-derived peptide UP-7 effectively inhibits metastatic growth of breast cancer through suppression of FAK activation [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 4901. doi:10.1158/1538-7445.AM2017-4901
Abstract 5518: Rgs8 and Rgs16 are tumor suppressor genes in mouse pancreatic ductal adenocarcinoma
Authors: Shreoshi Pal Choudhuri, Yalda Zolghadri, Luke Mascarenhas, Ozhan Ocal, Thomas Wilkie
Journal: Cancer Research (2017)

Abstract We have identified regulators of G protein signaling (Rgs8 and Rgs16) as a new class of tumor suppressor genes in a mouse model of pancreatic ductal adenocarcinoma (PDA). PDA is the 3rd leading cause of cancer related deaths in the United States. Kras mutations (e.g. KrasG12D) are associated with over 90% of human PDA and are an early event in the multistep process leading to PDA. Kras can be activated by protein kinase and G-Protein Coupled Receptor (GPCR) signaling. Rgs proteins regulate GPCR signaling by accelerating the GTPase activity of Gq- and Gi class alpha subunits. Activating alleles of Gq that are resistant to Rgs inhibition are associated with PDA in humans. We found Rgs8 and Rgs16 are in vivo reporters of Kras activity in pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and PDA progression (DMM 8, 2015). Rgs8 and Rgs16 are expressed in PanIN and IPMN, precursors of PDA, in KC mice (LSL-KrasG12D; p48::Cre). To test if Rgs8-16 function as tumor suppressor genes, we crossed the Rgs8-16 double knockout into KC (termed KCR8-16) mice. Compared to KC, PDA initiates earlier, is more aggressive, and KCR8-16 mice die earlier. Our study suggests that Rgs8 and Rgs16 control Kras-dependent PDA initiation and progression. Note: This abstract was not presented at the meeting. Citation Format: Shreoshi Pal Choudhuri, Yalda Zolghadri, Luke Mascarenhas, Ozhan Ocal, Thomas Wilkie. Rgs8 and Rgs16 are tumor suppressor genes in mouse pancreatic ductal adenocarcinoma [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 5518. doi:10.1158/1538-7445.AM2017-5518
Abstract 2860: 89Zr-trastuzumab immunoPET imaging to monitor src status after treatment in HER2 breast cancer
Authors: Brooke N. McKnight, Nerissa T. Viola-Villegas
Journal: Cancer Research (2017)

Abstract Around 30% of patients with early stage breast cancer have recurrent disease due to resistance. One of the putative causes of acquired resistance can be attributed to the hyperactivation of Src kinases, which are particularly stabilized by aberrant HER2 signaling, which itself is overexpressed in nearly 30% of early stage breast cancers. HER2 downstream effectors include Src, thus, we aim to investigate the use of a HER2-specific monoclonal antibody positron emission tomography (PET) probe, 89Zr-trastuzumab, to monitor Src therapy via surrogate HER2 expression. We hypothesize that 89Zr-trastuzumab can be a surrogate imaging tool for monitoring Src treatment. 89Zr-trastuzumab was previously developed and has demonstrated excellent specificity for breast cancer. Dasatinib-treated HER2+ BT474 (IC50 ~ 1.3 μM), SK-BR-3 (IC50 ~ 5.5 µM), and JIMT-1 (IC50 ~ 8 μM) breast cancer cells lines have shown a negative correlation between treatment and HER2. We next conducted tumorigenic studies using athymic nu/nu mice bearing JIMT-1 or BT474 xenografts, which were treated for 7 or 14 days with dasatinib (75 mg/kg/day). At the end of each treatment, the tumors were subsequently imaged with 18F-FDG, and then followed by 89Zr-trastuzumab, 24 h later. Images were analyzed using AsiPro (show version here and decay-corrected to the time of injection. Tumor uptake values were measured by drawing volumes-of-interest, expressed as % injected dose per gram (%ID/g) of tissue on regions showing the most binding. 18F-FDG did not demonstrate a predictive response in both treated and placebo tumors, whereas, HER2 PET was able to show differential response in treated vs. control cohorts. In JIMT-1 mice imaged with 89Zr-trastuzumab, a two-fold difference (p &amp;lt; 0.01) was observed between untreated and both treated groups (8.0 ± 1.5 %ID/g, n= 7 vs. 7-day treated: 3.8 ± 1.5 %ID/g, n=4, and 14-day-treated: 4.5 ± 1.3 %ID/g, n= 4) mice imaged with 89Zr-trastuzumab. Confirmatory ex vivo western blots of JIMT-1 tumors have shown a decrease in HER2 as treatment time increases, with a decrease in p-Src (Y-416). In vivo studies with BT-474 xenografts are currently underway. Immunohistochemistry on excised tumors, as well as treatment on a metastatic patient-derived xenograft model is currently in progress. We have shown that HER2 PET can potentially be a surrogate marker of Src treatment. The findings from this study potentially afford a powerful tool to non-invasively detect and monitor changes in Src-targeted therapy in man at the early phases of treatment. Citation Format: Brooke N. McKnight, Nerissa T. Viola-Villegas. 89Zr-trastuzumab immunoPET imaging to monitor src status after treatment in HER2 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 2860. doi:10.1158/1538-7445.AM2017-2860
Abstract 5874: Cdk4/6 kinase inhibitor resistance in prostate cancer
Authors: Renee de Leeuw, Matthew J. Schiewer, Christopher McNair, Michael A. Augello, Akihiro Yoshida, Edward S. Hazard, Sean Courtney, Gerard T. Hardiman, Justin Drake, Felix Y. Feng, Scott Tomlins, Maha H. Hussain, J Alan Diehl, William K. Kelly, Karen E. Knudsen
Journal: Cancer Research (2017)

Abstract Non-organ confined prostate cancer (PCa) is often effectively, but only transiently treated by targeting the androgen receptor (AR) signaling axis through androgen depletion strategies, often coupled with AR antagonists. Unfortunately, disease recurs within a median of 3-4 years, presenting as castration resistant PCa (CRPC), for which there are limited therapeutic options. This emphasizes the need for more efficacious drugs and a patient-tailored approach towards cancer therapy to improve disease outcome. One class of drugs currently tested clinically, Cdk4/6 kinase inhibitors, blocks phosphorylation of the retinoblastoma (RB) tumor suppressor, thereby boosting its function, and likely preventing castration resistance. As Cdk4/6 inhibitor resistance has already been reported in other cancers, some PCa patients are anticipated to develop drug resistance. Here, we created palbociclib-resistant PCa cell models by continuously culturing them in presence of the drug to unravel mechanisms of acquired resistance, and assessed them for cross-resistance to ribociclib and response to other therapeutics. While the parental PCa cell models, Cdk4/6 inhibitors efficiently induce a G1 cell cycle arrest, the resistant cell lines bypass this cell cycle checkpoint. Although loss of RB is a known mechanism for Cdk4/6i resistance, none of the models lost RB expression. Strikingly, these originally hormone-sensitive cell lines, upon developing Cdk4/6 inhibitor resistance display altered response to selected therapeutic regimens. Mechanisms of resistance, as informed by Whole Exome Sequencing and RNASeq, will be discussed. Citation Format: Renee de Leeuw, Matthew J. Schiewer, Christopher McNair, Michael A. Augello, Akihiro Yoshida, Edward S. Hazard, Sean Courtney, Gerard T. Hardiman, Justin Drake, Felix Y. Feng, Scott Tomlins, Maha H. Hussain, J Alan Diehl, William K. Kelly, Karen E. Knudsen. Cdk4/6 kinase inhibitor resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5874. doi:10.1158/1538-7445.AM2017-5874
Abstract 2998: Elotuzumab can costimulate NK cell responses by engaging SLAMF7
Authors: Tatiana Pazina, Ashley Mentlik James, Alexander W. MacFarlane, Natalie A. Bezman, Robert F. Graziano, Michael D. Robbins, Adam D. Cohen, Kerry S. Campbell
Journal: Cancer Research (2017)

Abstract Elotuzumab (Elo) is an IgG1 monoclonal antibody targeting SLAMF7 (CS1, CRACC, CD319) protein, which is highly and uniformly expressed on multiple myeloma cells. Improved survival has been observed in multiple myeloma patients treated with Elo in combination with immunomodulatory drugs such as dexamethasone and lenalidomide. Previous work showed that the main mechanism of Elo action in vitro is CD16-mediated antibody dependent cellular cytotoxicity (ADCC) via Fc interaction with CD16 (FcγRIIIa) receptor on NK cells. However, SLAMF7 is also expressed on NK cells where it transmits an activating signal. We hypothesized that Elo can directly activate NK cells via SLAMF7 ligation. Utilizing non-fucosylated Elo that has higher affinity to CD16 and Elo mutant that has an Fc region mutation that abrogates binding to CD16, we confirmed that Elo promotes NK cell activation and degranulation in a CD16-dependent manner. Specifically, non-fucosylated Elo had higher potency, whereas Elo mutant did not stimulate degranulation or CD69 expression. To test for co-stimulatory effects of Elo and Elo mutant we measured calcium signaling responses triggered by those antibodies in combination with antibodies to engage the activating receptors NKp46 and NKG2D. Elo or Elo mut alone had no effect on calcium signaling, but when added in combination with multimeric engagement of NKp46 and NKG2D both antibodies co-stimulated calcium signaling responses. We conclude that Elo stimulates NK cells via interaction with CD16, but direct engagement with SLAMF7 can also transduce co-activating signals to potentiate calcium signals generated through NKp46 and NKG2D in a CD16-independent manner. Our results provide evidence that direct engagement with SLAMF7 by Elo has the potential to reduce the threshold of NK cell activation triggered through other activating receptors. Citation Format: Tatiana Pazina, Ashley Mentlik James, Alexander W. MacFarlane, Natalie A. Bezman, Robert F. Graziano, Michael D. Robbins, Adam D. Cohen, Kerry S. Campbell. Elotuzumab can costimulate NK cell responses by engaging SLAMF7 [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 2998. doi:10.1158/1538-7445.AM2017-2998