tbuckley/cabot-search huggingface dataset:
Abstract 70: Oxidative stress and cell death in multidrug-resistant cancer
Authors: Baikuntha P. Aryal, Jean-Pierre Gillet, V Ashutosh Rao
Journal: Cancer Research (2019)

Abstract Reactive oxygen species (ROS) are constantly generated in mitochondria as a consequence of normal cellular metabolic reactions and play vital roles in cell signaling and homeostasis. Prolong production of elevated levels of ROS may lead to oxidative damage, genetic instability, and genetic mutation causing cancer initiation and progression. One proposed therapeutic strategy is to alter oxidative stress from a ROS-induced tumor promoting event to a ROS-induced apoptotic signaling to kill cancer cells. Most ROS inducing therapeutic agents initially induce ROS to kill cancer cells by apoptosis; however, prolonged exposure of such drugs may increase ROS scavenging enzymes resulting in a reduced ROS levels and an adaptive microenvironment that makes cancer cells resistant to the same ROS-inducing therapeutic agents. Chronic exposure of ROS may also upregulate the multidrug resistance associated protein expression in cancer cells. We hypothesize that induction of oxidative stress may sensitize drug resistant cancer cells leading to cell death. We used two pairs of cell lines, a mitoxantrone sensitive and mitoxantrone resistant MCF7 human breast adenocarcinoma (MCF7/MCF7MX) and a H460 non-small lung cancer cell line (H460/H460MX) for our experiments to study the impact of oxidative stress on drug resistance. We employed western blot, ELISA assays, and FACS analysis to determine the total and specific protein oxidative carbonylation, protein aggregation, and cell death by apoptosis or necrosis. At basal level, both mitoxantrone resistant MCF7MX and H460MX cells showed slightly lower level of total protein carbonylation compared to their mitoxantrone sensitive counterparts. Chemical induction of oxidative stress by external sources increased the total protein carbonylation and cell death in both mitoxantrone sensitive and resistance cancer cells. We also observed an increase in protein aggregation with increasing oxidative stress. Our results indicate that oxidative stress-induced protein oxidation by carbonylation and aggregation of oxidized protein which may sensitize drug resistant cancer cells leading to cell death. Citation Format: Baikuntha P. Aryal, Jean-Pierre Gillet, V Ashutosh Rao. Oxidative stress and cell death in multidrug-resistant cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 70.
Adjusting Dosage of Mercaptopurine By NUDT15 Polymorphisms in Childhood Acute Lymphoblastic Leukemia
Authors: Der-Shiun Wang, Chih-Hsiang Yu, Wen-Chien Chou, Ya-Hsuan Chang, Chien-Yu Lin, Kai-Hsin Lin, Shiann-Tarng Jou, Meng Yao Lu, Hsiu-Hao Chang, Shu-Wha Lin, Dong-Tsamn Lin, Hsuan-Yu Chen, Yung-Li Yang
Journal: Blood (2017)
CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC
Authors: Jeffrey H. Becker, Yandi Gao, Margaret Soucheray, Ines Pulido, Eiki Kikuchi, María L. Rodríguez, Rutu Gandhi, Aranzazu Lafuente-Sanchis, Miguel Aupí, Javier Alcácer Fernández-Coronado, Paloma Martín-Martorell, Antonio Cremades, José M. Galbis-Caravajal, Javier Alcácer, Camilla L. Christensen, Patricia Simms, Ashley Hess, Hajime Asahina, Michael P. Kahle, Fatima Al-Shahrour, Jeffrey A. Borgia, Agustín Lahoz, Amelia Insa, Oscar Juan, Pasi A. Jänne, Kwok-Kin Wong, Julian Carretero, Takeshi Shimamura
Journal: Cancer Research (2019)

Abstract Although EGFR mutant–selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK–ERK pathway via β-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition. CXCR7 overexpression was essential in reactivation of ERK1/2 for the generation of EGFR TKI–resistant persister cells. Many patients with non–small cell lung cancer (NSCLC) harboring an EGFR kinase domain mutation, who progressed on EGFR inhibitors, demonstrated increased CXCR7 expression. These data suggest that CXCR7 inhibition could considerably delay and prevent the emergence of acquired EGFR TKI resistance in EGFR-mutant NSCLC. Significance: Increased expression of the chemokine receptor CXCR7 constitutes a mechanism of resistance to EGFR TKI in patients with non–small cell lung cancer through reactivation of ERK signaling.
Abstract 3824: Increased production of endogenous hydrogen sulfide (H2S) induced resistance to 5-FU and Oxaliplatin in colon cancer cells
Authors: Shanwen Chen, Shuai Zuo
Journal: Cancer Research (2019)

Abstract The combination of 5-FU and Oxaliplatin has been widely adopted as one of the first line chemotherapeutic regimens for colon cancer patients. However, the development of chemoresistance can lead to early recurrence and metastasis to distant organs, thus remaining a leading cause of death from colon cancer. In the present study, the increased production of hydrogen sulfide (H2S) in colon cancer tissues was validated and the effect of inhibition of production of endogenous H2S on the responses of colon cancer cells to 5-FU and Oxaliplatin was further analyzed. The results suggested that inhibition of the enzymatic activity of cystathionine-β-synthase (CBS), a major producer of H2S in colon cancer cells, significantly decreased the IC50s of both 5-FU and Oxaliplatin. Inhibition of CBS leads to decreased PI3K-Akt signaling and consequently decreased expression of thymidylate synthetase (TYMS), which is the target of 5-FU. Inhibition of CBS utilizing aminooxyacetic acid (AOAA) leads to increased production of reactive oxygen species (ROS) and exaggerated mitochondrial damages in colon cancer cells. Analysis performed on CompuSyn confirmed the synergetic effect of AOAA with both 5-FU and Oxaliplatin. In vivo imaging of tumorigenesis in nude mice further confirmed the effect of inhibition of CBS on the therapeutic effect of both 5-FU and Oxaliplatin. Together, these results suggested that inhibition of production of endogenous H2S might be a promising target for chemoresistance in colon cancer. Citation Format: Shanwen Chen, Shuai Zuo. Increased production of endogenous hydrogen sulfide (H2S) induced resistance to 5-FU and Oxaliplatin in colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3824.
Abstract CT047: Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous Pembrolizumab in high grade nonmuscle invasive bladder cancer
Authors: Shaheen Alanee, Ahmed El Zawahry, Sherjeel Sana, Kevin McVary, Kathy Robinson, Krishna A. Rao
Journal: Cancer Research (2019)

Abstract PURPOSE: A phase I trial of intravesical bacillus Calmette-Guérin (BCG) in combination with systemic pembrolizumab was conducted in patients with high grade non-muscle invasive bladder cancer who had persistent or recurrent disease after failing treatment with at least 2 courses of intravesical therapy (one of which had to contain BCG) or BCG followed by maintenance BCG. The primary objective was to determine the safety of this combination. Secondary end points included response to treatment at 19 weeks (end of treatment) and 3 months post treatment. MATERIALS AND METHODS: A total of 9 patients with recurrent/persistent high-grade non-muscle invasive bladder cancer after at least two courses of intravesical therapy or one course of BCG treatment followed by one course of maintenance BCG were enrolled in the study. Six doses of pembrolizumab were given every 3 weeks over 16 weeks given concurrently with 6 weekly doses of BCG beginning at week 7. Patient safety was evaluated during and for 30 days following pembrolizumab treatment. Preliminary combination efficacy was determined at 19 weeks using cystoscopy. Bladder biopsy was performed in patients with suspicious lesions. RESULTS: The combination of BCG and pembrolizumab was well tolerated at both 100mg and 200mg fixed doses. Fatigue and cystitis-type symptoms (burning, spasm, urgency, sensitivity, and frequency) were the most common adverse events and all cases were either grade 1 or 2. Two patients died during the trial period. One patient died due to progression of low grade upper urinary tract transitional cell carcinoma. The other patient died after cystectomy (for progressive disease) due to causes unrelated to the trial treatment. Of the 9 patients treated, 6 (78%) had no evidence of disease in the bladder and 1 had a mixed response (progression in the upper urinary tract only) at 19 weeks (end of treatment) while 5 (56%) remained disease-free at the 3 month follow up. CONCLUSIONS: The combination of BCG and pembrolizumab was well tolerated with subjects exhibiting the expected adverse effects associated with the use of both medications. Intravesical BCG and pembrolizumab may have clinical activity in non-muscle invasive bladder cancer recurring after repeated intravesical therapy. .A phase III trial is now open and enrolling in the United States and other countries (NCT03711032). Citation Format: Shaheen Alanee, Ahmed El Zawahry, Sherjeel Sana, Kevin McVary, Kathy Robinson, Krishna A. Rao. Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous Pembrolizumab in high grade nonmuscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT047.
The Delivery of a Wnt Pathway Inhibitor Toward CSCs Requires Stable Liposome Encapsulation and Delayed Drug Release in Tumor Tissues
Authors: Chong Li, Yaoyao Liang, Jing Cao, Ning Zhang, Xiaohui Wei, Meiqing Tu, Fengwei Xu, Yuhong Xu
Journal: Molecular Therapy (2019)

The Wnt signaling pathway is involved in tumorigenesis and various stages of tumor progression, including the epithelial-mesenchymal transition, metastasis, and drug resistance. Many efforts have been made to develop drugs targeting this pathway. CGX1321 is a porcupine inhibitor that can effectively block Wnt ligand synthesis and is currently undergoing clinical trials. However, drugs targeting the Wnt pathway may frequently cause adverse events in normal tissues, such as the intestine and skin. Formulation of the drug inside liposomes could enable preferential drug delivery to solid tumor tissues and limit drug exposure in normal organs. We developed a strategy to stably encapsulate CGX1321 inside liposomes with minimal drug releases in circulation. The liposomal drugs were shown to interfere with the aberrant Wnt signaling specifically in tumor tissues, resulting in focused effects on LGR5+ CSCs (cancer stem cells), while sparing other cells from significant cytotoxicity. We showed it is feasible to use such a CSC elimination approach to treat malignant cancers prone to rapid progression using a LoVo tumor model as well as a GA007 patient derived xenograft (PDX) model. Nano drug delivery systems may be required for precision medicine in cancer therapy. The Wnt signaling pathway is involved in tumorigenesis and various stages of tumor progression, including the epithelial-mesenchymal transition, metastasis, and drug resistance. Many efforts have been made to develop drugs targeting this pathway. CGX1321 is a porcupine inhibitor that can effectively block Wnt ligand synthesis and is currently undergoing clinical trials. However, drugs targeting the Wnt pathway may frequently cause adverse events in normal tissues, such as the intestine and skin. Formulation of the drug inside liposomes could enable preferential drug delivery to solid tumor tissues and limit drug exposure in normal organs. We developed a strategy to stably encapsulate CGX1321 inside liposomes with minimal drug releases in circulation. The liposomal drugs were shown to interfere with the aberrant Wnt signaling specifically in tumor tissues, resulting in focused effects on LGR5+ CSCs (cancer stem cells), while sparing other cells from significant cytotoxicity. We showed it is feasible to use such a CSC elimination approach to treat malignant cancers prone to rapid progression using a LoVo tumor model as well as a GA007 patient derived xenograft (PDX) model. Nano drug delivery systems may be required for precision medicine in cancer therapy.
Shock Team Approach in Refractory Cardiogenic Shock Requiring Short-Term Mechanical Circulatory Support
Authors: Iosif Taleb, Antigone G. Koliopoulou, Anwar Tandar, Stephen H. McKellar, Joseph E. Tonna, Jose Nativi-Nicolau, Miguel Alvarez Villela, Frederick Welt, Josef Stehlik, Edward M. Gilbert, Omar Wever-Pinzon, Jack H. Morshedzadeh, Elizabeth Dranow, Craig H. Selzman, James C. Fang, Stavros G. Drakos
Journal: Circulation (2019)
Abstract 348: ABI-009 (nab-Sirolimus) improves tumor accumulation and antitumor activity over oral mTOR inhibitors
Authors: Shihe Hou, Anita Schmid, Neil Desai
Journal: Cancer Research (2019)

Abstract Background: mTOR pathway has been implicated in cell survival and proliferation and is an attractive target for cancer therapy. ABI-009 (nab-sirolimus) is an injectable nanoparticle form of human albumin-bound sirolimus with a mean particle size of approximately 100 nm developed with a proprietary nanoparticle albumin-bound (nab®) technology. ABI-009 is currently in phase 1 and 2 clinical studies for the treatment of multiple cancer types, including bladder cancer, soft-tissue sarcomas, neuroendocrine tumors, colorectal cancer, glioblastoma, and various childhood cancers, and a registrational phase 2 study for malignant perivascular epithelioid cell carcinoma (PEComa). In nonclinical and clinical studies, ABI-009 demonstrated a PK profile distinct from oral mTOR inhibitors. This study compared the antitumor activity, tissue penetration, and pharmacodynamics of ABI-009 with equal doses of oral mTOR inhibitors at clinically relevant doses in a mouse tumor xenograft model. Methods: Athymic mice bearing subcutaneous UMUC3 bladder cancer xenografts were treated with saline, ABI-009 (IV, 7.5 mg/kg, 2x/wk), sirolimus and everolimus (PO, 3 mg/kg/day, 5 days/wk). Body weights, tumor measurements, and clinical signs were recorded 3x/wk for up to 5 wks. Tumor and blood sirolimus concentrations were also obtained (tumor: D1 1h and 24h, D4 1h, D7; blood: D4 1h, D7). Markers for mTOR pathway activation (pS6, p4EBP1) will also be analyzed. Results: Overall, all treatments were well tolerated with no significant body weight loss in any group. ABI-009 IV resulted in significantly higher sirolimus concentrations in the tumor compared with oral mTOR inhibitors at all time points tested. Tumor AUC with ABI-009 IV over 1 week were significantly higher vs equal weekly dose of oral sirolimus (43 fold) and everolimus (12 fold) (p &amp;lt; 0.0001). The enhanced tumor drug delivery by ABI-009 corresponded with significantly greater tumor growth inhibition (TGI: ABI-009 69.6% vs oral sirolimus 24.3%, p &amp;lt; 0.00001; vs oral everolimus 36.2%, p = 0.0023) and longer animal survival (median OS: ABI-009 not reached vs oral sirolimus 21 days, p &amp;lt; 0.05; vs oral everolimus 19 days, p &amp;lt; 0.05). mTOR pathway inhibition in tissues is being assessed. Conclusions: Compared with equal weekly dose of oral mTOR inhibitors, ABI-009 at clinically relevant dose of administered IV demonstrated significantly greater tumor drug delivery, stronger antitumor activity, and prolonged animal survival. These advantages observed in this nonclinical study support the clinical investigation of ABI-009 in numerous oncology indications. Citation Format: Shihe Hou, Anita Schmid, Neil Desai. ABI-009 (nab-Sirolimus) improves tumor accumulation and antitumor activity over oral mTOR inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 348.
Abstract 3581: LncRNA THAP9-AS1 promotes pancreatic cancer growth via sponging miR-484 and interacting with YAP to enhance YAP activity
Authors: Nan Li, Guohua Yang, Zhimin He, Wanqing Liu, Haiying Liu, Guopei Zheng
Journal: Cancer Research (2019)

Abstract This study was supported by grants from the National Natural Science Foundation of China (No. 81872197, 81672616, 81401989 and 81602016); Guangdong Natural Science Funds for Distinguished Young Scholars (No.2016A030306003); Guangdong Special Support Program (No.2017TQ04R809); Science and Technology Program of Guangzhou (No.201710010100 and 201804010001). Abnormal expression of long non-coding RNAs (lncRNAs) has been observed in various cancer types, providing probability to exploit new diagnostic markers, prognostic factors and therapeutic targets in cancer treatment. Our analysis showed lncRNA THAP9-AS1 was highly overexpressed in pancreatic cancer. Here, we aimed to investigate the roles and mechanisms of THAP9-AS1 in pancreatic cancer. We confirmed the overexpression of lncRNA THAP9-AS1 in pancreatic cancer and validated the no protein-coding potential. THAP9-AS1 promotes pancreatic cancer cells growth in vitro and in vivo. Mechanically, THAP9-AS1 exerts its effects via enhancing YAP signaling. Ectopic YAP expression disrupts the effects of THAP9-AS1 knockdown. Inversely, YAP knockdown overcomes the effects of THAP9-AS1 overexpression. THAP9-AS1acts as a competing endogenous RNA for miR-484, leading to YAP upregulation. Moreover, THAP9-AS1 binds YAP protein and inhibits the phosphorylation mediated inactivation of YAP by LATS1. Reciprocally, YAP/TEAD1 complex promotes THAP9-AS1 transcription to form a feed-forward circuit. Importantly, THAP9-AS1 level positively correlates with YAP expression in pancreatic cancer tissues. THAP9-AS1 and YAP overexpression predicts a poor outcome of pancreatic cancer patients. Our findings indicate that THAP9-AS1 plays an important role in pancreatic cancer growth via enhancing YAP signaling at two aspects. THAP9-AS1/YAP axis may serve as a potential biomarker and therapeutic target for pancreatic cancer treatment. Note: This abstract was not presented at the meeting. Citation Format: Nan Li, Guohua Yang, Zhimin He, Wanqing Liu, Haiying Liu, Guopei Zheng. LncRNA THAP9-AS1 promotes pancreatic cancer growth via sponging miR-484 and interacting with YAP to enhance YAP activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3581.
Abstract 15885: A Novel Pore Region CACNA1C Missense Mutation Identified in a Patient With Ventricular Tachyarrhythmia Results in L-type Calcium Channel Selectivity Alteration
Authors: Dan Ye, David J Tester, Wei Zhou, Michael J Ackerman
Journal: Circulation (2017)

Introduction: Mutations in the CACNA1C-encoded L-type calcium channel (LTCC) have been associated with heritable arrhythmia syndromes, including Timothy syndrome, Brugada syndrome, early repolariza...
Abstract 13679: Excess Cardiovascular Risk in Women Relative to Men Referred for Coronary Angiography is Associated With Impaired Coronary Flow Reserve From Diffuse versus Obstructive Coronary Artery Disease
Authors: Viviany R Taqueti, Leslee J Shaw, Venkatesh L Murthy, Nishant R Shah, Courtney R Foster, Jon Hainer, Ron Blankstein, Sharmila Dorbala, Marcelo F Di Carli
Journal: Circulation (2015)

Introduction: Case fatality rates for cardiovascular disease (CVD) are higher for women of all ages as compared with men, yet obstructive coronary artery disease (CAD) is less prevalent in women. Coronary flow reserve (CFR) is an integrated measure of large and small vessel CAD and myocardial ischemia, and identifies patients at risk for CVD death, independently of angiographic disease severity. Methods: Consecutive patients (N=329, 43% women) referred for invasive coronary angiography after stress testing with myocardial perfusion PET and with LV ejection fraction &gt;40% were followed (median 3.0 years) for CVD death, nonfatal MI, or heart failure admission. The extent/severity of angiographic CAD was estimated using the CAD prognostic index (CADPI), and CFR quantified using PET. Results: Although women relative to men had lower pretest clinical scores, rates of prior MI, and burden of angiographic CAD (p&lt;0.001), they demonstrated greater risk of CVD events (adjusted HR 2.05, 95%CI 1.05-4.02, p=0.03), even after adjustment for clinical risk factors, LV ejection fraction and ischemia, angiographic disease and time-dependent early revascularization. Impaired CFR was similarly present among women and men, but in patients with low CFR (&lt;1.6, n=163), women showed higher frequency of nonobstructive CAD, while men showed higher frequency of severely obstructive CAD (p=0.002). After also adjusting for CFR (adjusted HR for unit decrease in CFR, 1.69; 95%CI 1.04-2.76, p=0.03), the effect of sex on outcomes was no longer significant (p=0.10). When stratified by sex and CFR (Figure), only women with impaired CFR demonstrated significantly increased adjusted risk of CVD events (p&lt;0.0001, model p for interaction=0.04). Conclusions: Although women referred for coronary angiography had significantly lower burden of obstructive epicardial CAD relative to men, they were not protected from CVD events. Impaired CFR from diffuse CAD may represent a target for CVD risk reduction.