tbuckley/cabot-search huggingface dataset:
Abstract 1319: Repotrectinib, a new generation ROS1 inhibitor, is highly potent against fusion ROS1s and emerging resistance mutations
Authors: Wei Deng, Dayong Zhai, Xin Zhang, Dong Lee, Evan Rogers, Jeffrey Whitten, J. Jean Cui
Journal: Cancer Research (2019)

Abstract Chromosome rearrangements of ROS1 have been identified as oncogenic drivers in many malignancies, especially non-small cell lung cancer (NSCLC). Crizotinib is the only approved treatment for ROS1+ NSCLC. The efficacy of crizotinib varies among different types of ROS1 fusion partners in patients with ROS1-rearranged NSCLC, and the most dominant fusion CD74-ROS1 was associated with a higher rate of brain metastases and shorter overall survival. Unfortunately, the emergence of drug resistance to crizotinib and other ROS1-targeted therapies represents a major obstacle. The most common resistance mutations to crizotinib in ROS1+ NSCLC are the solvent front mutation (SFM) ROS1 G2032R and gatekeeper mutation ROS1 L2026M. Repotrectinib was rationally designed to overcome resistance mutations. The activity of repotrectinib against multiple fusion ROS1s and corresponding resistance mutations is outlined in the Table. Repotrectinib potently inhibited both wildtype and mutated fusion ROS1s including SFMs and gatekeeper mutations. In cell growth assays using engineered Ba/F3 cells expressing ROS1 fusions with several different partners, such as SDC4, CD74, TPM3 and EZR, repotrectinib demonstrated superior potency in comparison to other ROS1 inhibitors against multiple ROS1 mutations, especially the solvent front and gatekeeper mutations. In xenograft tumor model studies, repotrectinib resulted in tumor regression in the tumors carrying WT or SFM ROS1 fusion genes. Overall, repotrectinib demonstrated a strong inhibition profile against WT and various mutated ROS1s across different fusion partners when compared to many other ROS1 TKIs. A Phase 1/2 clinical trial of repotrectinib is currently enrolling ROS1+ NSCLC patients (NCT03093116). Ba/F3 Cell Proliferation IC50 (nM)No Kinase Domain MutationROS1 G2032RROS1 L2026MInhibitorCD74-ROS1SDC4-ROS1EZR-ROS1TPM3-ROS1CD74-ROS1SDC4-ROS1EZR-ROS1TPM3-ROS1EZR-ROS1TPM3-ROS1Repotrectinib&amp;lt;0.20.2&amp;lt;0.1&amp;lt;0.13.33516.3&amp;lt;0.2&amp;lt;0.1Crizotinib14.619.619.431.1266.24661660500.695.6236.2Lorlatinib0.20.30.20.3160.7352.9190.5434.91.61.9Entrectinib10.5ND1.59.41813ND2947109313.340.7Ceritinib42.859.833.110513911883885.8543.712.666.5Brigatinib2138.725.86111721473360.6300024.441.3Cabozantinib0.530.44.511.3169.439.560.73.412.6Ensartinib39.5ND118.6433.1371.8ND17574814543.31463 Citation Format: Wei Deng, Dayong Zhai, Xin Zhang, Dong Lee, Evan Rogers, Jeffrey Whitten, J. Jean Cui. Repotrectinib, a new generation ROS1 inhibitor, is highly potent against fusion ROS1s and emerging resistance mutations [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 1319.
Implicit Bias in Surgery—Hiding in Plain Sight
Authors: Fahima Dossa, Nancy N. Baxter
Journal: JAMA Network Open (2019)

Arghavan Salles, MD, PhD; Michael Awad, MD, PhD; Laurel Goldin, MA; Kelsey Krus, BS; Jin Vivian Lee, BA; Maria T. Schwabe, MPHS; Calvin K. Lai, PhD
Abstract 2115: FOS contributes to 5-FU resistance and reversal effects of natural flavonoid GL-V9 in colon cancer
Authors: Li Zhao, Li Zhaohe, Ding Youxiang
Journal: Cancer Research (2019)

Abstract 5-FU is widely used in the treatment of colon cancers. Although 5-FU can improve response rates and survival, response rates for 5-FU-based chemotherapy as a first-line treatment for advanced colorectal cancer are only 10-15%. Meanwhile, cancer drug resistance often occurs, which is an important reason for poor treatment effect of 5-FU. Therefore, it is significant to uncover the mechanisms underlying 5-FU resistance and develop effective but nontoxic agent candidates for reversing cancer drug resistance. Here, we found that proto-oncogene FOS was activated in 5-FU-resistant colon cancer cells compared to parental cells. Additionally, FOS overexpression using lentivirus plasmid obviously triggered 5-FU resistance in colon cancer cells. Moreover, by analyzing two GEO datasets, we also found that FOS expression was associated with poor overall survival of colon cancer. Taken together, FOS confers 5-FU resistance to colon cancer and it is potential to be exploited as a therapeutical target. Lastly, we studied the reversal effects of natural flavonoid GL-V9 on the FOS activation and 5-FU resistance in order to develop candidates for FOS inhibitor which would be helpful for 5-FU-resistant colon cancer. Consequently, nontoxic doses of GL-V9 could significantly suppress activation of FOS and sensitize colon cancer cells to 5-FU. Therefore, the flavonoid is potential to be exploited as a synergetic agent for 5-FU-resistant colon cancer. Note: This abstract was not presented at the meeting. Citation Format: Li Zhao, Li Zhaohe, Ding Youxiang. FOS contributes to 5-FU resistance and reversal effects of natural flavonoid GL-V9 in colon 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 2115.
The medical necessity of advanced molecular testing in the diagnosis and treatment of brain tumor patients
Authors: Craig Horbinski, Keith L Ligon, Priscilla Brastianos, Jason T Huse, Monica Venere, Susan Chang, Jan Buckner, Timothy Cloughesy, Robert B Jenkins, Caterina Giannini, Roger Stupp, L Burt Nabors, Patrick Y Wen, Kenneth J Aldape, Rimas V Lukas, Evanthia Galanis, Charles G Eberhart, Daniel J Brat, Jann N Sarkaria
Journal: Neuro-Oncology (2019)

Abstract Accurate pathologic diagnoses and molecularly informed treatment decisions for a wide variety of cancers depend on robust clinical molecular testing that uses genomic, epigenomic, and transcriptomic-based tools. Nowhere is this more essential than in the workup of brain tumors, as emphasized by the incorporation of molecular criteria into the 2016 World Health Organization classification of central nervous system tumors and the updated official guidelines of the National Comprehensive Cancer Network. Despite the medical necessity of molecular testing in brain tumors, access to and utilization of molecular diagnostics is still highly variable across institutions, and a lack of reimbursement for such testing remains a significant obstacle. The objectives of this review are (i) to identify barriers to adoption of molecular testing in brain tumors, (ii) to describe the current molecular tools recommended for the clinical evaluation of brain tumors, and (iii) to summarize how molecular data are interpreted to guide clinical care, so as to improve understanding and justification for their coverage in the routine workup of adult and pediatric brain tumor cases.
Abstract 5172: Deposition of platelets in sinusoids and its contribution to hepatocarcinogenesis
Authors: Hiroki Tanaka, Kie Horioka, Masahiro Yamamoto, Koji Sawada, Takumu Hasebe, Kosuke Yamazaki, Katsuhiro Ogawa
Journal: Cancer Research (2019)

Abstract Platelets can activate hepatocyte proliferation not only via releasing the platelet factors, but also promoting for liver sinusoidal endothelial cells (LSEC) and Kupffer cells to produce the factors such as IL-6 and TGF-α that are indispensable for hepatocyte proliferation. We previously reported that in the transgenic (TG) mice with liver specific human BRAFV600E mutation, which corresponds to the mouse BrafV637E that is highly prevalent in mouse DEN-induced hepatic tumors, exhibit increased liver weight five times larger than that of normal mice. Furthermore, hepatocytes in these mice overexpress thrombopoietin (TPO) in association with megakaryocytosis/thrombocytosis, and large numbers of platelets were deposited in the liver sinusoids. In the present study, we investigated whether platelets are deposited in liver sinusoids in hepatic tumors in human and mice. CD61 immunohistochemical staining revealed the increased numbers of platelets were deposited in the sinusoids in foci, adenomas and hepatocellular carcinomas (HCC) induced by neonatal treatment with DEN compared to surrounding normal hepatic tissues. Moreover, increased numbers of platelets were deposited in sinusoids of dysplastic nodules and well-differentiated HCC compared to normal liver tissue and cirrhotic nodules in human. In addition, we evaluated the correlation between the tumor diameters and peripheral platelets numbers in the patients who were primarily diagnosed as HCC in our institute. The result indicated that the numbers of peripheral platelets are positively correlated with the tumor diameters. These results indicate that platelets contribute to development of HCC via interacting sinusoidal cells. Citation Format: Hiroki Tanaka, Kie Horioka, Masahiro Yamamoto, Koji Sawada, Takumu Hasebe, Kosuke Yamazaki, Katsuhiro Ogawa. Deposition of platelets in sinusoids and its contribution to hepatocarcinogenesis [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 5172.
Abstract 18990: Impact of Cavotricuspid Isthmus Dependent Right Atrial Flutter Ablation on the Incidence and Recurrence of Atrial Fibrillation
Authors: Madhu Reddy, Pramod Janga, Hema Pamulapati, Sudharani Bommana, Hallie Kretsinger, Chanakyaram Reddy, Brandon Barnds, Namratha Reddy, Donita Atkins, Dhanunjaya Lakkireddy
Journal: Circulation (2012)

Background: There is limited data evaluating the impact of cavotricuspid isthmus ablation for right Atrial Flutter (AFL) on the a) development of Atrial Fibrillation (AF) in those without AF and b) recurrence of AF in patients with previous AF. Methods: We studied all consecutive patients (with or without previous AF) undergoing cavotricuspid isthmus ablation for symptomatic drug resistant AFL in a large academic center. Results: 302 patients underwent AFL ablation between 2007 and 2011. Mean age was 65 yrs with 71% males. Mean left ventricular ejection fraction was 51±14%. Median duration since diagnosis of AFL was 2 months (IQ range 1-10) months. 136 (45%) patients had a history of AF (paroxysmal in 95%) and the remaining 166 (55%) patients did not have AF. Patients “with AF” were more likely to be females, have a previous stroke, had higher CHADS2 score, larger left atria and used more antiarrhythmics prior to ablation. 33 (25%) patients “with AF” had AF in the lab spontaneously, by programmed stimulation or with isoproterenol infusion when compared to 11(7%) patients “without AF”; p&lt;0.001. After a mean follow-up time of 24 months, 95 (31%) patients were on antiarrhythmics (46% vs 19% in patients with and without AF respectively). During follow up, 75 (55%) of the patients “with AF”, had a recurrence of AF and 36 (22%) patients “without AF” group developed AF; p&lt;0.001. The predictors of AF during follow up were female gender (p=0.03), number of antiarrhythmics used (p=0.009) and AF induction during the procedure (p&lt;0.001). AF induction during the procedure predicted AF recurrence in patients “with AF” (p=0.020) but not in patients “without AF” (p=0.243). Conclusions: At 2 years after AFL ablation a) 22% of the patients with isolated AFL develop AF and b) 45% of the patients with previous AF did not have AF recurrence. AF induction during the procedure predicts recurrence of AF after AFL ablation.
Abstract 12019: Inactivation of AMP-activated Protein Kinase Sensitizes Heart to Pressure Overload-induced Hypertrophy
Authors: Jinli Wang, Nanhu Quan, Lin Wang, Xu Chen, Dongyang Chu, Alireza Rezaie, Ji Li
Journal: Circulation (2016)

Introduction: Hypertrophy triggers activation of adenosine monophosphate-activated protein kinase (AMPK), an energy sensor in the heart. We have identified activated protein C (APC) is an endogenous AMPK agonist, and the non-anticoagulant APC-2Cys mutant but not the non-signaling APC-E170A mutant stimulates cardiac AMPK activation as well. Hypothesis: AMPK play a critical role in preventing heart from hypertrophy induced by pressure overload. APC as a AMPK agonist inhibits pressure overload-induced hypertrophy via APC’s cytoprotective signaling activity. Methods: Wild-type (WT) and AMPK-kinase dead (KD) transgenic mice were subjected to transverse aortic constriction (TAC) surgery. Echocardiography was performed to evaluate the heart function, and histology staining revealed the morphological changes. Real-time PCR and immunoblotting were used to detect mRNA and protein levels of signaling changes. Results: There is no phenotype difference between wild type (WT) and AMPK-kinase dead (AMPK KD) mice under normal physiological conditions. However after 4 weeks of TAC surgery, AMPK-KD mice demonstrated significantly bigger heart as compared to WT mice (p&lt;0.05). The cardiac functions measured by echocardiography in AMPK-KD hearts were significantly impaired as compared with WT hearts (p&lt;0.05). The immunohistochemical staining showed that the increased macrophage infiltration and reactive oxygen species (ROS) in AMPK-KD versus WT hearts after 4 weeks of TAC surgery. The immunoblotting results demonstrated that the redox status markers such as p66 shc , 4-hydroxynonenal and extracellular signal-regulated kinase (ERK) were up-regulated in the AMPK-KD hearts after 4 weeks of TAC surgery (all p&lt;0.05 versus WT hearts). APC and APC-2Cys but not APC-E170A administration significantly attenuated hypertrophy and fibrosis caused by pressure overload. The macrophage infiltration and p66 shc activation caused by pressure overload were also inhibited by APC and APC-2Cys but not by APC-E170A. Conclusions: Cardiac AMPK inactivation aggravates pressure overload induced hypertrophy. APC-2Cys without anticoagulant activity could be a therapeutic drug for treatment of hypertension-related hypertrophy patients without bleeding risk.
Abstract 891: Plumbagin and atovaquone inhibit Na+/K+-ATPase through the generation of oxidative stress
Authors: Yousef Alharbi, Arvinder Kapur, Mildred Felder, Lisa Barroilhet, Bikash Pattnaik, Manish S. Patankar
Journal: Cancer Research (2019)

Abstract Plumbagin and atovaquone are chemotoxic to ovarian, breast and other tumors. Both molecules inhibit oxidative phosphorylation causing a rapid increase in intracellular oxygen radicals and apoptosis. Oxidative stress is also known to inhibit the activity of Na+/K+-ATPase (NKA), the ion channel that maintains the membrane potential. Here, we investigate if the oxidative stress mediated by plumbagin and atovaquone also leads to inhibition of NKA activity. We confirm that plumbagin and atovaquone inhibit proliferation of three human (OVCAR-3, SKOV-3 and TYKNu) and one mouse (ID8) ovarian cancer cell lines. Using SKOV-3 and OVCAR-3 as models for ovarian cancer, we demonstrate that oxygen radical scavenger, N-acetylcysteine (NAC) attenuated the cytotoxicity of plumbagin and atovaquone. Using whole cell patch clamping we demonstrate that plumbagin and atovaquone inhibit outward and inward current flowing through NKA in SKOV-3 and OVCAR-3. Both drugs decrease cellular ATP. Providing exogenous ATP (5 mM) in the pipet solution used during patch clamping did not recover NKA activity in the plumbagin or atovaquone treated SKOV-3 and OVCAR-3 cells. However, pretreatment of the cells with NAC completely abrogated the NKA inhibitory activity of plumbagin and atovaquone. Exposure of the SKOV-3 cells to either of the drugs for 1-2 h resulted in a significant decrease in the expression of NKA. We conclude that oxidative stress caused by plumbagin and atovaquone degrades NKA and hence the membrane potential cannot be optimally maintained. Evaluation of compounds that induce oxidative stress should therefore consider contribution of NKA inhibition to the cytotoxic activity of such agents. Citation Format: Yousef Alharbi, Arvinder Kapur, Mildred Felder, Lisa Barroilhet, Bikash Pattnaik, Manish S. Patankar. Plumbagin and atovaquone inhibit Na+/K+-ATPase through the generation of oxidative stress [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 891.
Abstract LB-174: Genome-wide association meta-analysis identifies novel <i>GP2</i> gene risk variants for pancreatic cancer in the Japanese population
Authors: Yingsong Lin, Masahiro Nakatochi, Hidemi Ito, Yoichiro Kamatani, Hiromi Sakamoto, Hiroshi Ishii, Naoki Sasahira, Makoto Ueno, Naoto Egawa, Mitsuru Mori, Haruhisa Nakao, Yasushi Adachi, Kenji Wakai, Shoichiro Tsugane, Masayuki Yamamoto, Atsushi Shimizu, Takashi Kadowaki, Teruhiko Yoshida, Fumihiko Matsuda, Michiaki Kubo, Shogo Kikuchi, Keitaro Matsuo
Journal: Cancer Research (2019)

Abstract Pancreatic cancer is one of the most challenging malignancies because of its dismal prognosis, largely unknown etiology, and absence of early detection method. Here we report the results of a meta-analysis of three genome-wide association studies (GWAS) involving 2039 pancreatic cancer cases and 32592 control subjects, which represent the largest sample size in the Japanese population. To complement the SNP-based GWAS, we performed a gene-based GWAS using MAGMA. Given the pleiotropic effects observed for the top variants, we performed a Mendelian randomization (MR) analysis to address the possible causal relationship between type-2 diabetes (T2D) and pancreatic cancer risk, using 82 T2D-related SNPs and 25 hemoglobin A1c (HbA1c)-related SNPs as instrumental variables. We identified 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P&amp;lt;5.0×10-8), as well as 4 loci with suggestive evidence of association (P&amp;lt;1.0×10-6) for pancreatic cancer. Of the identified risk loci, 16p12.3 is novel; the lead SNP maps to rs78193826 (OR=1.46, 95%CI=1.29-1.66, P=4.28×10-9), an Asian-specific, non-synonymous variant of glycoprotein 2 (GP2) predicted to be highly deleterious. Additionally, gene-based GWAS identified a novel gene, KRT8, which is linked to exocrine pancreatic and liver diseases. The identified variants in the GP2 gene exhibited pleiotropic effects on multiple traits, including type 2 diabetes, Hemoglobin A1c (HbA1c) levels, and pancreatic cancer. MR analysis suggested that genetically increased HbA1c levels may be causally associated with increased pancreatic cancer risk. Further fine mapping and functional characterization are required to elucidate the effects of common GP2 gene variants on pancreatic cancer susceptibility. Moreover, our findings highlight genetic susceptibility factors shared between T2D and pancreatic cancer. Citation Format: Yingsong Lin, Masahiro Nakatochi, Hidemi Ito, Yoichiro Kamatani, Hiromi Sakamoto, Hiroshi Ishii, Naoki Sasahira, Makoto Ueno, Naoto Egawa, Mitsuru Mori, Haruhisa Nakao, Yasushi Adachi, Kenji Wakai, Shoichiro Tsugane, Masayuki Yamamoto, Atsushi Shimizu, Takashi Kadowaki, Teruhiko Yoshida, Fumihiko Matsuda, Michiaki Kubo, Shogo Kikuchi, Keitaro Matsuo. Genome-wide association meta-analysis identifies novel GP2 gene risk variants for pancreatic cancer in the Japanese population [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 LB-174.
Abstract 4452: GNE-0011, a novel monovalent BRD4 degrader
Authors: Robert A. Blake
Journal: Cancer Research (2019)

Abstract The bromodomain and extra-terminal (BET) family of proteins (BRD2, 3, 4 and T) has been the focus of an emerging paradigm in drug mechanism of action, whereby a drug is designed to trigger the proteolytic degradation of the target protein. The current design of protein degraders is typically based on bivalent molecules consisting of a ligand for the target protein and a ligand for a ubiquitin ligase (such as VHL, CRBN or XIAP). The degrader causes the association of the target protein with the E3 ubiquitin ligase and its subsequent ubiquitination and degradation. Due to their bivalent design such drugs typically have a higher molecular weight than classic small molecule drugs and may present some non-ideal properties as drugs. An alternative strategy for designing drugs that act through the degradation of the target protein is exemplified by the group of drugs termed SERDs (selective estrogen receptor degraders), for example fulvestrant. The molecular structures of SERDs are typically designed around an estrogen receptor ligand and a “degradation tail”, whose presence results in the degradation of the estrogen receptor. We will discuss the development of GNE-0011, which represents a novel class of monovalent BRD4 degrader that uses a “degradation tail” strategy. Citation Format: Robert A. Blake. GNE-0011, a novel monovalent BRD4 degrader [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 4452.
Abstract 4193: Epidemiological and clinical description of head and neck cancer cases in Bogotá, Colombia
Authors: Sandra P. Perdomo, Paula A. Rodriguez, Jose A. Hakim, Yubelly Avello, David A. Suarez, Alberto Escallón, Vanessa Ospina, Nicolás Useche, Alvaro Muñoz, Margarita Baldion, Mauricio Palau
Journal: Cancer Research (2019)

Abstract In 2018, almost 36,477 new head and neck cancer (HNC) cases were estimated to occur in South America. Colombia presents an intermediate age-standardized rate per 100,000 of 178.8 for both sexes. However, the incidence has not decreased in the las 10 years. Here, we present a description of the epidemiological and clinical characteristics of HNC patients studied in a private institution in Bogotá, Colombia. Between November 2014 and October 2018, 73 HNC cases were enrolled in the InterCHANGE- project: HNC in Latin America (http://interchange.iarc.fr/index.php). All cases had information on sociodemographic and lifestyle factors and complete clinical data. Stage at diagnosis was based on the 8th TNM AJCC classification. Inmmunohistochemical HPV studies included evaluation of p16INK4a (Clone E6H4). Mean age of diagnosis was 66 (SD 11.8), 66% of cases were male, 64% identified themselves as mestizos, 66% had superior complete educational level. 41% were nonsmokers, 56% former smokers and 52% current drinkers. 64% reported ever practiced oral sex. Tumors were mostly localized in the oral cavity (41.1%) and the oropharynx (41.1%), followed by larynx (16.4%) and hypopharynx (1.3%). 45% of cases were diagnosed at stage I and surgical treatment of primary tumor was performed in 66% of cases. Overall, 45% of cases were p16 positive. Interestingly, 93% of oropharyngeal cases were p16 positive, majority male (82%) with a mean age of diagnosis of 63 (SD 11.8) and among them, only 34% were nonsmokers. After a 2-year period of follow-up 82% of all cases were alive.In our population alcohol consumption and HPV infection are the major lifestyle risk factors associated to HNC. Oropharyngeal tumors were predominantly associated to HPV infection. Stage at diagnosis and percentage of survival is higher from what has been reported in other South American populations. Citation Format: Sandra P. Perdomo, Paula A. Rodriguez, Jose A. Hakim, Yubelly Avello, David A. Suarez, Alberto Escallón, Vanessa Ospina, Nicolás Useche, Alvaro Muñoz, Margarita Baldion, Mauricio Palau. Epidemiological and clinical description of head and neck cancer cases in Bogotá, Colombia [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 4193.