tbuckley/cabot-search huggingface dataset:
Abstract 4730: A novel RAD51 inhibitor, CYT01B, shows anti-cancer activity in preclinical models of AID expressing solid tumors
Authors: Melinda Day, Tyler Maclay, Kevin Mills
Journal: Cancer Research (2019)

Abstract AID, a DNA-directed cytidine deaminase, plays a critical role in somatic hypermutation and immunoglobulin class switching in maturing B-lymphocytes. Unlike site specific recombinases such as RAG1/2, AID is a promiscuous DNA damaging enzyme that deaminates cytidines at sites throughout the genome. AID expressing cells become critically dependent on the homologous recombination factor RAD51 to repair DNA double strand breaks that result from these off target deamination events. We have developed a novel small molecule, CYT01B, which inhibits RAD51 response to DSBs and is potent to a much greater extent in AID expressing cells. Previously, we have shown this molecule to have activity in mouse lymphoma xenograft models that constitutively express AID. Here we present new preclinical characterization data of CYT01B in solid cancer models. We first analyzed the frequency and levels of AID overexpression in solid tumor data in The Cancer Genome Atlas. Multiple solid tumor types displayed ectopic AID expression, including breast cancer, sarcoma, melanoma, pancreatic cancer, lung cancer, and head and neck cancers with about 30% of the patient samples 4-fold above the baseline expression level. We then tested CYT01B in several solid tumor derived human cell lines. We observed a correlation between AID expression and activity. Cell lines with low ectopic expression of AID had EC50 values in the low micromolar range (~2µM), while those without AID expression gave EC50 values of about 5µM and higher. Next, we examined the activity of our small molecule in 14 different PDX models with various levels of AID expression. These models included renal, head and neck, lung, pancreatic, ovarian, colorectal, and breast cancer samples. We observed a wide range of tumor growth inhibition across the different models (0% to 60%+), which tended to correspond with AID expression; the higher the AID expression the greater the observed tumor growth inhibition. Taken together, these data demonstrate that CYT01B shows anti-cancer activity in a range of solid tumor models. Overall, this provides the basis for continued development of CYT01B as an AID/RAD51 synthetic lethal therapeutic for solid cancers. Citation Format: Melinda Day, Tyler Maclay, Kevin Mills. A novel RAD51 inhibitor, CYT01B, shows anti-cancer activity in preclinical models of AID expressing solid tumors [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 4730.
Germline genetic landscape of pediatric central nervous system tumors
Authors: Ivo S Muskens, Chenan Zhang, Adam J de Smith, Jaclyn A Biegel, Kyle M Walsh, Joseph L Wiemels
Journal: Neuro-Oncology (2019)

Abstract Central nervous system (CNS) tumors are the second most common type of cancer among children. Depending on histopathology, anatomic location, and genomic factors, specific subgroups of brain tumors have some of the highest cancer-related mortality rates or result in considerable lifelong morbidity. Pediatric CNS tumors often occur in patients with genetic predisposition, at times revealing underlying cancer predisposition syndromes. Advances in next-generation sequencing (NGS) have resulted in the identification of an increasing number of cancer predisposition genes. In this review, the literature on genetic predisposition to pediatric CNS tumors is evaluated with a discussion of potential future targets for NGS and clinical implications. Furthermore, we explore potential strategies for enhancing the understanding of genetic predisposition of pediatric CNS tumors, including evaluation of non-European populations, pan-genomic approaches, and large collaborative studies.
Evaluation of neoangiogenesis in locally advanced gastric cancer before and after neoadjuvant radiochemotherapy by probe confocal laser endomicroscopy (PCLE)
Authors: R. Cannizzaro, R. Magris, M. Fornasarig, E. Pivetta, S. Maiero, M. Mongiat, V. De Re, V. Canzonieri, A. De Paoli, V. Turriziani, G. Guarnieri, A. Buonadonna, C. Belluco, D. Serraino, P. Spessotto
Journal: Annals of Oncology (2019)
Abstract 714: Cannabidiol-induced apoptosis is mediated by activation of Noxa in human colorectal cancer cells
Authors: Hye Kyeong Yun, Soyeon Jeong, Yoon A Jeong, Min Jee Jo, Jung lim Kim, Seong Hye Park, Bo Ram Kim, Yoo Jin Na, Dae Young Kim, Bu Gyeom Kim, Dae Hee Lee, Sang Cheul Oh
Journal: Cancer Research (2019)

Abstract Cannabidiol (CBD), one of the compounds present in the marijuana plant, has anti-tumor properties, but its mechanism is not well known. The authors aimed to evaluate the apoptotic action of CBD in colorectal cancer cells (CRC), and focused on its effects on the novel pro-apoptotic Noxa-reactive oxygen species (ROS) signaling pathway. CBD experiments were performed using the colorectal cancer cell lines HCT116 and DLD-1. CBD induced an apoptosis by regulating many pro- and anti-apoptotic proteins, of which Noxa showed a significantly higher expression. To understand the relationship between Noxa and CBD-induced apoptosis, authors downregulated Noxa levels using siRNA and confirmed that the expression of apoptosis markers was decreased. After ROS production was blocked, the level of Noxa also decreased, suggesting that ROS is involved in the regulation of Noxa. The Noxa and ROS are well-known pro-apoptotic signaling agents. As a result, CBD was found to induce apoptosis in a Noxa-and-ROS-dependent manner. The effects of CBD treatment were re-demonstrated in vivo, thus confirming its role as a novel, reliable anticancer drug Citation Format: Hye Kyeong Yun, Soyeon Jeong, Yoon A Jeong, Min Jee Jo, Jung lim Kim, Seong Hye Park, Bo Ram Kim, Yoo Jin Na, Dae Young Kim, Bu Gyeom Kim, Dae Hee Lee, Sang Cheul Oh. Cannabidiol-induced apoptosis is mediated by activation of Noxa in human colorectal 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 714.
Abstract P319: Changes in Perceptions of Neighborhood Environment and Cardiometabolic Outcomes in Two Predominantly African American Neighborhoods
Authors: Tiffany L Gary-Webb, Natalie Suder Egnot, Tamara Dubowitz, Wendy Troxel
Journal: Circulation (2018)

Introduction: Perceived neighborhood characteristics, including neighborhood satisfaction, are associated with lower obesity rates and more favorable cardiovascular risk factor profiles. However, prior studies have not evaluated how longitudinal changes in perceived neighborhood characteristics following revitalization efforts may associate with cardiometabolic health indicators. Methods: Changes in neighborhood perception scales (infrastructure, safety, aesthetics, and satisfaction) were determined from 2013-2016 and categorized into the following groups: improvement, no change, or worsening over the time-period. Multivariate linear regression was used to measure the association between perceived improvement in each of the neighborhood characteristics with cardiometabolic outcomes (BMI, SBP, HbA1c, HDL-c) assessed in 2016. Outcomes were compared for those who perceived neighborhood improvements to those who perceived no change/worsening of neighborhood characteristics. Models were adjusted for age, sex, income, education, marital status, physical function, neighborhood, years spent in neighborhood. Interaction terms for age and sex were tested in the adjusted models. Results: Among the 622 individuals who did not move during the time-period, 93% were African American, 80% were female, and the mean age was 58 years. Many participants reported some improvements in neighborhood environment; infrastructure (48% reporting improvements), safety (47%), aesthetics (46%) and satisfaction (28%). In covariate-adjusted models, those who perceived improvement in their neighborhood aesthetics over the follow-up period had a significantly higher BMI (kg/m 2 ) than those who perceived no improvement/worsening (β=1.2, p=0.05). Similarly, perceived improvements in neighborhood safety were associated with higher BMI (β=1.5, p=0.01); however, they were also significantly associated with lower SBP (mmHg) (β=-3.8, p=0.01). A significant interaction was observed between sex and perceived improvement in safety when predicting BMI (interaction term p=0.04), such that the relationship between perceived improvements in safety and higher BMI was observed only among women (β=2.3, p=0.02). We did not observe any statistically significant interactions by age. We also did not find significant associations between changes in neighborhood characteristics and HDL-c or HbA1c. Conclusions: These findings suggest that perceived neighborhood characteristics may have differing associations with multiple cardiometabolic outcomes (BMI, SBP). This highlights the complexity of the associations between neighborhood characteristics and health as well as the importance of considering how changes in perceived neighborhood characteristics associate with multiple clinically relevant cardiometabolic risk factors, and how associations may be sex dependent.
Abstract 3178: Comparative study of methods and platforms for T-cell receptor repertoire
Authors: Mukta Dutta, Mariya Smit, Heather Collins, Anjali Malge, Steve Anderson, Corey Braastad
Journal: Cancer Research (2019)

Abstract High-throughput sequencing technologies facilitate in-depth sequencing of T-cell receptor (TCR) repertoires to gain insights into human adaptive immunity. These studies can help decipher the diversity of T-cell receptors, relevant to physiological and disease conditions, and potential therapy responses. A variety of TCR kits and programs have been developed for the identification of V, D and J gene segments, complementarity-determining region 3 (CDR3) sequence extraction and clonality analysis. However, there is still a deficit of systematic comparative studies to assist in the selection of an optimal platform. Here, we present a detailed comparison of 4 state-of-the-art TCR platform on samples with different complexities (ranging from cancers to immune disorders) by taking into account aspects such as clonotype detection [unique V(D)J combination] and CDR3 identification. Our results provide new insights into the effect of method selection on analysis results, and will consequently inform users in the selection of an appropriate analysis method for the desired application(s). Citation Format: Mukta Dutta, Mariya Smit, Heather Collins, Anjali Malge, Steve Anderson, Corey Braastad. Comparative study of methods and platforms for T-cell receptor repertoire [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 3178.
Endoscopic full-thickness transoral outlet reduction with endoscopic submucosal dissection or argon plasma coagulation: does it make a difference?
Authors: Simon Kin Hung Wong
Journal: Endoscopy (2019)

Obesity continues to be a major and growing health concern globally. Bariatric surgery has been recognized as the most effective method to achieve weight reduction and an improvement in comorbidities. According to the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) worldwide survey [1], there has been a 50 % increase in the number of bariatric surgeries from 2013 to 2016 and approximately a third of these procedures are Roux-en-Y gastric bypasses (RYGBs). However, 20 % – 30 % of bypass patients will experience significant weight regain in the years following their nadir weight loss, which poses a difficult challenge for both surgeons and patients. While the factors leading to weight regain are complex, anatomically a dilated (> 10 mm) gastrojejunal anastomosis (GJA) has been shown to be a major factor in weight regain [2]. Surgical revision with either a restrictive and/or a malabsorptive component can achieve more weight reduction compared with endoscopic revision. However, surgical revision is technically more difficult and associated with high morbidity, with the reported rate of major complications ranging from 9 % to 44 % [3].
Abstract 3223: Overcome LKB1 mutated cancer resistance to anti-PD1 treatment
Authors: Jiehui Deng, Aatish Thennavan, Yuanwang Pan, Igor Dolgalev, Ting Chen, Heather Silver, Matthew Harris, Val Pyon, Fei Li, Chelsea Lee, Aristotelis Tsirigos, Eli Rothenberg, Charles M. Perou, Kwok-Kin Wong
Journal: Cancer Research (2019)

Abstract KRAS/STK11 (LKB1) mutant lung cancers are a subtype of cancer that respond poorly in the clinic to immunotherapies with shorter progression-free survival and overall survival comparing with other KRAS mutant lung cancer patients. Interestingly, this group of patients have high tumor mutational burden (TMB) comparable with other KRAS mutant lung cancers, which usually is an indicator for better response to anti-PD1 treatment. By using genetically engineered mouse model (GEMMs), we found that LKB1 loss of function can cause high level of nonsynonymous mutations, as a consequence of both replication dependent and independent DNA repair machinery dysfunctions. This LKB1 mutant dependent increased mutational load might further synergize with smoking mutagen exposures. When LKB1 function is defective, the neoantigens are not properly presented to T cells, which is required for proper T cell activation and effector T cells expansion. This will lead to insensitivity to anti-PD1 antibodies in high TMB tumors and tolerance to neoantigens produced by cancer cells. We further demonstrated that using a small molecule drug that impacts on the LKB1 downstream effector pathway, we can reverse this process through activating innate immunity in tumors, which will restore the antigen presentation functions. Combinational treatment of this small molecule with anti-PD1 can reverse the tumor progression in vivo, through releasing the suppressive tumor infiltrating lymphocytes (TILs) in LKB1 mutant lung cancers. Our study not only helps to further our understanding of the mechanism that contributes to immune evasion in high TMB tumors, but also provides a potential solution for LKB1 mutant cancers to overcome resistance to anti-PD1 treatment in the clinic. Citation Format: Jiehui Deng, Aatish Thennavan, Yuanwang Pan, Igor Dolgalev, Ting Chen, Heather Silver, Matthew Harris, Val Pyon, Fei Li, Chelsea Lee, Aristotelis Tsirigos, Eli Rothenberg, Charles M. Perou, Kwok-Kin Wong. Overcome LKB1 mutated cancer resistance to anti-PD1 treatment [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 3223.
Abstract 4962: Repurposing <i>bazedoxifene</i> to suppress gastrointestinal cancer growth
Authors: Pathum Thilakasiri, Tracy Nero, Michael W. Parker, Matthias Ernst, Ashwini L. Chand
Journal: Cancer Research (2019)

Abstract The interleukin (IL)6 family of inflammatory cytokines, characterized by the shared use of the gp130 receptor, supports the progression of solid cancers. Specifically, gp130 signaling becomes rate limiting for the growth of gastrointestinal tumors arising from oncogenic driver mutations in Apc, but remains dispensable for the homeostatic renewal of the gastrointestinal mucosa. In the present study we investigate the effects of the selective estrogen receptor modulator bazedoxifene, clinically approved for the treatment of osteoporosis, as a putative small molecule inhibitor of gp130 receptor oligomerization and activation. We assessed the effects of bazedoxifene on IL6 and IL11-dependent STAT3 activation and cell proliferation in gastric and colon cancer cell lines. In patient-derived colon cancer organoid cultures, we assessed bazedoxifene effects on IL11-dependent growth. The gp130Y757F, Lgr5CreERT2- or Cdx2CreERT2-driven Apc flox mouse models of gastrointestinal cancer, were used to examine the effects of bazedoxifene on tumour growth. In silico modeling suggests that the inhibitory activity of bazedoxifene is due to its ability to mimic the interaction between the Site III interface of gp130 receptor and the tryptophan-157 in IL6, or tryptophan-168 in IL11 cytokine. We show that bazedoxifene interferes with IL6 and IL11-dependent proliferation of BAF/03 cells. Bazedoxifene suppresses gastric tumor growth in gp130Y757F mice irrespective of their gender, in which tumors arise through excessive IL11-dependent STAT3 signaling. Strikingly, in sporadic colon cancer models based on aberrant activation of the β-catenin/canonical WNT pathway, bazedoxifene treatment also reduces tumor burden in mice following conditional ablation of the Apc suppressor gene using the Lgr5CreERT2- or Cdx2CreERT2-driver alleles. Consistent with our observation that nuclear accumulation of β-catenin remains unaffected in colonic tumors of bazedoxifene-treated mice, bazedoxifenetreatment of human SW480 colon cancer cells harboring mutant APC did not affect canonical WNT signaling, but suppressed IL11-dependent STAT3 signaling. Our findings provide compelling proof-of-concept for the repurposing of bazedoxifene for the treatment of gastrointestinal cancers that arise from bona fide oncogenic driver mutations. Note: This abstract was not presented at the meeting. Citation Format: Pathum Thilakasiri, Tracy Nero, Michael W. Parker, Matthias Ernst, Ashwini L. Chand. Repurposing bazedoxifene to suppress gastrointestinal cancer growth [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 4962.
Abstract 2211: Discovery of orally available and potent MPS1(TTK) kinase inhibitors for anti-cancer drugs
Authors: Younho Lee, Juhee Kang, Sein Kang, Hyunkyung Kim, Kyung-ah Seo, Jieun Choi, Jaeyoung Ahn, Jung Beom Son, Nam Doo Kim
Journal: Cancer Research (2019)

Abstract There are many cell cycle regulating kinases such as CDKs, Polo, Aurora, Bub, NEK/NimA, etc. Dual specificity protein kinase, MPS1(TTK) is one of them. The role of MPS1 is to regulate spindle assembly checkpoint(SAC) during cell mitosis. The inhibition of MPS1 activity causes cell death by premature mitotic exit. Some of MPS1 inhibitors (NMS-P153, BOS-172722, CFI-402257, BAY-1217389, and BAY-1161909) are in clinical trials. These compounds are treated for solid tumors with or without Paclitaxel. We discovered new orally available and potent inhibitors of MPS1 kinase (MPS1 enzyme IC50 &amp;lt; 10nM / MDA-MB-231 GI50 &amp;lt; 50nM, MDA-MB-468 GI50 &amp;lt; 50nM / HCT116 GI50 &amp;lt; 50nM, F% &amp;gt; 30%). The compounds selectively inhibit MPS1 based on kinase profiling and decrease phosphorylation of MPS1 and Phospho-HH3 signaling, effectively. Some of compounds were selected for further preclinical studies. Citation Format: Younho Lee, Juhee Kang, Sein Kang, Hyunkyung Kim, Kyung-ah Seo, Jieun Choi, Jaeyoung Ahn, Jung Beom Son, Nam Doo Kim. Discovery of orally available and potent MPS1(TTK) kinase inhibitors for anti-cancer drugs [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 2211.
Abstract 1987: Exosome from CAF-ESCC aggravates tumor progression by its containing molecular miR-3656
Authors: Xiaojia Chen, Yuan Jin, Bihui Zhang, Xiaocen LI, Baoqing Tian, Qiang Wang, An Hong
Journal: Cancer Research (2019)

Abstract Background: Exosome plays an important role in cell communication and cell environment. But the mechanism of how exosome derived from cancer-associated fibroblast (CAF) influent esophageal squamous cell carcinoma (ESCC) progression is not clear. In this work, compared with normal fibroblast-derived exosomes (NDEs), we found that CAF derived exosomes (CDEs) can enhance the growth, migration, and invasion of ESCC cells obviously. Therefore, we would like to clarify the role of CDEs in ESCC progression. Methods and Results: Using microRNA array to analyze the different miRNAs in the CDEs and NDEs, we got a series of up-regulation miRNAs and two down-regulation miRNAs in CDEs. Among them, miR-3656 shows a significantly highest level. Then, we transfected miR-3656 mimics to the ESCC cells and found the mimics increased the growth, migration, and invasion of ESCC cells in cell proliferation assay. cell scratch tests and chamber invasion experiments. We established recombinant ESCC cells with miR-3656 high expression by the lentiviral system. The cells were injected into mice to form the xenograft tumor. The results showed the miR-3656 can enhance the tumor formation. After that, aided by TargetScan software, we found ACAP2, one of miR3656 targets, was significantly down-regulating in ESCC cells at the high level of miR-3656. When ACAP2 expression was knocked-down by siRNA, the proliferation and migration of ESCC cells was increased, which indicated ACAP2 a potential anti-tumor factor. Furthermore, we detected the different proteins between ESCC cells with high expression miR-3656 and normal ESCC cells through LC_MS; the results were analyzed by Integrate Pathway Analysis (IPA) system and many differential proteins were found to be involved of PI3K/AKT and Wnt pathways. Conclusions: In this study, we found the CDEs promote the progression of their sounding ESCC cells in vitro and in vivo. The main reason is that CDEs carry some tumor-promoting miRNAs that influent the target ESCC cells. Especially, miR-3656 expresses the highest level of miRNAs in CDEs. It not only decreases the expression of ACAP2 but also impacts the expression of proteins involved PI3K/AKT and Wnt pathways in ESCC cells. The results indicate the CDEs playing a very important role in ESCC progression. Citation Format: Xiaojia Chen, Yuan Jin, Bihui Zhang, Xiaocen LI, Baoqing Tian, Qiang Wang, An Hong. Exosome from CAF-ESCC aggravates tumor progression by its containing molecular miR-3656 [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 1987.