tbuckley/cabot-search huggingface dataset:
Abstract 4103: Polyphenols from <i>Artemisia annua</i>L (pKAL) exhibit anticancer effects on radio-resistant MDA-MB-231 cells by suppressing stemness phenotype and EMT process
Authors: Won Sup Lee, Yougn Shin Ko, Anjugam paramanantham, GonSup Kim, Sung Chul Shin, Hye Jung Kim
Journal: Cancer Research (2020)

Abstract Artemisia annua L., (Gaddongsook in Korean) has been used as Korean folk medicine for anti-inflammatory, and anticancer activities. However, the molecular mechanisms for anti-cancer activities of Artemisia annua L. still need elucidating. Here, we determine whether pKAL exhibit the anti-cancer effects on RT-R breast cancer cells, and the molecular characteristics for the radio-resistant (RT-R) breast cancer. In addition, we further explore the molecular mechanisms for anticancer effects of pKAL on stemness and epithelial-mesenchymal transition (EMT). MTT and colony forming assay revealed that pKAL inhibited cell proliferation on both RT-R-MDA-MB-231 cells and MDA-MB-231 cells in a dose- and time-dependent manner. GO enrichment analysis of differentially expressed proteins between RT-R-MDA-MB-231 cells and MDA-MB-231 cells with the use of KEGG pathway analysis and PANTHER functional analysis revealed that MAPK signaling pathway might be used as a survival mechanism for the RT R-MDA-MB-231 cells to attain the resistance. The detailed western blot analysis for anti-cancer effects of pKAL revealed that it inhibited the expression of CD44 and Oct 3/4 (stem cell markers), and β-catenin and MMP-9 (EMT markers) of RT-R-MDA-MB-231 cells. In addition, pKAL inhibited STAT 3 activity that is upregulated in RT-R-MDA-MB-231 cells compared to in parental MDA-MB-231 cells. JNK and JAK2 inhibitors also inhibited STAT3 activity on both RT-R-MDA-MB-231 cells and MDA-MB-231 cells. However, JNK or JAK2 inhibitor could not suppress nor augment the anti-cancer effects of pKAL on CD44, and Oct 3/4 expression while JAK2 inhibitor could inhibit the expression of β-catenin, and MMP-9 expression. These findings suggest that pKAL-induced anticancer effects are not closely associated with JNK and JAK2/STAT3 signaling. In conclusion, this study suggested pKAL exhibit anticancer effects on radio-resistant MDA-MB-231 cells by suppressing stemness phenotype and EMT. Citation Format: Won Sup Lee, Yougn Shin Ko, Anjugam paramanantham, GonSup Kim, Sung Chul Shin, Hye Jung Kim. Polyphenols from Artemisia annuaL (pKAL) exhibit anticancer effects on radio-resistant MDA-MB-231 cells by suppressing stemness phenotype and EMT process [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4103.
Abstract 5763: Incidence and mortality predictors of ill-defined illness (non-diagnosed conditions) as a cause of death in cancer patients: A population-based study
Authors: Muhammed Khaled Elfaituri, Sara Morsy, Nguyen Tien Huy
Journal: Cancer Research (2020)

Abstract Introduction: This observational study characterised ill-defined illness (non-diagnosed conditions) mortality risk for multiple cancer sites, with respect to other factors related to the patient's condition and demographic information. Method: Using the Surveillance, Epidemiology and End Results (SEER) database (1975-2016), complete data on 24378 patients were identified; their death was due to non-diagnosed conditions were identified. Overall survival (OS) was estimated using the Kaplan-Meier method. Cox, the proportional hazards model, were used to produce adjusted hazard ratios (HR). Trend analysis was conducted using joinpoint regression analysis with four join points, and annual percentage change (APC) was calculated. Results: We found that 24378 cancer patients died due to unknown conditions. The mean age of the patients was 71.22, and most of them were female (50.6%). Most tumours were malignant 92.2% and grade II (n = 6650 (27.3%)). Most patients had surgery, only. White and married patients constituted most of the patients. The most common site associated with the ill-defined condition was GIT (n = 4578) followed by breast (n = 4003) followed by the male genital system (n = 3630). The most common pathology associated with ill-defined conditions was adenoma and adenocarcinoma (n = 9575) followed by ductal and lobular carcinoma (n = 3501) followed by squamous cell carcinoma (n = 2181). There were five trends observed for the mortality due to undiagnosed conditions. The rate of cases increased significantly from 1975 to 2008; then there was a decrease in cases from 2008 till 2015, but it was small and insignificant followed by a significant decrease in the number of cases [-59.4, (95% CI = -71.4; -42.5), p-value &amp;lt;0.001]. The overall average annual percent change was significant increase was 4.8% (95% CI = 4.8; 9.9, p-value &amp;lt; 0.001). Based on the logistic regression analysis, older males had a higher risk for the disease. Conclusion: Our study finding might serve as a reference for clinicians when evaluating patients with cancer to search for any underlying condition that was not diagnosed during the disease course, as this will help to reduce the mortality associated with these conditions. Citation Format: Muhammed Khaled Elfaituri, Sara Morsy, Nguyen Tien Huy. Incidence and mortality predictors of ill-defined illness (non-diagnosed conditions) as a cause of death in cancer patients: A population-based study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5763.
Abstract 6338: High-throughput screening program to target ovarian cancer leader cells
Authors: Nazanin Karimnia, Maree Bilandzic, Magdalena Plebanski, Andrew N. Stephens
Journal: Cancer Research (2020)

Abstract Despite its relatively low incidence ovarian cancer is one of the most lethal gynecological malignancies, characterized by high recurrence rate following primary therapy and almost universal acquisition of chemoresistance. Recently, we identified a subpopulation of “Leader Cells” (LCs) that control invasion, progression and acquired chemoresistance. Therapies targeting leader cells are likely to be pivotal to improving prognosis, particularly in patients who are refractory to standard-of-care. To investigate the role of LCs in chemoresistance, we used CRISPR to integrate an in-frame T2A-GFP expression cassette downstream of the native LC marker gene, Keratin 14 (KRT14). Genomic integration drives the LC specific expression of GFP, facilitating visualization and quantitative tracking of the LC subset. The status of GFP as a surrogate marker of LCs in vitro was confirmed by immunostaining and expression analyses. Chemotherapeutic intervention studies and co-staining with the apoptosis marker cleaved caspase 3, demonstrated a significant enrichment of LCs that represent a non-apoptotic subset of cells resistant to standard chemotherapy. High-throughput drug screening, combining large functional drug libraries with high-throughput viability and invasion assays, was used to identify drugs that could inhibit LC function in vitro. Ovarian cancer cell lines (SKOV3 and COV362.4 expressing KRT14-T2A-GFP) were screened against 1450 FDA-approved drugs, and 218 hits identified that inhibited LC viability, invasive capacity or both. Amongst the hits that we identified, the neural signaling pathway emerged as a potential novel mediator for LC function. Further validation experiments confirmed that inhibition of the neural signaling pathway did not affect viability but synergized with chemotherapy to reduce cisplatin IC50 by 10-20-fold. Our data demonstrate that the high-throughput screen developed is a viable approach to identify opportunities for drug repurposing. Moreover, the neural signaling pathway appears to be important in LC function and inhibiting this pathway results in increased sensitivity to chemotherapy in vitro. Ongoing work will evaluate the applicability of this new tool for clinical screening programs, and further, validate existing drugs for potential repurposing. Citation Format: Nazanin Karimnia, Maree Bilandzic, Magdalena Plebanski, Andrew N. Stephens. High-throughput screening program to target ovarian cancer leader cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6338.
Drug Repurposing Study Pinpoints Potential COVID-19 Antivirals
Authors: Jennifer Abbasi
Journal: JAMA (2020)

In the race to put existing drugs to the test for coronavirus disease 2019 (COVID-19), a National Institutes of Health–funded team winnowed down about 12 000 approved and investigational drugs to 13 promising candidates against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Abstract 1081: DNA methylation at the intersect of chromatin structure and transcriptome diversity
Authors: Angela H. Ting, Vishal Nanavaty, Elizabeth Abrash, Byron Lee, Emily Fink, Tae Hyun Hwang, Changjin Hong
Journal: Cancer Research (2020)

Abstract Dysregulation of DNA methylation and mRNA alternative cleavage and polyadenylation (APA) are both prevalent in cancer, but they have been studied as independent processes. We discovered a DNA methylation regulated APA mechanism when we compared genome-wide DNA methylation and polyadenylation site usage between DNA methylation-competent and DNA methylation-deficient cells. Here we show that removal of DNA methylation enables CTCF binding and recruitment of the cohesin complex, which in turn, promotes proximal polyadenylation site usage. In this DNA de-methylated context, depletion of the RAD21 cohesin complex component can recover distal polyadenylation site usage. We also confirmed, using chromosomal conformation capture (3C), that CTCF and the cohesin complex mediate chromatin loops in the absence of DNA methylation to modulate polyadenylation site usage. Leveraging data from The Cancer Genome Atlas, we authenticated the relationship between DNA methylation and mRNA polyadenylation isoform expression in vivo. This DNA methylation regulated APA mechanism demonstrates how aberrant DNA methylation impacts transcriptome diversity and highlights the potential sequelae of global DNA methylation inhibition as a cancer treatment. Citation Format: Angela H. Ting, Vishal Nanavaty, Elizabeth Abrash, Byron Lee, Emily Fink, Tae Hyun Hwang, Changjin Hong. DNA methylation at the intersect of chromatin structure and transcriptome diversity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1081.
Abstract 939: Evaluating anti-PD-1/4-1BB combination therapy: <i>In vivo</i> efficacy with humanized double knock-in mice
Authors: Tian Gan, Xiaofei Zhou, Yuting Hu, Chengzhang Shang, Gary Ng
Journal: Cancer Research (2020)

Abstract The transmembrane protein receptor 4-1BB is a member of the tumor necrosis factor (TNF) receptor super family and is involved in the co-stimulation of immune cells. 4-1BB is expressed in activated CD4 helper T cells, B cells, natural killer cells, natural killer T cells, dendritic cells, and activated endothelium. Most regulatory T cells (Tregs) also express 4-1BB, but it remains unclear that whether agonistic antibody treatment exerts pro- or anti-suppressive effect on these cells. 4-1BB enhances tumor rejection because it is upregulated on T cells following activation as its engagement increases T cell proliferation and pro-inflammatory cytokine production. Despite of the toxicity of 4-1BB-targeting drugs associated with overt immune activation, new therapeutic modalities using 4-1BB targeting aptamers, as well as combination therapies with other immuno-modulatory and traditional anti-cancer treatments, have revived excitement for the use of 4-1BB agonists in the clinic. Biocytogen has developed a double humanized B-hPD-1/h4-1BB mouse model to unlock the tremendous potential of combination therapy involving 4-1BB agonists and anti-PD-1 antibodies. In such model, mouse PD-1 gene exon 2, and 4-1BB gene exons 2-7 were replaced with their human counterparts. Murine colon cancer MC38 cells, humanized PD-L1 in MC38 cells, humanized PD-L1 in murine melanoma B16F10 cells, and murine lymphoma EL4 cells were subcutaneously implanted into homozygous B-hPD-1/h4-1BB mice. Combination treatment of Urelumab (anti-4-1BB) and Pembrolizumab (anti-PD-1) has shown enhanced inhibitory effects compared to single antibody treatments using the B-hPD-1/h4-1BB mice models. Based on these findings, it could be concluded that the B-hPD-1/h4-1BB double-humanized mouse model is a validated tool for in vivo evaluation of hPD-1 and h4-1BB antibody combination therapy. Citation Format: Tian Gan, Xiaofei Zhou, Yuting Hu, Chengzhang Shang, Gary Ng. Evaluating anti-PD-1/4-1BB combination therapy: In vivo efficacy with humanized double knock-in mice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 939.
Abstract 5779: The association of instrument assisted deliveries and the development of childhood brain tumors: A matched case control study
Authors: Karen Yeh, Johnni Hansen, Julia E. Heck
Journal: Cancer Research (2020)

Abstract Background: Pediatric brain tumors are the second most common type of childhood cancer and have the highest mortality rate among all pediatric cancer types. New information on potentially preventative measures would be of great value. Previous studies have suggested that instrument-assisted delivery (forceps and vacuum) may be associated with an increased risk for childhood brain tumors. The goal of this study was to determine if there was an association of exposure to instrument-assisted deliveries with childhood brain tumors in Denmark. We additionally examined risk with emergency or planned cesarean section. Methods: This was a matched case-control study with childhood brain tumor cases in Denmark diagnosed from 1978-2013. Cases were identified from the Danish Cancer Registry. Birth outcomes, maternal procedures and covariates were obtained from the Danish Medical Births Register and the nationwide Hospital Register. A total of 3,698 brain tumor cases were recruited and 25 controls were matched to each case based on child's sex and birth year (N=89,554). We used conditional logistic regression to determine associations of delivery instruments types with various childhood brain tumors. Results: Compared to children birthed by spontaneous vaginal delivery, children who later developed ependymomas (N=136) had a greater likelihood of having been delivered by vacuum assisted deliveries (OR=1.69, 95% CI 1.01-2.83). An overall increased risk for cesarean section with any CNS tumor (OR= 1.20, 95% CI 1.06-1.36) dropped to 1.10 when we limited the age range to 4 or older (N=1,087). This suggests no clear increased risk for cancer with cesarean section, as there is a possibility that the CNS tumor was present before birth and influenced a larger head size, thus requiring a cesarean section. Planned cesarean and emergency cesarean section were not related to risk increases. While the use of forceps was rare in this population (1.2% in controls), we could not confirm previously reported associations with astrocytoma (OR=0.84), though there was a weak increase for ependymoma with wide confidence intervals (OR=2.69, 95% CI 0.77, 9.38). Conclusions: Based on objective data, the findings in our study suggest that there might be an association between vacuum assisted deliveries and ependymomas. Our data did not support a strong association of childhood brain tumors with cesarean sections. Citation Format: Karen Yeh, Johnni Hansen, Julia E. Heck. The association of instrument assisted deliveries and the development of childhood brain tumors: A matched case control study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5779.
Abstract 4541: QL315, A CD3 bispecific antibody redirecting T cell activation to the tumor stroma antigen LRRC15
Authors: Monica Jin, Aaron Kurtzman, Weiwei W. Prior, Allan Chan, Anna McClain, Shenda Gu, Irene Tang, Zijie Cai, Lauren Schwimmer, Hieu Tran, Shihao Chen
Journal: Cancer Research (2020)

Abstract Leucine-rich repeat containing 15 (LRRC15) antigen is highly expressed on both stromal fibroblasts of multiple solid tumors and on cancer cells of mesenchymal origin. As its expression is very low in normal tissues, targeting LRRC15 has shown therapeutic potential as an antibody-drug conjugate (Demetri, ASCO 2019), which could lead to significant tumor inhibition by solely targeting stromal LRRC15 expression. In this study, we have developed and rank ordered an array of IgG-based CD3 bispecific molecules based on biophysical and biologic attributes and anti-cancer efficiency through T-cell engagement and redirection/activation against LRRC15-expressing tumors. The selected lead, QL315, robustly and conditionally induced T cell activation and proliferation only in the presence of LRRC15-expressing cancer cells with an EC50 in a picomolar range in vitro but not in the coculture with LRRC15-negative cancer cells. Moreover, QL315 strongly induced tumor cell lysis in vitro and led to significant tumor regression and T cell expansion in a mouse xenograft model. Importantly, toxicologic evaluation of QL315 in cynomolgus monkeys showed antibody-like stability and half-life, and good tolerability with no changes of circulating blood cell homeostasis and organ damage. At highest levels, liver enzymes, as well as cytokine release, were transiently elevated but returned to normal within one week of treatment. In conclusion, these data demonstrate drug-like properties, promising anti-tumor capability and good tolerability of the anti-LRRC15/CD3 bispecific antibody, QL315, indicating its potential as a therapeutic option in the treatment of solid tumors of diverse origin by targeting either tumor stromal micro environment or patient cancers expressing LRRC15. Citation Format: Monica Jin, Aaron Kurtzman, Weiwei W. Prior, Allan Chan, Anna McClain, Shenda Gu, Irene Tang, Zijie Cai, Lauren Schwimmer, Hieu Tran, Shihao Chen. QL315, A CD3 bispecific antibody redirecting T cell activation to the tumor stroma antigen LRRC15 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4541.
Abstract 3009: Targeting MDM2-amplified tumors with AMG-232 to overcome drug resistance, inflammatory pro-tumorigenic cytokine production and hyperprogression with immune checkpoint therapy
Authors: Ilyas Sahin, Shengliang Zhang, Lanlan Zhou, Don Dizon, Howard Safran, Wafik S. El-Deiry
Journal: Cancer Research (2020)

Abstract Mouse double minute 2 homolog (MDM2) is E3 ubiquitin-protein ligase which facilitates proteasomal degradation of p53. MDM2 amplification has been reported in different tumor types and recently been implicated as a potential marker for accelerated tumor growth or hyperprogression in various types of cancer after receiving immune checkpoint inhibitors. Thus, targeting MDM2 might be a promising treatment strategy in the era of cancer immunotherapy especially for tumor with MDM2 amplification or overexpression that may be predisposed to hyperprogression after exposure to immune checkpoint therapy. To investigate the potential of targeting MDM2 strategy, we explored the role of inhibition of MDM2 by AMG-232, an investigational oral selective MDM2 inhibitor. MDM2-amplified and MDM2-non-amplified ovarian clear cell carcinoma cell lines carrying p53 wild-type were treated with AMG-232 and showed a dose-dependent reduction in cancer cell viability. MDM2 amplification showed more resistance to the treatment with AMG-232. Consistent with previous data, treatment with AMG-232 led to activation of the p53 signaling pathway in cancer cells in a dose-dependent manner. Importantly, the effect of MDM2 inhibition on cytokines expression was tested and significant reduction in Interleukin-6 (IL-6), a proinflammatory cytokine which promotes tumorigenesis by multiple signaling pathways, was observed in a dose-dependent manner. Ongoing experiments are examining the role of targeting MDM2 using AMG-232 in combination with immunotherapy, including the impact on killing of MDM2-amplified ovarian cancer cells by T-cells in the presence of immune checkpoint therapy. Overall, our data suggest a potential therapeutic role of targeting MDM2 especially in tumors with overexpression or amplification of MDM2 to overcome drug resistance including hyperprogression in the context of immune checkpoint therapy. Citation Format: Ilyas Sahin, Shengliang Zhang, Lanlan Zhou, Don Dizon, Howard Safran, Wafik S. El-Deiry. Targeting MDM2-amplified tumors with AMG-232 to overcome drug resistance, inflammatory pro-tumorigenic cytokine production and hyperprogression with immune checkpoint therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3009.
Abstract 5431: Subungual melanoma: It may be a distinct entity
Authors: Blair N. Holman, Robert J. Van Gulick, Carol Amato, Kasey Couts, William A. Robinson
Journal: Cancer Research (2020)

Abstract Subungual melanoma (SUM) is a type of malignant melanoma that arises beneath the nails of the hands and feet. Subungual melanomas represent a small subset of melanoma patients and have not been well characterized by current molecular techniques. In most studies they have been included in the category of acral melanoma (AM), but there are numerous reasons to believe that they may be different. New effective melanoma treatments rely on both clinical and molecular data to select therapy. In this study, we reviewed characteristics in 29 patients with subungual melanomas seen at our institution in an attempt to provide better understanding and treatment. The median age was 56, almost equally distributed between males and females, with a higher percentage of non-Caucasians than seen in cutaneous melanoma. The most common sites were the thumb (28%), big toe (21%), and index finger (17%). Most were deep at diagnosis (mean Breslow depth 4.21 mm), and 72% had, or developed, metastases and responded poorly to therapy of all kinds. In 12 of the 29 cases, molecular testing via targeted sequencing through Foundation Medicine was done on either a primary or metastatic lesion. These 12 cases were compared to 20 cases of AM seen at our institution. One BRAF mutation was found (1/12, 4%) in SUM, whereas BRAF mutations occurred in about 20% of patients with AM. No patients with SUM had an NRAS mutation, compared to a 45% mutation rate in AM. Two SUM patients had KRAS mutations (2/12, 17%), whereas no patients with AM had a KRAS mutation. Three SUM patients had mutations in KIT (3/12, 25%) compared to one (1/20, 5%) in AM. In addition, 3 patient tumors had a recurrent variant (K587R) in the tuberous sclerosis related gene TSC-1, which has not been described in patients with AM. While our profile of subungual melanoma has some similarities with non-subungual acral melanomas, the high number of KRAS, KIT and TSC1 mutations and lack of BRAF and NRAS mutations suggests that these melanoma may have unique characteristics, different causation, and need specific therapy different from acral melanomas. Citation Format: Blair N. Holman, Robert J. Van Gulick, Carol Amato, Kasey Couts, William A. Robinson. Subungual melanoma: It may be a distinct entity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5431.