bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4103: Polyphenols from Artemisia annuaL (pKAL) exhibit anticancer effects on radio-resistant MDA-MB-231 cells by suppressing stemness phenotype and EMT process
Authors: Lee Won Sup , Ko Yougn Shin , paramanantham Anjugam , Kim GonSup , Shin Sung Chul , Kim Hye Jung 
Published: September 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 4108: The use of conditionally reprogrammed cells for high throughput screening for novel drug combinations to treat drug resistant triple negative breast cancers
Authors: Aguilar-Mahecha Adriana , Chabot Catherine , Santos-Martinez Nancy , Darini Cedric , Hajira Midhet , Kong Tim , Morin Genevieve , Huang Sidong , Park Morag , Basik Mark 
Published: September 2020

Abstract
Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer, with prognosis tightly dependent on its responsiveness to cytotoxic chemotherapy. Indeed, overcoming chemoresistance is a major unmet need in this disease. Patient derived xenografts (PDXs) are now widely used in research since they faithfully represent the patient's tumor. However, testing novel drug combinations is a challenge in these models since it is time consuming and quite expensive to test each novel combination. The development of conditionally reprogrammed cells (CRCs) offers the opportunity to perform high throughput screens on clinically relevant models in a more timely and less expensive manner. To this end, we developed a 7 CRCs from PDXs of drug-resistant TNBC tumors. We characterized these CRCs at the molecular level and validated drug resistance to confirm they matched treatment response in both clinical and PDX tumors from which they were derived. These CRCs underwent high-throughput screens of both compound and shRNA libraries of genes targeted by FDA-approved drugs to identify novel drug combinations as well as genetic vulnerabilities that could re-sensitize these cells to carboplatin or paclitaxel chemotherapy. We found that drugs such as mitomycin C and oxfendazole were putative chemo-sensitizers while genes such as ATR and CDK2 were identified as novel genetic vulnerabilities. Treatment of these drug-resistant cells with combinations of carboplatin with mitomycin C or with an ATR inhibitor resulted in synergistic growth inhibition in proliferation and colony formation assays. We are further validating these combinations in organoid models derived from PDXs. These results have the potential to lead to novel therapeutic strategies against chemoresistant TNBCs.
Citation Format: Adriana Aguilar-Mahecha, Catherine Chabot, Nancy Santos-Martinez, Cedric Darini, Midhet Hajira, Tim Kong, Genevieve Morin, Sidong Huang, Morag Park, Mark Basik. The use of conditionally reprogrammed cells for high throughput screening for novel drug combinations to treat drug resistant triple negative breast cancers [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 4108.
Abstract 4112: OTULIN promotes Wnt/β-Catenin activation by genotoxic treatments and enhances drug-resistance in breast cancer
Authors: Wang Wei , Mingqi Li , Chi Yayun , Xue Jingyan , Fahmy Beshoy , Wu Jiong , Wu Zhaohui 
Published: September 2020

Abstract
Patients with basal-like breast cancer and triple-negative breast cancer (TNBC) generally have a worse prognosis than other breast cancer subtypes due to rapid-arising therapeutic resistance accompanied by aggressive metastasis. The drug-resistant tumor cells, including cancer stem-like cells with intrinsic resistance or tumor cells acquired resistance during treatments, could adopt a drug-tolerant state and serve as seeds for recurrent metastatic lesions. However, the molecular events orchestrating the innate and adaptive therapeutic resistance are not completely understood. We found that a linear ubiquitin-specific deubiquitinase OTULIN is overexpressed in breast tumors, especially in the basal-like subtype. Increased OTULIN levels were also observed in PDX samples from chemo-refractory TNBC patients compared to those were responsive to chemotherapy. OTULIN overexpression significantly increased TNBC cell resistance to chemotherapy and is associated with shorter OS and DFS in breast cancer patients. Mechanistically, we found genotoxic treatments induce OTULIN phosphorylation, which is required for the activation of Wnt/β-Catenin signaling in TNBC cells. Inhibiting Wnt/β-Catenin signaling or OTULIN sensitized TNBC xenografts to Doxorubicin treatment in vivo. In TNBC patients, increased OTULIN levels are higher in subtypes enriched with Wnt/β-catenin signaling signature. Our findings suggest that OTULIN may increase TNBC therapeutic resistance and aggressiveness by promoting Wnt/β-Catenin activation in response to chemotherapy. Targeting OTULIN and the chemotherapy-induced Wnt/β-Catenin activation may serve as a promising strategy to mitigate drug resistance and reduce metastasis in TNBC patients.
Citation Format: Wei Wang, Li Mingqi, Yayun Chi, Jingyan Xue, Beshoy Fahmy, Jiong Wu, Zhaohui Wu. OTULIN promotes Wnt/β-Catenin activation by genotoxic treatments and enhances drug-resistance in breast cancer [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 4112.
Abstract 4123: ORIC-101 overcomes glucocorticoid receptor-mediated chemoresistance in pancreatic cancer models
Authors: Sun Jessica D. , Zhou Haiying , Kong Wayne , Yuen Natalie , Duong Frank L. , Barkund Shravani , Pankov Aleksandr , McWeeney Dan , Ye Qiuping , Kabbarah Omar , Friedman Lori S. , Daemen Anneleen , Junttila Melissa 
Published: September 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and one of the most lethal cancers, with a 5-year survival rate of 8%. Chemotherapy remains the main treatment option for patients with advanced and metastatic tumors. However, intrinsic resistance to chemotherapeutics and lack of effective targeted therapies are major factors contributing to the dismal prognosis. Activation of glucocorticoid receptor (GR) signaling confers resistance to chemotherapy in solid tumors, making GR antagonism an attractive combination treatment strategy to overcome chemotherapeutic resistance. ORIC-101 is a novel selective GR antagonist under clinical evaluation in combination with anticancer therapies. We previously reported that ORIC-101 can sensitize triple-negative breast cancer cells to chemotherapy by reversing multiple GR-modulated pathways. Here, we investigate the effects of ORIC-101 in preclinical models of PDAC. Employing in vitro functional assays and gene expression analysis, ORIC-101 exhibited chemo-potentiation in a panel of PDAC cell lines. Biomarker analysis of transcription activity following ORIC-101 treatment in vitro confirmed pharmacodynamic (PD) modulation of core GR target genes, indicative of suppressed GR signaling. Extending these findings in vivo across several PDAC xenograft models (SW1990, BxPC3, and HPAC) revealed that ORIC-101 blocks GR transcriptional activity induced by dexamethasone in a dose-dependent manner. The PD modulation observed in vivo correlated with ORIC-101 plasma exposure. Consistent with ORIC-101's ability to suppress GR activity, in vivo efficacy studies in combination with paclitaxel significantly inhibited PDAC tumor growth compared to the paclitaxel control group. These results in PDAC preclinical models support the clinical development of ORIC-101 in overcoming GR-driven chemoresistance. A phase 1b study of ORIC-101 in combination with nab-paclitaxel in patients with advanced or metastatic solid tumors is ongoing (NCT03928314).
Citation Format: Jessica D. Sun, Haiying Zhou, Wayne Kong, Natalie Yuen, Frank L. Duong, Shravani Barkund, Aleksandr Pankov, Dan McWeeney, Qiuping Ye, Omar Kabbarah, Lori S. Friedman, Anneleen Daemen, Melissa Junttila. ORIC-101 overcomes glucocorticoid receptor-mediated chemoresistance in pancreatic cancer models [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 4123.
Abstract 4138: Glycogen synthase kinase-3 inhibition impairs DNA damage response through ubiquitin ligase hHYD-mediated TopBP1 degradation
Authors: Ding Li , Roeck Kaely R. , Alekhina Olga , Schmitt Daniel M. , Billadeau Daniel D. 
Published: September 2020

Abstract
Glycogen synthase kinase-3 (GSK-3) is overexpressed and accumulates in the nucleus in several human malignancies including pancreatic cancer. We recently demonstrated that GSK-3 inhibition sensitizes pancreatic cancer cells to chemotherapy by abrogating the TopBP1/ATR-mediated DNA damage response. Specifically, GSK-3 kinase activity is required to stabilize TopBP1 protein. Herein, we investigated the mechanism by which GSK-3 phosphorylation of TopBP1 prevents its degradation. Interestingly, GSK-3 inhibition not only decreased the total levels of TopBP1, but also reduced the ability of TopBP1 to bind chromatin following gemcitabine treatment. Mutation of a putative GSK-3 phosphorylation site in TopBP1 (S860A) resulted in decreased TopBP1 stability and chromatin recruitment, whereas a phosphomimetic mutant (S860E) had the opposite effect. Furthermore, we found enhanced TopBP1 ubiquitination after GSK-3 inhibition as well as an increased interaction between TopBP1 and hHYD, an ubiquitin ligase that has been shown to ubiquitylate TopBP1 resulting in its degradation. Significantly, the S860A mutation showed a stronger interaction with hHYD compared to WT or the S860E mutant of TopBP1. In conclusion, our study identifies GSK-3 phosphorylation of TopBP1 as a mechanism to prevent the interaction with and ultimate ubiquitylation-mediated degradation by hHYD.
Citation Format: Li Ding, Kaely R. Roeck, Olga Alekhina, Daniel M. Schmitt, Daniel D. Billadeau. Glycogen synthase kinase-3 inhibition impairs DNA damage response through ubiquitin ligase hHYD-mediated TopBP1 degradation [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 4138.
Abstract 4139: Investigations of drug synergy reveal promising efficacy of EphA2 inhibition combined with CDK inhibition in triple-negative breast cancer
Authors: Wilson Kalin L. , Brantley-Sieders Dana M. 
Published: September 2020

Abstract
Triple-negative breast cancer (TNBC) is an aggressive malignancy with poor prognosis relative to other breast cancers. Due to its lack of expression of commonly targeted cell surface markers and hormone receptors, there is a dearth of precision treatment options for this malignancy, with chemotherapy and radiation therapy remaining the major mainstays of care. Our group has previously reported that the receptor tyrosine kinase EphA2 is enriched in the basal-like/triple-negative breast cancer subtype and that this expression is associated with reduced recurrence-free survival. Furthermore, genetic knockdown or inhibition of EphA2 with the small molecule ALW-II-41-27 (ALW) reduces cancer cell growth in vitro and in vivo. In these studies, we sought to investigate whether the antitumor properties of ALW can be augmented by addition of other compounds to further reduce cancer cell growth and induce apoptosis. To this end, TNBC lines MDA-MB-231, BT-549, HCC1395, and HCC1187 were seeded in 96-well plates and exposed to ALW alone or in combination with chemotherapeutic agents doxorubicin and paclitaxel, CDK inhibitor SCH-727965, and MCL-1 inhibitor S63845 and cell viability assessed by MTT assay at 48 hours. While there was no significant reduction in viability for cells treated with ALW plus chemotherapy and no consistent improvement with addition of S63845 across cell lines, the combination of ALW with SCH-727965 performed significantly better than either drug alone (p &lt; 0.05) in HCC1395 and BT-549 cells. To evaluate drug synergy, cells of all lines above were exposed to variable concentrations of SCH-727965, ALW, and the combination in a fixed ratio of their respective IC50 values to generate dose response curves, and these data analyzed via CompuSyn software. Combination indices (CI) were &lt;1 for the majority of conditions across all cell lines, supporting synergistic interaction. Effects were most pronounced in HCC1395 cells with average CI 0.82. Furthermore, TUNEL assays show that addition of SCH-727965 to ALW significantly increases the induction of apoptosis by HCC1395 and HCC1187 cells. These preclinical studies demonstrate that combination of ALW and SCH-727965 potently reduces TNBC cell growth and promotes cell death, representing promising early data on the effects of EphA2 inhibition as part of a combination targeted therapeutic approach for triple-negative breast cancer.
Citation Format: Kalin L. Wilson, Dana M. Brantley-Sieders. Investigations of drug synergy reveal promising efficacy of EphA2 inhibition combined with CDK inhibition in triple-negative breast cancer [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 4139.
Abstract 4165: Stable RUNX1p.(Leu56Ser) kinetics during the course of myeloid neoplasms disagree with putative RUNX1 poor prognosis status
Authors: Rai Lena , Phyo Sai , Nacheva Elisabeth 
Published: September 2020

Abstract
‘De novo Acute Myeloid Leukemia (AML) with mutated RUNX1' is a provisional WHO entity with poor prognosis. Missense variant, RUNX1c.167T&gt;C, NP_001745.2:p.(Leu56Ser), with COSMIC reference and FATHMM score of 0.90 suggests it is ‘Pathogenic'; while dbSNP reference and population frequencies of &gt;1.5% suggests ‘Benign'. To address this discrepancy, we studied RUNX1p.(L56S) kinetics in patients with primary or secondary Myeloid neoplasms receiving varied chemotherapy regimen. Bone marrow (BM) samples received were subjected to routine diagnostic algorithm including targeted next-generation sequencing. ¶Out of 227 patients with RUNX1 mutated Myeloid neoplasms, 75 (33%) had RUNX1p.(L56S) making it the most frequent RUNX1 variant (Table-1). RUNX1p.(L56S) was present at ≈55% (46.6%-62.4%) Variant Allele Frequency (VAF) in all cases except one where VAF was 99%. Paired T-test (95% CI) analysis of RUNX1p.(L56S) VAF at diagnosis and remission (p-value=0.89) or relapse/AML transformation (p-value=0.7017) showed no significant difference; similar to that of single nucleotide polymorphisms (SNPs) identified in these cases (remission samples, p-value=0.15; disease evolution, p-value=0.79). In contrast, VAF of other coexisting gene variants was significantly different between diagnostic and remission (p-value=0.02) or relapse/transformation (p-value=0.01) samples, largely owing to acquisition or loss of pathogenic variants. RUNX1p.(L56S) VAF remained stable in sequential samples despite variable BM blasts; nor was it significantly different amongst patients with adverse risk cytogenetics versus those with favourable or intermediate risk (p-value=0.60). In the MDS cohort, RUNX1p.(L56S) was not associated with morphological subtypes. ¶Our data demonstrates RUNX1p.(Leu56Ser) kinetics remain stable during Myeloid disease course, similar to co-occurring SNPs. Our data strongly recommend considering clinical relevance of individual variant when assessing gene mutation-based disease entities.
Table-1:Patient characteristics [includes only those with RUNX1p.(Leu56Ser)]AML (1o or 2o) [No./Median (Range)]MDS (1o or 2o)/MPN [No./Median (Range)]Fisher Exact (2-tailed; 95% CI)No. of patients1758No. of samples76105Genderp-value=0.27Male631Female1127Age (years)57.5 (13.6- 71.4)65 (20.8- 88.2)Cytogenetic risk groupp-value=1.00Favourable228Intermediate1215Adverse33Unavailable012Clinical outcomep-value= 0.24No. of patients in remission (immunophenotypic)79No. of patients with relapse/transformation63Time to event (months)21.0 (8-68)24.0 (10-49)
Citation Format: Lena Rai, Sai Phyo, Elisabeth Nacheva. Stable RUNX1p.(Leu56Ser) kinetics during the course of myeloid neoplasms disagree with putative RUNX1 poor prognosis status [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 4165.
Abstract 4169: The novel thioredoxin reductase inhibitor A-Z2 triggers intrinsic apoptosis and shows efficacy in the treatment of acute myeloid leukemia
Authors: Zhou Fuling , Zhang Dongdong 
Published: September 2020

Abstract
Chemoresistance and high incidence of relapse in acute myeloid leukemia (AML) patients are associated with thioredoxin (Trx) overexpression. Thus, targeting the Trx system has emerged as a promising approach to treating AML. Both arsenicals and azelaic acid (AZA) are thioredoxin reductase inhibitors (TrxR) and possess antileukemic effects. In this study, to exploit agents with higher potency and lower toxicity, we got some organic arsenicals and further synthesized a series of targeted compounds by binding AZA to organic arsenicals, and then screened the most effective one, N-(4-(1, 3, 2-dithiarsinan-2-yl) phenyl)-azelamide (A-Z2). A-Z2 showed a stronger inhibitory effect against TrxR activity and in AML cell lines than did AZA or arsenicals. Additionally, A-Z2 was less toxic to healthy cells compared with traditional chemotherapeutic drugs. A-Z2 induces apoptosis by collapsing of mitochondrial membrane potential, reducing ATP level, releasing of cytochrome c and TNF-α, activating of caspase 9, 8 and 3. Analysis of the mechanism revealed that A-Z2 activates the intrinsic apoptotic pathway by directly selectively targeting TrxR/Trx and indirectly inhibiting NF-κB. A-Z2's better efficacy and safety profile against arsenicals and azelaic acid were also evident in vivo. A-Z2 had better plasma stability and biological activity in rats. A-Z2-treated mice displayed significant symptom relief and prolonged survival in a patient-derived xenograft (PDX) AML model. Herein, our study provides a novel antitumor candidate and approach for treating AML.
Keywords: Acute myeloid leukemia, Thioredoxin reductase, TrxR inhibitor, organic arsenicals, NF-κB
Citation Format: Fuling Zhou, Dongdong Zhang. The novel thioredoxin reductase inhibitor A-Z2 triggers intrinsic apoptosis and shows efficacy in the treatment of acute myeloid leukemia [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 4169.