bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4177: Anticancer agent Aminoflavone restores the expression of tumor suppressor miRNA 26a and inhibits putative stemness biomarker α6-integrin in Tamoxifen resistant cells
Authors: Campbell Petreena , Rowland Leah , Opoku-Agyeman Anna , Mavingire Nichole , Soto Ubaldo , Nagaraj Gayathri , Zhang Yonghong , Chen Sean (Xin) , Wang Charles , Brantley Eileen 
Published: July 2017

Abstract
Despite the efficacy of anti-estrogen agent Tamoxifen, commonly used to treat patients with estrogen receptor positive (ER+) tumors, up to 40% of patients experience recurrence. Breast tumor-initiating cells (TICs), or breast cancer stem cells, exhibit Tamoxifen resistance and contribute substantially to recurrence. We recently demonstrated that investigational anticancer agent Aminoflavone (AF) disrupts mammospheres (in vitro clusters of cells enriched with TICs) by thwarting the expression of α6-integrin. In the current study, we found AF potently inhibited Tamoxifen resistant (TamR) cell growth and blocked Tamoxifen-mediated stimulation of TamR cell proliferation using the Alamar Blue assay. qPCR analyses revealed α6-integrin expression was significantly elevated in ER+ breast cancer cell models of acquired and de novo Tamoxifen resistance relative to Tamoxifen sensitive cells. In particular, AF decreased the expression of both A and B variants of α6-integrin, the B variant being essential for TIC function. Western blotting revealed AF reduced total α6-integrin expression in TamR cells. Furthermore, we found that an anti-α6-integrin blocking antibody sensitized TamR cells to the active Tamoxifen metabolite, 4-hydroxy-Tamoxifen, and enhanced the efficacy of AF in these cells. AF also reduced the protein expression of p-Src, a downstream target of α6-integrin that is linked to Tamoxifen resistance and decreased breast cancer survival. In addition, miRNA sequencing of Tamoxifen sensitive and TamR mammospheres revealed differential expression of several miRNAs. Notably, miR-26a expression was down-regulated 2-fold in TamR mammospheres compared to Tamoxifen sensitive mammospheres and AF restored miR-26a expression 5-fold in TamR mammospheres. Using miRNA target prediction algorithms TargetScan and PicTar, we found miR-26a binding sites on the α6-integrin promoter. Taken together, our data suggest that AF re-expresses tumor suppressor miR-26a and inhibits the α6-integrin/Src signaling axis to reduce TIC capacity and counteract Tamoxifen resistance.
Citation Format: Petreena Campbell, Leah Rowland, Anna Opoku-Agyeman, Nichole Mavingire, Ubaldo Soto, Gayathri Nagaraj, Yonghong Zhang, Sean (Xin) Chen, Charles Wang, Eileen Brantley. Anticancer agent Aminoflavone restores the expression of tumor suppressor miRNA 26a and inhibits putative stemness biomarker α6-integrin in Tamoxifen resistant cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4177. doi:10.1158/1538-7445.AM2017-4177
Abstract 418: Adaptive resistance to chemotherapy in triple-negative breast cancer revealed by single cell DNA and RNA sequencing
Authors: Kim Charissa , Gao Ruli , Sei Emi , Brandt Rachel , Crosetto Nicola , Foukakis Theodoros , Navin Nicholas 
Published: July 2017

Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype that displays extensive intratumor heterogeneity and frequently (46%) develops resistance to neoadjuvant chemotherapy (NAC). Currently, the genomic basis of chemoresistance remains poorly understood. An important question is whether resistance to chemotherapy is driven by the selection of rare pre-existing subclones with genomic mutations and transcriptional programs that confer resistance to chemotherapy (adaptive resistance) or by the spontaneous induction of new mutations and expression changes that confer a resistant phenotype (acquired resistance). To investigate this question we applied single cell DNA and RNA sequencing methods and deep-exome sequencing to longitudinal time-point samples collected from a cohort of 20 TNBC patients. Deep-exome sequencing of the cohort at three time points revealed a random death model, wherein multiple clones were targeted, as opposed to the selection of specific somatic mutations. In contrast, single cell copy number profiling of ~800 cells from 8 patients identified an adaptive resistance model, wherein minor subclones from the pre-treatment tumors were selected and expanded in response to NAC. Similarly, single cell RNA sequencing of ~8000 cells from 8 patients identified subclones with chemoresistant phenotypes that were selected in response to NAC, resulting in the expansion of the resistant tumor mass. These data suggest that chemoresistance evolves through the selection of copy number changes and expression changes in signaling pathways associated with chemoresistance, rather than point mutations. This adaptive resistance model has important translational implications in clinical diagnostics, by suggesting that resistant clones can be detected in TNBC patients prior to the administration of chemotherapy.
Citation Format: Charissa Kim, Ruli Gao, Emi Sei, Rachel Brandt, Nicola Crosetto, Theodoros Foukakis, Nicholas Navin. Adaptive resistance to chemotherapy in triple-negative breast cancer revealed by single cell DNA and RNA sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 418. doi:10.1158/1538-7445.AM2017-418
Abstract 4181: Discovery of a selective small molecule inhibitor of Tankyrase by structure-based screening
Authors: Ryu Hwani , Kim Ah-young , Song Jie-Young , Hwang Sang-Gu , Ahn Jiyeon 
Published: July 2017

Abstract
The Wnt/β-catenin signaling pathway is critical for colorectal cancer (CRC) development, progression and metastasis. Tankyrase enzymes (TNKS1 and TANKS2), members of the PARP (Poly(ADP-ribose)polymerases) superfamily, PARsylate and target Axin for degradation via ubiquitin-proteasome pathway, leading to accumulation of β-catenin into nucleus. In addition, aberrant YAP/TAZ singling contributes to anticancer drug resistance, but inhibition of TNKS suppresses YAP/TAZ signaling through stabilizing Angiomotin (AMOT). Therefore, inhibition of TNKS has emerged as an attractive strategy for treatment of cancers. To identify potent and selective small molecule inhibitors of TNKS1, a TNKS1-ligand docking was used for computational-based virtual screen of a chemical library containing 1.6 million compounds and 24 virtual hits were further subjected to in vitro evaluation for TNKS1 inhibition. Using an in vitro TNKS1 enzyme assay, we identified a novel pyridine derivative (AZ236106) significantly inhibited TNKS1 enzyme activity in a concentration-dependent manner, but not PARP1/2. Treatment of AZ236106 stabilized Axin, reduced β-catenin in nucleus and downregulated β-catenin target genes in DLD-1 cells harboring adenomatous polyposis coli (APC) mutation. Moreover, we observed that AZ236106 inhibited accumulation of YAP in the nucleus and expression of YAP garget genes. Combination treatment of AZ236106 with either radiation or PLX4032, a BRAF inhibitor, decreased cell proliferation and increased apoptotic cell death in DLD-1 and SK-MEL28 cells, compare to AZ236106, radiation or PLX4032 alone. Our findings suggest that AZ236106 may have therapeutic potential in cancers, and could be further refined for efficacy and safety to develop a lead compound.
Citation Format: Hwani Ryu, Ah-young Kim, Jie-Young Song, Sang-Gu Hwang, Jiyeon Ahn. Discovery of a selective small molecule inhibitor of Tankyrase by structure-based screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4181. doi:10.1158/1538-7445.AM2017-4181
Abstract 4196: Anti-tumor activity of a TAM kinase-targeting compound in CT-26 syngeneic mouse model
Authors: Lai Shenshen , Zhang Hong , Yan Jun , Zhang Zaihui 
Published: July 2017

Abstract
Aberrant expression of TAM family receptor tyrosine kinases, comprising Tyro3, Axl and Mer, is found in virtually every type of human cancer. The expression levels correlate positively with disease staging and prognostic outcome, attributing to metastasis and drug resistance. The TAM kinases have recently emerged as a dual oncological therapeutic target, owing to their immunosuppressive activity. Apart from targeting tumor-survival/growth pathways their inhibition also unleash the anti-tumor immunity in the tumor microenvironment. In our efforts to develop small-molecule inhibitors targeting the TAM kinases, we identified SLC-391 as one of the most promising preclinical candidates with potent activity towards both Axl and Mer, which play roles in maintaining tumor survival and immunosuppressive tumor microenvironment, respectively. Pharmacodynamic studies of SLC-391 in CT26 syngeneic mouse model revealed increase in the number of NK cells and the ratio of M1/M2-polarized macrophages in the treatment group relative to the vehicle control, followed by the rise of CD8+ T/Treg ratio and reduction in immunosuppressive myeloid cells. This is indicative of sequential engagement and stimulation of pro-inflammatory innate immune response and adaptive immune response. In addition, a synergistic anti-tumor effect was observed when the anti-PD-1 insensitive CT-26 model was treated with a combination of SLC-391 and an anti-PD-1 antibody, suggesting that blocking the Axl/Mer-mediated immunosuppressive pathway may significantly enhance the therapeutic efficacy of immune checkpoint inhibitors. In summary, the anti-tumor activity of SLC-391 is mediated by directly inhibiting tumor cell growth as well as reversing the immunosuppressive tumor microenvironment.
Citation Format: Shenshen Lai, Hong Zhang, Jun Yan, Zaihui Zhang. Anti-tumor activity of a TAM kinase-targeting compound in CT-26 syngeneic mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4196. doi:10.1158/1538-7445.AM2017-4196
Abstract 420: Preclinical evaluation of the SF3B1 inhibitor E7107 in triple negative breast cancer
Authors: Sridhar Praveen , Chan Stefanie , Lock Ying-Jie , Petrocca Fabio 
Published: July 2017

Abstract
Triple-negative breast cancers (TNBC) are the most aggressive subtype of breast cancer and account for roughly 15% of human breast cancers. No effective targeted therapies are currently available against these tumors, at least in part due to their genetic and epigenetic heterogeneity. Yet, TNBCs are commonly enriched for cells arrested in a progenitor-like state. We therefore performed a genome-wide siRNA lethality screen to identify selective TNBC dependencies associated with this particular phenotype in vitro. These studies led to the identification of several spliceosome genes, including the core splicing factor SF3B1, as selectively and recurrently essential for progenitor-like (or basal-A) TNBC cell lines. On this basis, we examined the antitumor effect of E7107, a clinically tested SF3B1 inhibitor, on multiple TNBC cell lines. In vitro, treatment with E7107 for 24-48 hr selectively killed basal-A cell lines relative to differentiated luminal cell lines, decreasing viability by ≈40% or more in 5 of 6 basal-A lines tested. E7107-treated cells appeared to die of apoptosis based on immunoblotting for multiple apoptotic markers. In mice, E7107 (5 mg/kg i.v. for 4 consecutive days) suppressed the growth of preformed tumors by ≈80% and ≈50% in 2 different cell-line-derived xenograft models and was remarkably well-tolerated at this dose. Of note, tumor response in vivo closely mirrored cell sensitivity in vitro, suggesting that in vitro analysis provides a fair estimate of TNBC response to E7107 in mice. Amongst 2 additional patient-derived xenograft (PDX) models tested, E7107 inhibited tumor growth by ≈50% in one model. Thus, E7107 was therapeutically active against 3 of 4 xenograft models tested. Preliminary mechanistic studies in vitro and in vivo pointed to MCL1 inactivation as a major mechanism of action of E7107 in top responders. Together, these data suggest that the spliceosome is a druggable target in TNBC, and that E7107 or similar SF3B1 inhibitors could be effective in a TNBC subset that needs to be further defined.
Citation Format: Praveen Sridhar, Stefanie Chan, Ying-Jie Lock, Fabio Petrocca. Preclinical evaluation of the SF3B1 inhibitor E7107 in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 420. doi:10.1158/1538-7445.AM2017-420
Abstract 4200: Targeting cancer stem cells in serous ovarian carcinoma using RP6530, a dual PI3k δ/γ inhibitor
Authors: S Sneha , R Nivetha , Nagare R P. , Viswanadha Srikant , Vakkalanka Swaroop , Ganesan T S. 
Published: July 2017

Abstract
Ovarian cancer is one of the most lethal gynecological malignancies as most patients are diagnosed at an advanced stage and have a poor prognosis. Several studies have prospectively isolated cancer stem cells (CSCs) from samples of tumor from patients with serous adenocarcinoma of the ovary (SOC). This has been achieved by using cell surface antigens or functional assays. Targeting this subpopulation could be critical to overcome drug resistance, recurrence, and hence improve the survival of patients. The PI3K pathway is deregulated in 37% of SOC with PI3Kδ and γ amplified in 16% of tumors (TCGA data). We have used a novel and selective PI3K γ/δ inhibitor (RP6530) with high potency against PI3Kγ (IC50=25 nM) and δ (IC50=33 nM) enzymes and selectivity over α (&gt;300-fold) and β (&gt;100-fold) isoforms. RP6530, an orally active and sensitive small molecule inhibitor, is currently being tested in Phase-1 trials in US and Europe to evaluate its safety and efficacy in patients with hematological malignancies. The objective of this study was to test the efficacy of RP6530 against CSCs of EOC. Spheroids, enriched for CSCs were employed as an approach to evaluate the specific potency of the drug. In the experiments, Salinomycin was used as a control drug that targets CSCs. Initially, we have analyzed 3 cell lines (PEO4, OVCAR-5 and CAOV-2) with and without addition of 5µM RP6530. RP6530 significantly inhibited spheroid formation in PEO4 (0.001) and OVCAR-5 (p&lt;0.05) and CAOV-2 (p&lt;0.01) (mean of ≥3 experiments in triplicate). In cell viability assay, RP6530 had no cytotoxic effect as compared to Cisplatin in any of the cell lines. To evaluate the effect of the compound on CSC, we performed analysis of side population (SP) with Hoechst 33342 at 355 nm by flow cytometry. RP6530 either caused a significant reduction (&gt;50%) in the fraction of SP cells (PEO4 and CAOV-2) or was neutral (OVCAR-5) indicating that the compound preferentially targets CSC in ovarian cancer cell lines. Colony assay revealed significantly lesser number of colonies in RP6530 treated cells. Phosphorylation of Akt that is downstream of PI3 kinase was inhibited in a dose dependent manner in all three cell lines. Evaluation of drugs that are intended to target CSCs is different from that of conventional cytotoxic drugs. Taken together, the results indicate that RP6530 shows potent inhibitory effect on CSCs in ovarian cancer cell lines.
Citation Format: Sneha S, Nivetha R, R P. Nagare, Srikant Viswanadha, Swaroop Vakkalanka, T S. Ganesan. Targeting cancer stem cells in serous ovarian carcinoma using RP6530, a dual PI3k δ/γ inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4200. doi:10.1158/1538-7445.AM2017-4200
Abstract 4212: Natural compounds alone and in combination with platinum drugs found to show significant anti-tumour activity against ovarian cancer cell lines
Authors: Anwar Md Sheikh , Yu Jun Qing , Beale Philip , Huq Fazlul 
Published: July 2017

Abstract
Acquired drug resistance remains major problem in platinum based chemotherapy against ovarian cancer. It is believed that elevated expression of NF-kB and AKT/PKB is one of the prime reasons for acquired drug resistance. Since tumour active natural compounds can dampen NF-kB and AKT/PKB expression, it is thought that platinum drugs in combination with the natural compounds may produce synergism in killing tumor cells. The present study aimed to apply combinations of platinum drugs cisplatin, oxaliplatin, and carboplatin with natural compounds mycophenolic acid, honokiol, cholecalciferol and 6-shogaol to four ovarian cancer cell lines: A2780, A2780CisR, A2780ZD0473R and SKOV-3 towards overcoming drug resistance. IC50 values of single compounds were determined followed by administration of binary combinations. Studies on DNA damage, cellular platinum accumulation, and platinum-DNA binding levels were carried out. Proteomic studies will be done to explore the key proteins involve with drug resistance. Mycophenolic acid (IC50: 1.34-7.83 μM) from Penicillium brevicompactum and 6-shogaol (IC50: 6.79-10.20 μM) from Zingiber officinale showed significant activity against ovarian cancer cell lines. Ginger derived pure compound 6-shogaol showed prominent synergism in combination with platinums when administered as a bolus (0/0h) and with 0/4 h sequence. Honokiol from Magnolia virginia alone and in combination with cisplatin showed significant DNA damage in A2780 cell line whereas cholecalciferol did the same to A2780cisR cell line. Bolus combination of cisplatin and 6-shogoal produced increased cellular platinum accumulation and 3 times more Pt-DNA binding than cisplatin alone treated A2780 cells. Though honokiol and cisplatin (0/0 h) combination have half cellular platinum accumulation in compare to cisplatin alone treated A2780 cells but showed 9 times higher Pt-DNA binding. Cholecalciferol and 6-shogaol in combination with cisplatin also showed promising Pt-DNA in A2780CisR cell line. In conclusion, 6-shogaol, cholecalciferol and honokiol showed significant activity alone and in combination with cisplatin and oxaliplatin against ovarian cancer tumour models.
Note: This abstract was not presented at the meeting.
Citation Format: Md Sheikh Anwar, Jun Qing Yu, Philip Beale, Fazlul Huq. Natural compounds alone and in combination with platinum drugs found to show significant anti-tumour activity against ovarian cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4212. doi:10.1158/1538-7445.AM2017-4212
Abstract 4215: Cancer-related fatigue and physical activity vary by age for black women with a history of breast cancer
Authors: Swen Melody A. , Mann Amandeep , Paxton Raheem , Dean Lorraine T. 
Published: July 2017

Abstract
Purpose: Cancer-related fatigue is the most discomforting symptom among women with a history of breast cancer. Black women are more likely to experience risk factors for cancer-related fatigue, like physical inactivity and obesity, yet cancer-related fatigue studies have not explicitly focused on Black women. This cross-sectional analysis assesses cancer-related fatigue and physical activity among Black female breast cancer survivors.
Methods: In May and July of 2012, 266 members of the Sisters Network, Inc completed an online survey on: demographics, cancer history and treatment, fatigue using the 13-item Function Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale, and engagement in ≥150 minutes per week of physical activity (CDC guideline). Multiple linear regression assessed relationships between fatigue and physical activity.
Results: The average participant was 54 (SD=9) with a FACIT score of 13.63, indicating “severe fatigue”. Fatigue was greater (p=0.02) among the 56% of women meeting physical activity guidelines. Multivariable analysis showed that meeting physical activity guidelines (β=-3.01, p=0.01) and higher age group (50-59: -4.75, p=0.001; 60+: -4.38, p=0.01) were associated with greater fatigue. An interaction plot showed that differences in fatigue for those meeting or not meeting physical activity guidelines is largest among Black women under age 50.
Conclusions: Meeting physical activity guidelines was associated with greater cancer-related fatigue, which was most pronounced for those under age 50. Interventions for Black breast cancer survivors with cancer-related fatigue should consider physical activities that can be integrated into existing tasks and provide age-appropriate resources to address physical and emotional fatigue domains.
Keywords: breast cancer; fatigue; age; Black/African-American; physical activity
Citation Format: Melody A. Swen, Amandeep Mann, Raheem Paxton, Lorraine T. Dean. Cancer-related fatigue and physical activity vary by age for black women with a history of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4215. doi:10.1158/1538-7445.AM2017-4215