bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2969: Senescent stromal cells promote cancer resistance via Sirt1 loss-potentiated biogenesis of small extracellular vesicles
Authors: Han Liu , Long Qilai , Lam Eric , Sun Yu 
Published: September 2020

Abstract
Cellular senescence is a potent tumor-suppressive program that prevents neoplastic events. Paradoxically, senescent cells develop an inflammatory secretome, termed the senescence-associated secretory phenotype (SASP) and implicated in age-related pathologies including cancer. Here we report that senescent cells actively synthesize and release small extracellular vesicles (sEVs) with a distinctive size distribution. Mechanistically, SIRT1 loss supports accelerated sEV production despite enhanced proteome-wide ubiquitination, a process correlated with ATP6V1A downregulation and defective lysosomal acidification. Senescent stromal cell-derived sEVs carry a special set of cargoes, including small RNA species such as microRNAs (miRNAs) whose spectrum markedly differ from that of proliferating cell-secreted sEVs. Once released, senescent stromal sEVs significantly alter the expression profile of recipient cancer cells and enhance their aggressiveness, specifically drug resistance mediated by expression of ATP binding cassette subfamily B member 4 (ABCB4). Targeting SIRT1 with an agonist SRT2104 prevents development of cancer resistance through restraining sEV production by senescent stromal cells. In clinical oncology, sEVs in peripheral blood of posttreatment cancer patients are readily detectable by routine biotechniques, presenting a novel biomarker to monitor therapeutic efficacy and predict long term outcome. Together, our study identifies a distinct mechanism supporting pathological activities of senescent cells, and provides a novel avenue to circumvent advanced human malignancies by co-targeting cancer cells and their surrounding microenvironment, which contributes to drug resistance via secretion of sEVs from senescent stromal cells.
Citation Format: Liu Han, Qilai Long, Eric Lam, Yu Sun. Senescent stromal cells promote cancer resistance via Sirt1 loss-potentiated biogenesis of small extracellular vesicles [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 2969.
Abstract 2975: Imipramine, an FDA approved anti-depressant, suppresses triple negative breast cancer growth and progression through inhibition of FOXM1 and DNA repair pathways
Authors: Timilsina Santosh , Rajamanickam Subapriya , Jatoi Ismail , Chen Yidong , Vadlamudi Ratna , Kaklamani Virginia , Rao Manjeet K. 
Published: September 2020

Abstract
Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer that lacks effective targeted therapies with the main therapeutic option being cytotoxic chemotherapies, which have toxic side effects on patient's health. Less toxic alternatives that could target key pathways that are altered in TNBCs could lead to better outcomes for the patients. Important distinguishing traits of TNBCs is the high amounts of genomic instability and high number of alterations in key proteins in DNA repair and cell proliferation that helps the cancer grow, survive and progress. Previous findings from our lab indicate that Imipramine Blue, a derivative of anti-depressant imipramine, may be a potential inhibitor of proliferation and DNA repair pathways in TNBC. Therefore, we tested the therapeutic efficacy of Imipramine on TNBCs using various in vitro assays for viability, migration, invasion as well as in vivo xenograft assays for tumor growth. Our results demonstrate that Imipramine inhibits cancer cell viability and progression in vitro. Similarly, in vivo xenograft assays showed reduced tumor growth in pre-clinical models upon imipramine treatment. Importantly, at the molecular level, Imipramine treatment suppressed key players in both cell proliferation, and DNA repair pathways, including FOXM1; a proto-oncogene that is a master regulator of both cell proliferation and DNA Repair pathways. These findings suggest that Imipramine may be a potential therapeutic option for TNBC patients. A clinical trial is ongoing to test the efficacy of Imipramine in Triple Negative Breast Cancer patients.
Citation Format: Santosh Timilsina, Subapriya Rajamanickam, Ismail Jatoi, Yidong Chen, Ratna Vadlamudi, Virginia Kaklamani, Manjeet K. Rao. Imipramine, an FDA approved anti-depressant, suppresses triple negative breast cancer growth and progression through inhibition of FOXM1 and DNA repair pathways [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 2975.
Abstract 2988: PLAC8 confers the chemoresistance of placental site trophoblastic tumor and choriocarcinoma to etoposide in an autophagy-dependent manner
Authors: Feng Xuan , Yu Huandi , Tao Xiang , Du Yan , Wu Jing , Yu Yinhua , Xu Congjian , Zhao Hongbo 
Published: September 2020

Abstract
Chemotherapy is commonly used to treat gestational trophoblastic neoplasia (GTN), but placental site trophoblastic tumor (PSTT) and a small proportion of choriocarcinoma demonstrate chemotherapy resistance, which becomes the major obstacle for the treatment. However, the underlying mechanism remains elusive. In the present study, we found that PLAC8 expression in PSTT tissues was higher than that in placental site intermediate trophoblast cells. In addition, PLAC8 was also highly expressed in human choriocarcinoma tissues compared with normal placental villi. Over-expression of PLAC8 inhibited p53 protein stability and induced the autophagic flux in HTR-8 and JAR cells. PLAC8-induced autophagic activity could be partially recovered by p53 re-expression. Further, PLAC8 over-expression conferred chemoresistance of trophoblast cells to etoposide, which can be effectively abrogated by autophagic inhibitors 3-methyladenine (3-MA) or chloroquine (CQ). In conclusion, over-expression of PLAC8 in PSTT and choriocarcinoma tissues may endow the trophoblast cells with enhanced chemoresistance via inducing autophagy activity. Therefore, PLAC8 may serve as a potential therapeutic target for the treatment of PSTT and choriocarcinoma.
Citation Format: Xuan Feng, Huandi Yu, Xiang Tao, Yan Du, Jing Wu, Yinhua Yu, Congjian Xu, Hongbo Zhao. PLAC8 confers the chemoresistance of placental site trophoblastic tumor and choriocarcinoma to etoposide in an autophagy-dependent manner [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 2988.
Abstract 2998: Linear confined space migration induces treatment resistance and gene expression changes in glioblastoma multiforme
Authors: Babu Anish , McKernan Patrick , Cai Xue , Battiste James 
Published: September 2020

Abstract
Background: Glioblastoma Multiforme (GBM), an aggressive brain cancer, is known for its treatment resistant recurrence and lethality. The diffuse migration and invasion of GBM cells commonly occurs along brain white matter tracts in linear confined spaces between axons and has significant clinical implications as these cells survive initial therapies forming the main source of recurrent tumors resistant to therapies. In this context, this project aims to analyze the treatment resistance mechanism associated with linear confined space migrating cells (LCSM) to devise a better treatment strategy for GBM.
Methods: We used a combination of microfluidic technology (5 µM wide channels in PDMS block) emulating linear white matter tracts in brain and standard molecular analysis (confocal microscopy, high content imaging, western blot, and flow cytometry) to investigate LCSM cells compared to Standard Monolayer Culture cells (SMCs) for the mechanism of drug resistance. Both established and patient derived GBM cell lines were used in the study.
Results: LCSM cells were more resistant to chemo-drugs (Temozolomide and Doxorubicin) than SMCs as observed in cell viability assays. Enhanced drug efflux was observed in LCSM cells compared to SMC cells indicating the activation of drug efflux pumps. Protein expression analysis indicated that ABC drug efflux transporters (ABCB1, ABCC1, ABCG2) were activated or enhanced at varying levels in different LCSM cells compared to SMCs. Pharmacological inhibition of the prominently expressed ABCG2 protein using KO143 resulted in enhanced cell death by chemo drugs, suggesting that chemo resistance in LCSM, at least in part, is conferred by ABCG2 or other efflux transporters. In addition, CD133 (a marker of treatment resistant stem cell population in GBM) and AQP4 (Aquaporin 4; pro-migratory marker in GBM) were also enhanced in LCSM compared to SMC suggesting their possible roles in treatment resistance.
Conclusion: Preliminary studies reveal that the enhanced expression ABC transporters, prominently ABCG2, might be responsible for enhanced drug efflux and low therapeutic sensitivity in GBM- LCSM cells. The over expression of AQP4 and CD133, and differential expression of other genes suggest that more complex mechanisms might be involved, which are currently under investigation.
Citation Format: Anish Babu, Patrick McKernan, Xue Cai, James Battiste. Linear confined space migration induces treatment resistance and gene expression changes in glioblastoma multiforme [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 2998.
Abstract 3000: Evaluating the efficacy of a novel class of covalent microtubule stabilizers in taxane resistant ovarian cancer
Authors: Yee Samantha S.M. , Du Lin , Risinger April L. 
Published: September 2020

Abstract
Ovarian cancer has few targeted therapies and high rates of metastasis. Taxane microtubule stabilizers, including paclitaxel, are a mainstay in the treatment of adult solid tumors as single agents and in combination with other cytotoxic chemotherapies, targeted therapies, and immunotherapies. The standard of care for ovarian cancer patients comprises of combination chemotherapy consisting of a taxane with a platinum agent administered intravenously or intraperitoneally. Although this approach is highly effective initially, up to 70% of ovarian cancer patients will acquire taxane resistance. Therefore, it is essential to identify drugs that retain efficacy in clinically relevant models of taxane resistance, including those with elevated P-glycoprotein (Pgp) expression. The development of a microtubule stabilizer that retains efficacy in taxane resistant ovarian cancer would be optimal since microtubule disruption is proven to be an effective target in this disease. The taccalonolides are a novel class of covalent and irreversible microtubule stabilizers that circumvent clinically relevant forms of taxane resistance in vitro and in vivo breast cancer models. However, the taccalonolides have a narrow therapeutic window and short serum half-life that would benefit from a more targeted delivery. We hypothesized that localized intraperitoneal delivery of the taccalonolides in ovarian cancer models may be an optimal strategy for the treatment of intraperitoneally disseminated disease. We have found that the taccalonolides are less susceptible than paclitaxel to Pgp-mediated drug resistance in a human ovarian cancer cell line model. Additional experiments have demonstrated that the taccalonolides retain long-term antiproliferative and cytotoxic efficacy following acute treatment of human and murine ovarian cancer cells, demonstrating superior cellular persistence as compared to other classes of microtubule stabilizing drugs. We are currently evaluating the efficacy of the taccalonolides in ovarian cancer models using localized, intraperitoneal administration in a syngeneic and orthotopic murine model, which may be optimal for delivery of this irreversible microtubule stabilizer.
Citation Format: Samantha S.M. Yee, Lin Du, April L. Risinger. Evaluating the efficacy of a novel class of covalent microtubule stabilizers in taxane resistant ovarian 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 3000.
Abstract 3008: A new mechanism of drug resistance in cancer: Extracellular ATP-induced resistance through ATP internalization and upregulation of ATP-binding cassette multidrug transporters
Authors: Zhang Haiyun , Wang Xuan , Chen Xiaozhuo 
Published: September 2020

Abstract
Cancer is the second leading cause of death in the US. Multidrug resistance (MDR) and the resulting ineffectiveness of the drug treatment are responsible for most relapses of cancer and cancer-related death. One major mechanism of MDR is the efflux of multiple drugs mediated by ATP-binding Cassette (ABC) multidrug transporters. ABC transporters pump drugs with different structures and mechanisms of action out of cancer cells using ATP-provided energy. And ABC activities is also intimately linked to epithelial mesenchymal transition and metastasis. The opportunistic uptake of extracellular molecules has been named as a key emerging hallmark of cancer metabolism. Intratumoral extracellular ATP levels of various cancer types are 103 to 104 times higher than those in their corresponding normal tissues. Our previous studies have shown that extracellular ATP is internalized by cancer cell via macropinocytosis, and promotes cancer drug resistance by directly fueling ABC transporters and increase its drug efflux activities. However, whether extracellular ATP can induce change in the expression of ABC transporters and the underlying mechanisms remain unclear. Our results from quantitative reverse transcription PCR and flow cytometry show that extracellular ATP significantly alters mRNA levels and cell surface expression of ABC transporters. These results suggest that extracellular ATP has profound regulatory effects on ABC transporters and thus promotes drug resistance, linking the ATP-rich tumor microenvironment with cancer drug resistance. On-going studies include identification of mechanisms for the extracellular ATP-induced drug resistance via ABC transporters. The completion of the study will expand our understanding of the roles of extracellular ATP in cancer, and reveal new therapeutic targets for reducing drug resistance and enhancing anticancer efficacy of chemotherapeutics and targeted drugs.
Citation Format: Haiyun Zhang, Xuan Wang, Xiaozhuo Chen. A new mechanism of drug resistance in cancer: Extracellular ATP-induced resistance through ATP internalization and upregulation of ATP-binding cassette multidrug transporters [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 3008.
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: Sahin Ilyas , Zhang Shengliang , Zhou Lanlan , Dizon Don , Safran Howard , El-Deiry Wafik S. 
Published: September 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 3012: ONC201 induces apoptosis in gastric adenocarcinoma and exhibits synergy with rhTRAIL
Authors: Parker Cassanda Susan , Zhou Lanlan , El-Deiry Wafik S. 
Published: September 2020

Abstract
Gastric adenocarcinoma is highly lethal with a 5-year survival of only 31.5%, largely due to late presentation of disease and ineffective chemotherapy options. ONC201 is a first-in-class small molecule anti-cancer therapy that induces cell death in many different types of malignant tumors via a multitude of mechanisms including up-regulation of TNF-related apoptosis-inducing ligand (TRAIL) by Foxo3a and death receptor 5 (DR5) via activation of the integrated stress response. We investigated the efficacy of ONC201 in inducing cell death in gastric adenocarcinoma cells as monotherapy and in combination with recombinant human TRAIL (rhTRAIL).
AGS (caspase 8 and PIK3CA mutant, HER2 amplified) and SNU-16 (p53 mutant) gastric adenocarcinoma cell lines were treated with ONC201 and rhTRAIL and viability assays were performed to determine cell line sensitivities. Both cell lines were then treated with combination therapy based on sensitivities and viability assays were performed in order to determine combination indices. Cell death was verified with sub-G1 analysis via flow cytometry and protein expression was established via western blotting.
SNU-16 cells were sensitive to ONC201, while AGS cells were shown to be resistant to monotherapy. Both cell lines were sensitive to rhTRAIL and exhibited synergy when treated in combination with ONC201, resulting in combination indices of less than 0.5 at doses that did not induce cell death in fibroblasts. The proportion of cells in sub-G1 phase of the cell cycle increased in a dose-dependent manner with combination treatment. PARP cleavage increased in a dose-dependent manner after combination therapy, indicating apoptosis and ATF4 and CHOP expression also increased with increasing doses of combination therapy, indicating activation of the integrated stress response.
These results suggest that ONC201 may be an effective therapeutic agent for gastric adenocarcinoma in combination with rhTRAIL by inducing apoptosis via the integrated stress response. We are currently expanding the in vitro model to include additional cell lines SNU-1(Ras mutant, microsatellite instability) and SNU-5 (p53
and CDH1 mutant). We are further exploring the role of ONC201 in priming cells via up-regulation of DR5 receptors such that they have increased sensitivity to rhTRAIL when pretreated with ONC201 as a potential source for the established synergy in gastric adenocarcinoma cells. We will also apply this study regimen to an organoid and in vivo model.
Citation Format: Cassanda Susan Parker, Lanlan Zhou, Wafik S. El-Deiry. ONC201 induces apoptosis in gastric adenocarcinoma and exhibits synergy with rhTRAIL [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 3012.
Abstract 304: Androgen deprivation induces epithelial to mesenchymal transition and neuroendocrine differentiation of prostate cancer via LIF-mediated phosphorylation of Smad2
Authors: Liu Yen-Nien , Lin Shian-Ren , Mokgautsi Ntlotlang , Yeh Hsiu-Lien , Huang Jiaoti 
Published: September 2020

Abstract
The current therapies for prostate cancer, which can either be androgen-sensitive or androgen-insensitive ones, are based on AR-targeting approaches; however, there is no available treatment for neuroendocrine prostate cancer (NEPC). We previously identified the leukemia inhibitory factor (LIF), which is stimulated by androgen deprivation therapy (ADT). Here, we further elucidated the physiological relevance of LIF, whereby the high LIF output is associated with the activation of epithelial-to-mesenchymal transition (EMT), and neuroendocrine differentiation of prostate cancer cells through stimulation of transforming growth factor (TGF)-β signaling. We have elucidated the effect of LIF on inducing the EMT and NEPC progression through the stimulated TGF-β signaling via phosphorylation of Smad2. We also demonstrated that the inverse relationship between inhibition of AR signaling and induction of LIF-Smad2 signaling may predispose prostate cancer to metastasis. Importantly, an established activation in prostate cancer cells was shown between recombinant LIF protein and phosphorylation of Smad2, supporting the connection between LIF and p-Smad2. This was supported by the results obtained in high-LIF samples with elevated expression of p-Smad2 in tissues from high-grade prostate cancer. This study highlights the role of the important crosstalk between the LIF and TGF-β signaling pathways may exist and provide a new direction for investigating NEPC development.
Citation Format: Yen-Nien Liu, Shian-Ren Lin, Ntlotlang Mokgautsi, Hsiu-Lien Yeh, Jiaoti Huang. Androgen deprivation induces epithelial to mesenchymal transition and neuroendocrine differentiation of prostate cancer via LIF-mediated phosphorylation of Smad2 [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 304.