bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6129: A scalable, non-biased screen for isolating functionally metastatic cell populations
Authors: Xiao Jerry , Lekan Alex , Stanton Kelly , Glasgow Eric , Agarwal Seema 
Published: September 2020

Abstract
Up to 90% of cancer-associated deaths are due to metastasis. Nonetheless, the mechanisms of metastasis are poorly understood, largely because of a lack of technologies to routinely and robustly isolate, propagate, and culture metastatic cells. Current cellular models for metastasis are hindered by a lack of scalability, a high cost per experiment, and the length of experiments. In this proof-of-principle study, we injected an invasive triple-negative breast cancer cell line, MDA-MB-231, into zebrafish embryos. Cells were monitored for invasion from the yolk sac into the zebrafish circulatory system, representing a cell population analogous to metastatic, circulating tumor cells. Within 5 days, cells had migrated from the primary injection site to the tail. Tails showing migration of cells were excised, digested, and the labeled human-cancer cells were propagated. Re-injection of propagated cells resulted in serial generations (F1 and F2). The time required for migration decreased with each succeeding generation; with the latest (F2) generation migrating to the tail within 24 hours. In addition to being more invasive, cells that migrated to the tail displayed a more mesenchymal phenotype compared to parental cells. Consistent with this finding, RNA-seq analysis showed an upregulation of genes involved in an epithelial to mesenchymal transition. Moreover, the highest differentially expressed genes have been independently associated with metastasis. Finally, in silico analyses demonstrated that the upregulated genes were clinically significant. Together these data provide proof-of-principle that we have established a scalable, rapid, and robust method that can provide routine access to invasive metastatic cells. The platform combines in vivo and in vitro components that can be used to isolate, enrich, and propagate metastatic cells from individual patients, and has the potential to advance basic and translational research in tumor metastasis. This cellular model relies solely on cell behavior and is a non-biased method that can be widely applied to all tumor types as it does not require specific biomarkers. In addition to providing a tool for advancing our understanding of metastases, the technology has the potential to be used in screening for drugs that specifically target metastatic cells; a critical unmet need in the treatment of human cancers.
Citation Format: Jerry Xiao, Alex Lekan, Kelly Stanton, Eric Glasgow, Seema Agarwal. A scalable, non-biased screen for isolating functionally metastatic cell populations [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 6129.
Abstract 6163: Integrated stress response contributes to triple negative breast cancer radioresistance by regulating glutathione biosynthesis
Authors: Bai Xupeng , Ni Jie , Li Yong , Beretov Julia 
Published: September 2020

Abstract
Triple negative breast cancer (TNBC) is one of the most malignant gynecological cancer worldwide. Radiotherapy (RT) is an effective option for TNBC local control. However, TNBC tends to develop a radioresistant phenotype which results in a poor response of TNBC to following therapy. In this study, we identified integrated stress response (ISR) as the most activated signaling in radioresistant MDA-MB-231, MDA-MB-436, and MDA-MB-468 cells. We found that constitutive phosphorylation of eIF2α in radioresistant TNBC cells promoted the activation of activating transcription factor 4 (ATF4) via increasing its translational efficiency, which elicited the transcription of a set of genes implicated in GSH biosynthesis, including glutamate-cysteine ligase catalytic subunit (GCLC), solute carrier family 7 member 11 (SLC7A11), and cystathionine-γ-lyase (CTH), leading to a higher intracellular level of reduced glutathione (GSH) and an efficient reactive oxygen species (ROS) scavenging after irradiation (IR). Treating radiosensitive TNBC cells with salubrinal, a selective inhibitor of eIF2α dephosphorylation, can mimic the stress-resistant phenotypes of their radioresistant counterparts. In contrast, eIF2α dephosphorylation or ATF4 knockdown accelerated IR-induced ROS accumulation and increased IR-induced cell apoptosis in radioresistant TNBC cells in vitro. In combination with eIF2α dephosphorylation, IR significantly reduced the size and weight of radioresistant TNBC xenograft tumors in vivo. These data reveal ISR as an important mechanism underlying TNBC radioresistance and provide a rationale for exploring eIF2 signaling as a novel therapeutic target for TNBC treatment.
Citation Format: Xupeng Bai, Jie Ni, Yong Li, Julia Beretov. Integrated stress response contributes to triple negative breast cancer radioresistance by regulating glutathione biosynthesis [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 6163.
Abstract 62: Destabilization of NOXA mRNA as a common resistance mechanism to targeted therapies
Authors: Montero Joan , Gstalder Cecile , Kim Daniel J. , Sadowicz Dorota , Miles Wayne , Manos Michael , Cidado Justin R. , Secrist J. Paul , Tron Adriana E. , Flaherty Keith , Hodi F. Stephen , Yoon Charles H. , Letai Anthony , Fisher David E. , Haq Rizwan 
Published: September 2020

Abstract
Most targeted cancer therapies fail to achieve complete tumor regressions or attain durable remissions. To understand why these treatments fail to induce robust cytotoxic responses despite appropriately targeting oncogenic drivers, here we systematically interrogated the dependence of cancer cells on the BCL-2 family of apoptotic proteins after drug treatment. We observe that multiple targeted therapies, including BRAF or EGFR inhibitors, rapidly deplete the pro-apoptotic factor NOXA, thus creating a dependence on the anti-apoptotic protein MCL-1. This adaptation requires a pathway leading to the destabilization of the NOXA mRNA transcript. We find that interruption of this mechanism of anti-apoptotic adaptive resistance dramatically increases cytotoxic responses in cell lines and a murine melanoma model. Durable control of disease in vivo can be achieved with combinations of targeted therapy with an MCL-1 inhibitor. However, consistent with an adaptive resistance mechanism we have identified, the timing of drug treatment strongly influences the efficacy of the combination therapy. Collectively, our results identify NOXA mRNA destabilization/MCL-1 adaptation as a non-genomic mechanism that limits apoptotic responses. Our data indicate that optimal sequencing of MCL-1 inhibitors with targeted therapies could overcome widespread and clinically important therapeutic resistance, and achieve prolonged tumor responses in solid tumors.
Citation Format: Joan Montero, Cecile Gstalder, Daniel J. Kim, Dorota Sadowicz, Wayne Miles, Michael Manos, Justin R. Cidado, J. Paul Secrist, Adriana E. Tron, Keith Flaherty, F. Stephen Hodi, Charles H. Yoon, Anthony Letai, David E. Fisher, Rizwan Haq. Destabilization of NOXA mRNA as a common resistance mechanism to targeted therapies [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 62.
Abstract 6224: Novel antitumor semi-synthetic heliomycin derivatives direct targeting tNOX-NAD+-SIRT1 axis to activate apoptosis/autophagy, as determined by the cellular thermal shift assay (CETSA)
Authors: Chueh Pin Ju , Islam Atikul , Chen Xiao Qi , Chiu Shi Han , Tikhomirov Alexander S. , Shchekotikhin Andrey E. 
Published: September 2020

Abstract
The antibiotic heliomycin (resistomycin) has been studied since the 1950s, however, its low solubility in aqueous media has restricted its systemic bioavailability and therapeutic potential. We recently synthesized a series of novel aminomethyl derivatives that are readily soluble in aqueous solution. In this study, we examined their antiproliferative properties and underlying molecular mechanisms in p53 wild-type and p53-mutated cancer cells. We continuously monitored the cellular impact of these compounds using the xCELLigence System, a label-free, real-time cell monitoring platform that measures electrical impedance, displaying results as cell index values. The results from the system showed that heliomycin and its derivatives exhibited different biological effects on tumor cells. To further our understanding of the interactions between the novel derivatives and cellular targets, we utilized the cellular thermal shift assay (CETSA). Our CETSA results revealed that some of the derivatives that were directly engaged with tNOX enhanced its thermal stability, which in turn resulted in a marked attenuation of the intracellular NAD+/NADH ratio. This attenuated ratio signifies a decrease in the NAD+-dependent activity of Sirtuin 1 (SIRT1) deacetylase and triggers apoptosis/autophagy, with varying amounts of decrease depending on the cellular environment. We have successfully transformed heliomycin into derivatives that are much more soluble, allowing the more efficient modulating of biological activities - a significant step closer towards finding a novel anti-cancer candidate.
Citation Format: Pin Ju Chueh, Atikul Islam, Xiao Qi Chen, Shi Han Chiu, Alexander S. Tikhomirov, Andrey E. Shchekotikhin. Novel antitumor semi-synthetic heliomycin derivatives direct targeting tNOX-NAD+-SIRT1 axis to activate apoptosis/autophagy, as determined by the cellular thermal shift assay (CETSA) [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 6224.
Abstract 6236: Mil protein-shelled gold nanoparticle to treat glioblastoma multiform
Authors: Kim Hyungshik , Park In-Kyu , Huh Kang-Moo , Lee Dong-Yun 
Published: September 2020

Abstract
Gold nanoparticle (AuNP) as a photothermal therapy (PTT) agent has been reported in various application due to its physical properties. If gold nanoparticle can be orally absorbed, its application may be extended. Unfortunately, it has low absorption efficiency from the gastrointestinal (GI) tract to blood stream. To overcome its limitation orally, here we newly synthesized lactoferrin (Lf; a milk protein)-conjugated gold nanoparticles (Lf-AuNP). Interestingly, this Lf-AuNP could be orally absorbed and targeted to the brain cancer cells due to its interaction with lactoferrin receptor (Lf-R) on the intestinal cells, Blood-Brain Barrier (BBB) and cancer cells. Based on these findings, the Lf-AuNP was orally absorbed with higher bioavailability and targeted to the brain cancer cells (U87MG cells) that was orthotopic animal model. Fortunately, when specified wavelength of laser was noninvasively irradiated to the head of orthotopic animals, the Lf-AuNP made the higher temperature to the head, thereby killing the brain cancer cells. Collectively this milk protein-based oral delivery of AuNP could be a promising strategy as a platform technology.
Citation Format: Hyungshik Kim, In-Kyu Park, Kang-Moo Huh, Dong-Yun Lee. Mil protein-shelled gold nanoparticle to treat glioblastoma multiform [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 6236.
Abstract 6259: Exosomal formulation escalates cellular uptake of honokiol leading to enhanced antitumor efficacy in pancreatic cancer
Authors: Khan Mohammad Aslam , Kanchanapally Rajashekhar , Deshmukh Sachin Kumar , Srivastava Sanjeev K. , Singh Seema , Singh Ajay P. 
Published: September 2020

Abstract
Pancreatic cancer (PC) is the third leading cause of cancer-related death in the United States. It is challenging to treat PC due to the existence of intrinsic and extrinsic chemoresistance mechanisms. We previously reported that honokiol, a phytochemical isolated from Magnolia plant, targets important signaling pathways involved in PC associated with survival, chemoresistance and stromal remodeling, and exhibits significant anti-tumor activity both in vitro and in vivo. However, considering poor bioavailability and tumor uptake as major hurdles in clinical translation, we made efforts to develop an exosomal nanoformulation of honokiol. Mesenchymal cell-derived exosomes are non-immunogenic and express surface markers that could support tumor-targeted delivery. Maximum entrapment of honokiol was achieved when it was used in 1:4 weight ratio with exosomes and subjected to 6 cycles of sonication. Data from dynamic light scattering suggested that key features of exosomes (size, polydispersity and integrity) remained intact post-honokiol encapsulation. The comparative half maximal inhibitory concentration (IC50) data suggested 4 to 5 times greater therapeutic efficacy of exosomal honokiol as compared to that of free honokiol. Similarly, exosomal-honokiol had significantly superior effect on cell cycle progression, apoptosis and expression of cell cycle- and survival-associated proteins than that observed in PC cells treated with equivalent doses of free honokiol. We also found that the cellular uptake of honokiol was significantly greater for exosomal-honokiol as compared to its free form. Together, our work is the first demonstration of exosomal encapsulation of honokiol and its improved anti-tumor efficacy against pancreatic cancer.
Citation Format: Mohammad Aslam Khan, Rajashekhar Kanchanapally, Sachin Kumar Deshmukh, Sanjeev K. Srivastava, Seema Singh, Ajay P. Singh. Exosomal formulation escalates cellular uptake of honokiol leading to enhanced antitumor efficacy in pancreatic 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 6259.
Abstract 627: Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma
Authors: Koivisto Christopher Steven , Melodie Parrish , Santosh Bonala , Ngoi Soo , Nahhas Georges J. , Liu Bei , Torres Adrian , Gallagher James , Snchez-Hodge Rebekah , Zeinner Victor , Cohn David , Backes Floor , Goodfellow Paul , Chamberlin Helen , Leone Gustavo 
Published: September 2020

Abstract
Androgen Receptor (AR) signaling is a critical driver of hormone-dependent prostate cancer and has also been proposed to have biological activity in female hormone-dependent cancers, including type I endometrial carcinoma (EMC). In this study, we evaluated the preclinical efficacy of a third-generation AR antagonist, enzalutamide, in a genetic mouse model of EMC, Sprr2f-Cre;Ptenfl/fl. In this model, ablation of Pten in the uterine epithelium leads to localized and distant malignant disease as observed in human EMC. We hypothesized that administering enzalutamide through the diet would temporarily decrease the incidence of invasive and metastatic carcinoma, while prolonged administration would result in development of resistance. Short-term treatment with enzalutamide reduced overall tumor burden through increased apoptosis but failed to prevent progression of invasive and metastatic disease suggesting that AR signaling may have biphasic, oncogenic and tumor suppressive roles in EMC. Enzalutamide treatment increased Progesterone Receptor (PR) expression within both stromal and tumor cell compartments. Prolonged administration of enzalutamide decreased apoptosis, increased tumor burden and resulted in the clonal expansion of tumor cells expressing high levels of p53 protein, suggestive of acquired Trp53 mutations. In conclusion, we show that enzalutamide induces apoptosis in EMC but has limited efficacy overall as a single agent. Induction of PR, a negative regulator of endometrial proliferation, suggests that adding progestin therapy to enzalutamide administration may further decrease tumor burden and result in a prolonged response.
Citation Format: Christopher Steven Koivisto, Parrish Melodie, Bonala Santosh, Soo Ngoi, Georges J. Nahhas, Bei Liu, Adrian Torres, James Gallagher, Rebekah Snchez-Hodge, Victor Zeinner, David Cohn, Floor Backes, Paul Goodfellow, Helen Chamberlin, Gustavo Leone. Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma [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 627.
Abstract 6274: Radiosensitizing effect of beta-Apopicropodophyllin is mediated from ER stress against colorectal cancer
Authors: Kang A-Ram , Lee Na-Kyung , Shin Hyun-Jin , Um Hong-Duck , Park Jong Kuk 
Published: September 2020

Abstract
β-Apopicropodophyllin (APP) is a synthesized derivative of podophyllotoxin (PPT), which is a natural product that has been used as a traditional drug to decrease immunosuppression, exert antiviral effects for the treatment of influenza, venereal warts, measles and herpes, and even to treat skin cancer. In this study, we tested whether β-apopicropodophyllin (APP) could act as a radiosensitizer in colorectal cancer. To demonstrate radiosensitizing activity of APP, several in vitro tests such as clonogenic assay, immunoblotting, Annexin V-Propidium iodide (PI) assay, detection of mitochondrial ROS/intracellular of H2O2, mitochondrial membrane potential detection were performed. We also tested in vivo radiosensitizing activity of APP as performing colorectal cancer-derived xenograft experiments with mice, and detected tumor volumes and apoptotic cell death. Clonogenic assay showed a combination of APP and γ-ionizing radiation (IR) inhibits cell growth and increases cell death in colorectal cancer cells. Several signal transduction pathways were examined for its potential involvement, and then these results indicated enhanced ER stress is main radiosensitization effect of APP as assessed by immunoblotting analyses. In addition, disrupted mitochondrial membrane potential and increased reactive oxygen species (ROS) were also observed in cells co-treated with APP and IR; these phenomena were followed by the cytosolic release of cytochrome c and consequent activation of caspase-3 and -9. Interestingly, pharmaceutical inhibition of JNK or p38, which prevents caspase activation, blocked the APP/IR-induced activations of ER stress and apoptotic cell death. Therefore, our results implied APP has a radiosensitizing function to induce apoptotic cell death via activation of ER stress, disruption of mitochondrial membrane potential, and induction of the caspase pathway via JNK or p38 induction.
Citation Format: A-Ram Kang, Na-Kyung Lee, Hyun-Jin Shin, Hong-Duck Um, Jong Kuk Park. Radiosensitizing effect of beta-Apopicropodophyllin is mediated from ER stress against colorectal 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 6274.
Abstract 6305: Monitoring the activities of ectonucleotidases CD39 and CD73 and their specific modulation by antibodies and small molecules using homogenous HTS formatted platform
Authors: Goueli Said A. , Hsiao Kevin , Zegzouti Hicham 
Published: September 2020

Abstract
The success of immune oncology for treating a wide variety of cancers ushered a new paradigm in cancer therapy. However, due to some limitations in some patients, it is imperative to identify other pathways that are exploited by cancer cells to circumvent immune surveillance, and possibly synergize immune checkpoint treatment in those cases. Recent recognition of significant increase in adenosine levels in the tumor microenvironment and that adenosine/adenosine receptors play a powerful role as immunosuppressant and attenuating several effector T cell functions have spurred interest in targeting ectonucleotidases that generate adenosine. The two main enzymes responsible for generating adenosine in the microenvironment are the ectonucleotidases CD39 and CD73, the former utilizes both ATP and ADP and producing AMP while the latter utilizes AMP and generates adenosine. Thus, these two enzymes combined are the major source for the bulk of adenosine produced in the microenvironment. They were shown to be validated targets in oncology leading to several clinical trials that include small molecules as well as antibodies, showing positive and encouraging results in the preclinical arena. To facilitate the development of novel drugs to target these enzymes, we have developed a platform that can be utilized to monitor the activities of both enzymes in vitro (biochemical) as well as in cells (cell based) assays. It is very sensitive, and the assays are homogenous and enabled us to monitor the activity of both purified enzymes and enzymes bound to the cellular membranes. Most significant is the ability to discern the selectivity of known small molecule inhibitors as well as selective monoclonal antibodies. Our recent expansion of testing of many small molecules and several antibodies have confirmed the utility of this approach for discovering novel therapeutics that might synergize other regiments such as chemotherapies, and in the design of targeting inhibitors. This should speed up screening for novel inhibitors leading to more effective cancer therapy
Citation Format: Said A. Goueli, Kevin Hsiao, Hicham Zegzouti. Monitoring the activities of ectonucleotidases CD39 and CD73 and their specific modulation by antibodies and small molecules using homogenous HTS formatted platform [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 6305.