bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3721: MMP9 responsive molecular beacon-loaded nanovesicles for imaging and therapy for triple negative breast cancer
Authors: Ranjan Amalendu P. , Fudala Rafal , Shah Sunil , Gdowski Andrew , Kumar Piyush , Grycznski Ignacy , Grycznski Zygmunt , Vishwanatha Jamboor K. 
Published: August 2018

Abstract
African American women are disproportionately affected by triple negative breast cancer (TNBC). Combination of tumor chemotherapy and imaging in an ‘all-in-one system' provides a useful multi-modal approach in the battle against metastatic breast cancer. A promising imaging technique, time gated molecular beacon probes, is a noninvasive and painless method for detection and monitoring. Molecular beacon probe-based theranostic nanoparticles is a novel concept in next-generation medicine that combines simultaneous diagnostics and therapeutics to radically change the way we diagnose, image and treat breast cancer. In this study, we formulated pH sensitive nanovesicles containing molecular beacons specific to MMP-9 for imaging tumor microenvironment along with an anticancer drug, thereby enabling visualization of the tumor together with therapy at the tumor site. This theranostic nanosystem will provide an exciting new tool for breast cancer diagnosis and therapy. Formulation of novel pH responsive nanovesicles were carried out using DMPC and DSPE-PG-8CH. Molecular beacons specific to MMP-9, along with cabazitaxel were encapsulated within the nanovesicles. Characterization of the formulated nanovesicles along with intracellular uptake studies were carried out in breast cancer cell lines. The hydrodynamic diameters of the vesicles were measured using a dynamic light scattering (DLS) instrument (Malvern Zetasizer Nano-ZS) and found to be ~65nm. The zeta potential varied between -55 to -60 mV. Validation of molecular beacon loading in liposome and its stability were done using spectroscopy. Results indicated a molecular beacon loading of ≈29 % in the liposomes and the liposomes were stable for atleast 2 weeks. Comparison of cleavage sequence with time MB and MB-loaded liposome showed that even after 72 hours, molecular beacon released from the liposomes were able to cleave MMP-9 and elicit an effect. This unique and innovative combinatorial theranostic strategy can improve the accuracy of imaging and therapy, provide better assessment of the severity of disease and even monitor the response to drug therapy. This innovative proposal of combining an imaging technique together with delivery of anticancer drug at the tumor site will enhance their clinical potential for diagnosis and therapy in metastatic breast cancer therapy.
Citation Format: Amalendu P. Ranjan, Rafal Fudala, Sunil Shah, Andrew Gdowski, Piyush Kumar, Ignacy Grycznski, Zygmunt Grycznski, Jamboor K. Vishwanatha. MMP9 responsive molecular beacon-loaded nanovesicles for imaging and therapy for triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3721.
Abstract 3723: Nanoengineered mesenchymal stem cells successfully inhibit tumor progression in a syngeneic mouse model
Authors: Layek Buddhadev , Panyam Jayanth , Prabha Swayam 
Published: August 2018

Abstract
Active tumor-targeted drug delivery holds great promise for enhancing therapeutic efficacy and mitigating toxic side effects resulting from nonspecific distribution of chemotherapeutic agents to healthy tissues. However, the majority of current drug delivery strategies depend on inefficient passive accumulation of the drug carrier in the tumor. We have developed a novel and truly active tumor-targeting approach that relies on the tumor tropism of mesenchymal stem cells (MSCs). Our work emphases nanoengineering of MSCs with paclitaxel-loaded nanoparticles to create cellular drug depots capable of selectively homing to tumor sites and releasing the drug over an extended duration. Paclitaxel-loaded PLGA nanoparticles (18.1 ± 1.9 % w/w paclitaxel; diameter of 282.5 ± 5.2 nm; and zeta potential of −18.4 ± 2.5 mV) were formulated by emulsion-solvent evaporation method. Nanoengineered MSCs were generated by incubating MSCs with 100 µg/mL paclitaxel-loaded nanoparticles for 4 hours at 37°C without altering their viability and migration potential. Anticancer efficacy of nanoengineered MSCs was evaluated in C57BL/6 albino female mice bearing orthotopic Lewis Lung Carcinoma (LL/2-luc) tumors. Despite significantly lower doses of paclitaxel (~2.5 mg/kg total dose for nanoengineered MSCs vs. 120 mg/kg for free- and nanoparticle-encapsulated drug), nanoengineered MSCs resulted in significant greater tumor inhibition and superior survival. Furthermore, administration of human MSCs did not elicit any overt immunologic responses in mice. In summary, our results demonstrate that nanoengineered MSCs can serve as an efficient carrier for tumor-specific delivery of anticancer drugs, resulting in greatly improved therapeutic efficacy.
Citation Format: Buddhadev Layek, Jayanth Panyam, Swayam Prabha. Nanoengineered mesenchymal stem cells successfully inhibit tumor progression in a syngeneic mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3723.
Abstract 3724: 5-FU-loaded Nucleoside Nanoparticles for Therapeutic Efficiency of Oral Cancer by various administrations
Authors: FENG HUI , ZHAO Hang , Ji Ning , Li Jing , Wang Zhiyong , jiang lu , Chen Qianming 
Published: August 2018

Abstract
Drug delivery systems are designed to improve bioavailability, reduce degradation, and alleviate the side effect of the loaded drugs. Here, we reported the development of a novel monomeric self-assembled nucleoside nanoparticle (SNNP) into an efficient drug delivery system in such field. Initially, we used a L-configurational pyrimido[4,5-d]pyrimidine nucleoside building nano-bundles and then found its high biocompatibility and low toxicity in vitro and in vivo. Afterwards, the stability in blood circulation and the distribution of 5-FU in OSCC tissues was remarkably increased by the loading with SNNP. Most importantly, 5-FU-SNNP markedly retarded the in vivo growth of OSCC xenografts in mouse models compared with free 5-FU and SNNP by intratumoral, intraperitoneal and intravenous injection, respectively. It was worth mentioning that, SNNP can even reduce the toxic side effects of 5-FU using intraperitoneal injection on OSCC xenograft mouse model. Furthermore, the superior in vivo antitumor efficacy of 5-FU-SNNP compared with free 5-FU and SNNP was related to inhibit cell proliferation and promote cell apoptosis by TUNEL and immunohistochemistry analyses. These findings indicated that when loaded with 5-FU loaded with SNNP has better antineoplastic efficacy using various administrations and lower side-effects, suggesting that this new type of SNNP has a high hope to be a promising candidate nanoparticle-delivery strategy for cancer therapy clinically in the future.
References
Hang Zhao, Hui Feng, Dongjuan Liu, Jiang Liu, Ning Ji, Fangman Chen, Xiaobo Luo, Yu Zhou, Hongxia Dan, Xin Zeng, Jing Li, Congkui Sun, Jinyu Meng, Xiaojie Ju, Min Zhou, Hanshuo Yang, Longjiang Li, Xinhua Liang, Liangyin Chu, Lu Jiang, Yang He, and Qianming Chen. Self-Assembling Monomeric Nucleoside Molecular Nanoparticles Loaded with 5-FU Enhancing Therapeutic Efficacy against Oral Cancer. ACS nano. 2015; 9(10): 9638 - 9651.
The authors gratefully acknowledge support from the National Natural Science Foundation of China (81520108009, 81500860,81700988).
Citation Format: HUI FENG, Hang ZHAO, Ning Ji, Jing Li, Zhiyong Wang, lu jiang, Qianming Chen. 5-FU-loaded Nucleoside Nanoparticles for Therapeutic Efficiency of Oral Cancer by various administrations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3724.
Abstract 3787: Exploring the effect of chemotherapies on STING-dependent cytokine release
Authors: Wilkinson Richard D. , Johnston David I. , Parkes Eileen E. , McCabe Nuala , Kennedy Richard D. 
Published: August 2018

Abstract
Introduction: Blockade of PD-1/PD-L1 has shown potent antitumor activity but these therapies are limited to certain diseases with higher intrinsic somatic mutation burden. A key research priority is now optimising response to these agents in diseases with limited clinical response. Activation of the cGAS-STING innate immune pathway has been identified as synergistic with anti-PD-1 therapy, and also a means of overcoming resistance to IO (immune-oncology therapy). We have reported activation of the cGAS-STING immune pathway as a result of cytosolic DNA released in response to intrinsic and extrinsic DNA damage, and that upregulation of PD-L1 in response to DNA damage is dependent on STING. Therefore, activating the STING pathway as a combination treatment with IO therapy could result in improved clinical responses. Experimental procedures: We perform qPCR analysis of the STING target genes, CXCL10/CCL5 after treatment with different classes of chemotherapy. We perform immunofluorescence to determine dsDNA translocation to the cytosol and the requirement of STING for this, an siRNA screening approach was used to identify the key nucleases involved in cytosolic dsDNA translocation and chemokines expression. Results: We observed increased expression of CXCL10/CCL5 gene expression following treatment with the topoisomerase I (irinotecan) and II (Doxorubicin and Etoposide) inhibitors. This chemokine expression was associated with increased expression of dsDNA in the cytosol. Using an siRNA approach, depletion of STING and the DNA nuclease MUS81 demonstrated abrogation of CXCL10/CCL5 expression following treatment with Doxorubicin. Conclusions: Here, we show that topoisomerase I and II inhibitors are the most potent chemotherapy at activating the cGAS-STING pathway and associated expression of interferon-dependent chemokines. We propose that combination therapies of topoisomerase I and II inhibitors with IO therapy will be effective in tumours which have had limited clinical response to single agent IO therapy.
Citation Format: Richard D. Wilkinson, David I. Johnston, Eileen E. Parkes, Nuala McCabe, Richard D. Kennedy. Exploring the effect of chemotherapies on STING-dependent cytokine release [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3787.
Abstract 3811: Targeted Interleukin 2 and synergy with immune check-point inhibitors
Authors: Hutmacher-Berndt Cornelia Deborah , Neri Dario 
Published: August 2018

Abstract
Systemic high-dose Interleukin 2 (IL2) is able to elicit complete responses in patients suffering from metastatic melanoma. However, the majority of patients cannot receive the whole treatment dose due to severe toxicities. Other approved drugs for the treatment of metastatic melanoma include chemotherapeutics (e.g. Dacarbazine), a protein kinase B-raf inhibitor (Vemurafenib) and an immune check-point inhibitor (Ipilimumab, an anti CTLA-4 antibody). These drugs provide a clear benefit to patients, but cancer cures are still rare.
Targeting IL2 to the site of disease represents a promising strategy to circumvent the toxicity and maximize the efficacy of this immunomodulatory payload. Various formats of targeted IL2 fusion proteins are currently in clinical development. Furthermore, recent successful approaches in the field of immunotherapy focus on the inhibition of check-point pathways, aiming to release the immunosuppressive brakes of the immune system. To explore the possibility of improving therapeutic efficacy of the single agents, a targeted version of IL2 (namely F8-IL2, where the F8 antibody recognizes the alternatively-spliced extra-domain A of fibronectin) was investigated in combination with an anti PD-1, anti PD-L1, or anti CTLA-4 antibody in an immunocompetent mouse model of CT26 colon carcinoma. In a first study, the combination of F8-IL2 and CTLA-4 blockade led to significant tumor growth retardation (curing 3/ 5 mice). Increasing the dose of F8-IL2 from 30 to 45 µg led to a 100 % cure rate with no signs of toxicity (body weight loss &lt;5 %). Moreover, all cured mice acquired protective long-term immunity, which prevented tumor growth upon subsequent rechallenge with CT26 colon carcinoma cells. Furthermore, high dose F8-IL2 combined with the anti PD-1 antibody showed better therapeutic results than the respective monotherapies. In contrast, combination of F8-IL2 with the anti PD-L1 antibody did not improve the therapeutic outcome.
Taken together, these data provide a strong rationale for the clinical use of targeted IL2 in combination with Ipilimumab.
Citation Format: Cornelia Deborah Hutmacher-Berndt, Dario Neri. Targeted Interleukin 2 and synergy with immune check-point inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3811.
Abstract 383: Metabolomic analysis of uterine serous carcinoma with acquired resistance to paclitaxel
Authors: Seino Manabu , Ohta Tsuyoshi , Sakaki Hirotsugu , Sudo Takeshi , Nagase Satoru 
Published: August 2018

Abstract
Introduction: Uterine serous carcinoma (USC) is more aggressive than other subtypes of endometrial carcinoma and is associated with a poor prognosis. We analyzed the metabolomic profile of USC with acquired resistance to paclitaxel.
Method: We compared metabolic profiles and reactions to paclitaxel in both a wild-type USC cell line (USPC-1) and PTX-1, a cell line derived from USPC-1 that acquired paclitaxel resistance, using a capillary electrophoresis CE-MS/MS system.
Results: Glutathione (GSH) concentration in PTX-1 cells was higher than in USPC-1 cells. In addition, GSH concentration in the USPC-1 cells increased after treatment with paclitaxel but was unchanged in PTX-1 cells. Glucose-6-phosphate (G6P) and ribose-5-phosphate (R5P) concentrations in PTX-1 cells were higher than those in USPC-1 cells. G6P concentration in the USPC-1 cells was unchanged after treatment with paclitaxel, while it decreased in PTX-1 cells.
Conclusion: Our results indicate that increased GSH and glucose metabolism may be related to acquiring resistance to paclitaxel in USC and thus may be targets for anti-USC therapy.
Citation Format: Manabu Seino, Tsuyoshi Ohta, Hirotsugu Sakaki, Takeshi Sudo, Satoru Nagase. Metabolomic analysis of uterine serous carcinoma with acquired resistance to paclitaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 383.
Abstract 3844: TAK-659, a SYK kinase inhibitor, demonstrates preclinical antitumor activity in solid tumor models
Authors: Sappal Jessica J. , Theisen Matthew , Xiang Zhongmin , Tirrell Stephen , Christmas Rudy , Yu Jie , Zhang Mengkun , Kannan Karuppiah 
Published: August 2018

Abstract
TAK-659 is a highly potent, reversible inhibitor of spleen tyrosine kinase (SYK) and fms related tyrosine kinase 3 (FLT3) that is currently being investigated in Phase I and II clinical trials. SYK is expressed ubiquitously in hematopoietic cells, and abnormal function of SYK has been implicated in several types of hematopoietic malignancies, including diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), and peripheral T-cell lymphoma (PTCL). Although there are considerable data supporting a role for SYK signaling in hematological cancers, data on the relevance of SYK in solid tumors are emerging. The literature suggests that SYK expression plays a role in the growth of breast and ovarian cancers, and the pancreatic adenocarcinoma microenvironment has been shown to be B-cell rich, giving us a basis to explore the activity of TAK-659 in these indications. Furthermore, ovarian cancer patients with recurrent disease have been shown to have an increase in pSYK at the time of relapse versus at diagnosis, suggesting a role for SYK in chemoresistance. The ability of TAK-659 to inhibit ex vivo colony formation of cells with the ability to grow anchorage independently in semi-solid medium was examined in 31 different human tumor xenografts. TAK-659 showed concentration-dependent inhibition of tumor colony growth in 5/31 tumor models tested, including gastric, breast, and ovarian cancers. Pre-clinically, TAK-659 has exhibited significant antitumor activity in a number of mouse xenograft models of solid tumors. We demonstrate here that daily oral administration of TAK-659 at 60mg/kg over 21 days leads to significant antitumor activity in primary human tumor models of gastric, pancreatic, triple negative breast (TNBC), and ovarian cancers, all of which express pSYK. Significant anti-tumor activity was also observed in the HCC70 TNBC xenograft model which does not express total SYK, demonstrating that TAK-659 may have anti-tumor effects beyond the inhibition of pSYK signaling. A decrease in myeloid derived suppressor cells was seen following TAK-659 treatment in this xenograft model, suggesting an immunomodulatory response may be driving the antitumor activity. Taken together, these data along with published information support the rationale for the investigation of TAK-659 in solid tumor cancer indications.
Citation Format: Jessica J. Sappal, Matthew Theisen, Zhongmin Xiang, Stephen Tirrell, Rudy Christmas, Jie Yu, Mengkun Zhang, Karuppiah Kannan. TAK-659, a SYK kinase inhibitor, demonstrates preclinical antitumor activity in solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3844.
Abstract 3851: Novel small-molecule inhibitor of PD1/PDL1 pathway demonstrated single agent and drug combo effectiveness in cancer immunotherapy
Authors: Wang Yuguang , Zhou He , Zhang Nong , Wang Feilan , Zhao Qiang , Wu Tianzhi , Zhu Haiyan , Liu Yuzhi 
Published: August 2018

Abstract
With 5 antibodies approved for cancer treatments, PD-1/PD-L1 pathway has been the most successful target in cancer Immuno-therapy. Small molecules that inhibit PD-1/PD-L1 interaction are also attractive because their better tissue penetration may lead to stronger and broader anti-tumor efficacy in addition to more convenient dosing regimen. A series of such small molecule inhibitors have been developed by Maxinovel. Among them, Max 10043 and its 2nd generation compound MAX-10129 potently inhibited PD-1/PD-L1 interaction, reversed PD-L1 suppression of anti-CD3 mediated activation of human T cells, and was well tolerated in animal studies. MAX-10043 also demonstrated anti-tumor efficacy in CT26 murine colorectal carcinoma model. MAX-10129, with improved oral bioavailability, displayed significant inhibition of tumor progression with dose dependency in murine colorectal carcinoma MC-38 model. MAX-10129 also demonstrated synergistic anti-tumor efficacy in different combinations with an anti-CTLA4 antibody, an IDO inhibitor Epacadostat, a COX-2 inhibitor Celebrex and a chemo drug Cisplatin, respectively. The p value of the combo treatment group relative to the vehicle group is less than 0.01 for the Epacadostat combo, the Celebrex Combo and the Cisplatin combo while it is less than 0.05 for the anti-CTLA4 combo. More studies are on-going to illustrate mechanism of action as well as the possibility of all oral triple and quadruple combinations . These data suggest the MAX-10129, a small molecule inhibitor of PD-1/PDL-1 interaction, may represent a novel, orally administrated, safe and effective immunotherapy agent.
Citation Format: Yuguang Wang, He Zhou, Nong Zhang, Feilan Wang, Qiang Zhao, Tianzhi Wu, Haiyan Zhu, Yuzhi Liu. Novel small-molecule inhibitor of PD1/PDL1 pathway demonstrated single agent and drug combo effectiveness in cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3851.
Abstract 386: Heme function in promoting tumorigenic potential of lung cancer cells
Authors: Vidal Chantal , Sohoni Sagar , Zhang Li 
Published: August 2018

Abstract
Heme, also known as iron protoporphyrin IX, is an essential molecule for living organisms. Heme serves as a prosthetic group in enzymes, and acts as a signaling molecule in diverse cellular processes. Mammalian cells can synthesize heme endogenously, or they can import heme from circulation via heme transporters. The synthesis of heme is carried out by eight enzymes, the first of which is the rate-limiting enzyme 5-aminolevulinate (ALA) synthase. Heme can also be transported intracellularly by transporters, such as HCP1 (heme carrier protein 1) and HRG1 (heme responsive gene 1). Finally, levels of heme are also maintained by the degrading enzyme, heme oxygenase-1 (HO-1). HO-1 is localized to the endoplasmic reticulum and is the rate-limiting enzyme in the catabolism of heme. HO-1 cleaves heme to biliverdin and carbon monoxide. Biliverdin is converted to bilirubin, which is an antioxidant and scavenger of ROS. Heme also serves as a catalytic site for various proteins that are involved in aerobic metabolism, such as respiratory chain cytochromes. For example, complex II, III, and IV of the mitochondria require heme for proper function. Importantly, epidemiologic studies have shown the association of dietary heme intake, mainly from red meat, with different cancers, including lung cancer. Therefore, we have analyzed the levels of heme synthesis, uptake, degradation, oxygen consumption and mitochondrial proteins in an immortalized, nontumorigenic human bronchial epithelial cell line (NL20) compared to the tumorigenic counterpart (NL20-TA). These studies showed that the tumorigenic cell line expressed significantly higher levels of heme flux compared to the nontumorigenic cell line. This led us to alter heme availability by overexpressing the rate-limiting enzyme of heme synthesis as well as the rate-limiting enzyme of heme degradation. Experiments are under way to characterize their effects on tumor growth and metastasis.
Citation Format: Chantal Vidal, Sagar Sohoni, Li Zhang. Heme function in promoting tumorigenic potential of lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 386.