tbuckley/cabot-search huggingface dataset:
Abstract 3103: Nanoengineered mesenchymal stem cells for targeted lung cancer therapy
Authors: Swayam Prabha, Tanmoy Sadhukha, Buddhadev Layek
Journal: Cancer Research (2017)

Abstract Solid tumors are characterized by increased interstitial fluid pressure and enhanced solid stress, contributing to poor intra–tumoral penetration of nano drug carriers. This offsets the benefits of enhanced permeation and retention effect often attributed to these drug carriers. We have developed a novel cell based targeting approach using mesenchymal stem cells (MSCs) as cellular drug carriers. MSCs have been indicated in the tumor-targeted therapy owing to their selective ability to home to tumors. Our work is focused on non–genetic modification of MSCs by incorporating nanoparticles loaded with chemotherapeutics to create cellular drug depots capable of homing to tumors and releasing drugs over a sustained period of time. Nano–engineered MSCs were manufactured by incubating MSCs with 100µg/mL of paclitaxel loaded (18.5% w/w paclitaxel) PLGA nanoparticles for 4 hours at 37°C without affecting their viability and migration potential. Anti-cancer efficacy of nano-engineered MSCs was evaluated in the A549 lung tumor model. Bioluminescence imaging was used to monitor tumor growth. Animals that developed tumors (lung bioluminescence between 0.5 x 106 – 1 x 106 photons/sec) were randomly divided into different treatment groups. Animals received 1 million nano-engineered MSCs (equivalent to 5 mg/kg of paclitaxel) or 106 MSCs that were either unmodified or loaded with equivalent concentration of blank nanoparticles. The animals were then re-dosed with half the initial dose of MSCs every two weeks. Additional groups of animals received three doses of 40 mg/kg of nanoparticle-encapsulated or free paclitaxel once every week. Treatment with nano-engineered MSCs resulted in a significant inhibition of the lung tumor growth (p &amp;lt; 0.01) compared to that with other controls. It was interesting to note that despite being dosed at a significantly lower concentration of paclitaxel (~17.5 mg/kg vs. 120 mg/kg total dose), nano-engineered MSCs were significantly more effective than free paclitaxel or paclitaxel nanoparticles, suggesting better delivery to the tumor. The biodistribution studies and pharmacokinetic analysis indicated a rapid migration and enhanced retention of the nano–engineered MSCs to the lung tumors. Our studies demonstrated that nano-engineered MSCs are efficient carriers for tumor-specific drug delivery. Funding: R01EB022558 Citation Format: Swayam Prabha, Tanmoy Sadhukha, Buddhadev Layek. Nanoengineered mesenchymal stem cells for targeted lung cancer therapy [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 3103. doi:10.1158/1538-7445.AM2017-3103
Abstract 753: Human epidermal growth receptor-2 immunohistochemistry in gastric cancer
Authors: Babatunde M. Duduyemi, Mary Y. Afihene, Emmanuel A. Asiamah
Journal: Cancer Research (2017)

Abstract Introduction: Gastric cancer is the second most common GI cancers and third leading cause of cancer-related deaths worldwide. In Ghana, gastric cancer contributes significantly to cancer morbidity and mortality. The recent development on the benefit of targeted therapy in the management of gastric cancer using HER-2 monoclonal antibody in combination with chemotherapy has greatly improved the overall survival of patients. This study therefore aims at determining the frequency of Her-2 over-expression in gastric carcinomas in Kumasi, Ghana and comparing with other prognostic factors. Methodology: Demographic data and histological diagnosis were retrieved from the surgical day book of the Department of Pathology, Komfo Anokye Teaching Hospital, Kumasi. The slides were retrieved and reviewed to confirm diagnosis, grading and classification of gastric cancer. Immunohistochemistry was done with anti-HER-2 antibody to confirm HER-2 over-expression. The data was analysed with SPSS version 17. Results: Of the 99 cases of gastric cancer seen over the 8 year period, there were 57 males and 42 females, adenocarcinoma (91), GIST (5) and Non Hodgskin Lymphoma (3). The age range of the study population was 8-90 years with modal age group in the 6th decade. There were more biopsies (63) than resections (36). Of the adenocarcinomas, 45 were poorly differentiated, 38 moderately differentiated and 8 well differentiated. Diffuse type is most common with 47 cases followed by intestinal 41cases and mixed type 3 cases. Three of the 4 patients under the age of 30 years had lymphoma. HER-2 over-expression was seen in 14 out of the 47 tested and all were intestinal type. Conclusion: HER -2 over-expression was seen a small cohort of our patients with gastric cancer especially those with intestinal type. Citation Format: Babatunde M. Duduyemi, Mary Y. Afihene, Emmanuel A. Asiamah. Human epidermal growth receptor-2 immunohistochemistry in gastric 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 753. doi:10.1158/1538-7445.AM2017-753
Abstract 5849: Exosomes promote survival and migration in squamous head and neck cancer cells after ionizing radiation: Evidence for a bystander effect
Authors: Lisa Mutschelknaus, Omid Azimzadeh, Theresa Heider, Klaudia Winkler, Marcus Vetter, Soile Tapio, Juliane Merl-Pham, Rosemarie Kell, Stephan Huber, Lena Edalat, Vanja Radulovic, Natasa Anastasov, Carsten Peters, Michael John Atkinson, Simone Moertl
Journal: Cancer Research (2017)

Abstract Exosomes are important intercellular communicators in the acute radiation stress-response. Here we show that exosomes from head and neck tumor cells confer protective signals to their neighboring cells. This promotes the tumorigenic and radioresistant phenotype of head and neck cancer cells. Isolation of exosomes was performed by serial ultracentrifugation of conditioned medium collected from irradiated or non-irradiated head and neck cancer cell lines BHY and FaDu. Quantification by NanoSight technology indicated an increased exosome release from irradiated compared to non-irradiated cells 24 hours after treatment. To test whether the released exosomes influence the radiation response, exosomes isolated from non-irradiated and irradiated donor cells were transferred on non-irradiated and irradiated recipient cells. We found an enhanced uptake of exosomes, when transferred to irradiated recipient cells compared to the transfer to non-irradiated cells. Functional analyses indicate increased survival of irradiated recipient cells after exosome transfer. These findings mesh with increased DNA double strand break repair that we found after the transfer of exosomes isolated from irradiated cells. Moreover we observed an increased migration and enhanced chemotaxis induced motility after the transfer of exosomes isolated from irradiated cells. To investigate whether differential protein loading into exosomes is responsible for the functional differences we performed proteome analysis of the exosomes. We have identified 679 proteins, of which 39 were up- and 36 were downregulated by irradiation of the donor cells. In a good agreement with our functional assays, the proteome profiling showed that exosomal proteins were mainly involved in wound healing. Exosomes are functional components of the response of tumor cells to therapeutic radiation exposure. In a clinical context these results suggests that radiotherapy modified exosomes may influence the cancer progression, metastasis and therapeutic success. Citation Format: Lisa Mutschelknaus, Omid Azimzadeh, Theresa Heider, Klaudia Winkler, Marcus Vetter, Soile Tapio, Juliane Merl-Pham, Rosemarie Kell, Stephan Huber, Lena Edalat, Vanja Radulovic, Natasa Anastasov, Carsten Peters, Michael John Atkinson, Simone Moertl. Exosomes promote survival and migration in squamous head and neck cancer cells after ionizing radiation: Evidence for a bystander effect [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 5849. doi:10.1158/1538-7445.AM2017-5849
Abstract 2600: Analysis of drug resistance mechanisms and strategies for overcoming resistance in cancer therapy using a curated clinical knowledgebase
Authors: Sara E. Patterson, Cara M. Statz, Taofei Yin, Susan M. Mockus
Journal: Cancer Research (2017)

Abstract Emergence of resistance to targeted therapies is a critical problem in cancer therapy, and understanding both the mechanisms of resistance and strategies for overcoming resistance are crucial to effective treatment of cancer patients. The JAX Clinical Knowledgebase (JAX-CKB), which incorporates data on therapeutic efficacy in the context of molecular alterations, enables rapid analysis of known therapy resistance mechanisms and current data surrounding strategies for overcoming resistance, both in the preclinical and clinical setting. Using the JAX-CKB, we have identified over 1250 lines of evidence corresponding to therapy resistance across tumor types. Of those lines, 147 correspond to therapy resistance in lung cancer. The JAX-CKB contains 22 variants in ALK associated with ALK therapy resistance. Within ALK fusion-positive lung cancer, evidence lines corresponding to ALK inhibitor resistance are associated primarily with complex molecular profiles containing secondary ALK mutations, and mechanisms for overcoming resistance in this setting were associated with use of novel agents. Within EGFR mutation positive lung cancer, lines associated with resistance to EGFR inhibitor therapy included copy number alterations, primary resistance mutations, secondary resistance mutations, and expression level changes. Strategies for overcoming resistance in these settings include novel agents and/or various combination therapies. The JAX-CKB provides a unique global view into current data on resistance to targeted therapies in oncology, which may enable more rapid assessment of effective therapy options and expose opportunities for additional research into strategies for overcoming resistance. Citation Format: Sara E. Patterson, Cara M. Statz, Taofei Yin, Susan M. Mockus. Analysis of drug resistance mechanisms and strategies for overcoming resistance in cancer therapy using a curated clinical knowledgebase [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 2600. doi:10.1158/1538-7445.AM2017-2600
Coil poly(ethylene glycol)-brush-like poly(L-lysine) block copolymers as efficient nanocarriers for insulin delivery
Authors: Xin Li, Fei Tong, Xiangyuan Tang, Shaoqiang Xu, Chao Lu, Wenquan Xia, Yukui Zheng, Daojun Liu
Journal: Journal of Controlled Release (2017)
Abstract 248: Eicosapentaenoic acid attenuates obesity-related hepatocellular carcinogenesis
Authors: Akane Inoue-Yamauchi, Hiroko Itagaki, Hideaki Oda
Journal: Cancer Research (2017)

Abstract The population of obesity caused by excess energy intake and insufficient physical activity is increasing worldwide. Excess accumulation of body fat is a risk of health, indeed obesity is associated with the pathogenesis of various disease including type II diabetes, cardiovascular disease and cancer. Among various kinds of cancer, the risk of hepatocellular carcinoma (HCC) is strongly influenced by obesity. Studies using diet-induced obesity mouse models show that obesity enhances tumor development inducing chronic inflammation in liver. In fact, obesity failed to promote HCC formation in the absence of inflammatory cytokines IL-6 and TNF-α. Eicosapentaenoic acid (EPA), an omega-3 polysaturated fatty acid, has been shown its anti-inflammatory properties and could be therapeutically useful to ameliorate inflammatory diseases. However, little is known about the effects of EPA on liver cancer which is linked to obesity-related inflammation. Therefore, we tested the effects of EPA on obesity-induced inflammatory response and following tumor development. We used the hepatic procarcinogen dietylnitrosamine (DEN) to induce HCC formation in mice. Since high-fat diet (HFD) can induce obesity and significantly enhance HCC formation in DEN-injected mice, this model is useful to assess tumor promotion on obesity. Using this model, we examined therapeutic potential of EPA in obesity-related cancer. As a result, we found that tumor growth in mice fed HFD supplemented with EPA was reduced compared to HFD-fed mice, indicating that EPA attenuates obesity-related hepatocarcinogenesis. Interestingly, EPA had no obvious effects on obesity-induced inflammation, instead, inhibited tumor growth by suppression of the protumorigenic transcription factor Stat3 signaling. These data suggest translational implications for the treatment of obesity-related HCC. Citation Format: Akane Inoue-Yamauchi, Hiroko Itagaki, Hideaki Oda. Eicosapentaenoic acid attenuates obesity-related hepatocellular carcinogenesis [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 248. doi:10.1158/1538-7445.AM2017-248
Abstract 2033: Testing the combined effects of low dose olaparib plus ibrutinib on MCL cytotoxicity
Authors: Adam D. Curtis, Todd A. Hoffert, Sheila S. Rajan, Jens Rueter, Lindsay S. Shopland
Journal: Cancer Research (2017)

Abstract Mantle cell lymphoma (MCL) presents a therapeutic challenge, with frequent relapses after therapy due to high levels of DNA damage and disease evolution. One currently approved MCL therapeutic, ibrutinib, is a tissue-specific agent with relatively few adverse effects. However, ibrutinib is administered at high dose for MCL and provides only a short progression-free survival time. To potentially improve ibrutinib therapy for MCL, we tested the effects of combining ibrutinib with the DNA damage response inhibitor, olaparib, on MCL cells in vitro. We confirmed that ibrutinib monotherapy is cytotoxic to MCL cell lines only at high doses (&amp;gt; 25 μM). In contrast, single-agent olaparib treatment is cytotoxic at lower concentrations (10 μM). Importantly, the addition of low dose olaparib to ibrutinib has an additive cytotoxic effect. Notably, the effects of ibrutinib alone and in combination are dependent on cell medium composition. Our findings support clinical testing of ibrutinib plus olaparib therapy to reduce MCL cell burden initially and to potentially slow MCL cell evolution in the longer term. Our data also suggest the possibility for more effective ibrutinib-based therapy via manipulation of the MCL cell niche. Citation Format: Adam D. Curtis, Todd A. Hoffert, Sheila S. Rajan, Jens Rueter, Lindsay S. Shopland. Testing the combined effects of low dose olaparib plus ibrutinib on MCL cytotoxicity [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 2033. doi:10.1158/1538-7445.AM2017-2033
Abstract 3067: Galectin-3, a target for KRAS-addicted lung cancer
Authors: Laetitia Seguin, Maria F. Camargo, Hiromi I. Wettersten, Shumei Kato, Tami von Schalscha, Kathryn C. Elliott, Sara M. Weis, David A. Cheresh
Journal: Cancer Research (2017)

Abstract KRAS-mutant cancers are notoriously therapy-resistant. While responsible for oncogenesis, mutant KRAS or the sustained activation of KRAS-driven effectors may or may not be required throughout the course of cancer progression. Thus, understanding which tumors remain dependent on oncogenic KRAS could lead to the identification of unique vulnerabilities and opportunities to treat them. We previously discovered that the carbohydrate-binding Galectin-3 (Gal-3) brings together KRAS with integrin αvβ3 at the cell membrane in epithelial cancer cells to promote tumor progression. Here, we show that by directly binding to the cell surface receptor integrin αvβ3, Gal-3 drives addiction to oncogenic KRAS by enhancing macropinocytosis and reducing mitochondrial reactive oxygen species (ROS). This pathway drives increased expression of SOD2, a superoxide dismutase that clears mitochondrial ROS to protect against cell death. Targeting Gal-3 with a clinically active drug decreases macropinocytosis and increases ROS to eradicate KRAS-addicted lung cancer in patient-derived xenografts and spontaneous KRAS-driven lung cancer in mice. Our work reveals Gal-3 as a druggable target for KRAS-addicted lung cancer, and indicates integrin αvβ3 as a biomarker to identify this dependence. Citation Format: Laetitia Seguin, Maria F. Camargo, Hiromi I. Wettersten, Shumei Kato, Tami von Schalscha, Kathryn C. Elliott, Sara M. Weis, David A. Cheresh. Galectin-3, a target for KRAS-addicted lung 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 3067. doi:10.1158/1538-7445.AM2017-3067
FKBP3 Promotes Proliferation of Non-Small Cell Lung Cancer Cells through Regulating Sp1/HDAC2/p27
Authors: Wenzhuo Zhu, Zhao Li, Liwen Xiong, Xiaobo Yu, Xi Chen, Qiang Lin
Journal: Theranostics (2017)

FKBP3 is a member of FK506-binding proteins (FKBPs). Little is known about the expression and functional role(s) of FKBP3 in non-small cell lung cancer (NSCLC). In the present study, we demonstrated up-regulation of FKBP3 expression, both at mRNA and protein levels, in NSCLC samples which closely correlated with poor survival in NSCLC patients. In vitro and in vivo experiments revealed that FKBP3 could promote NSCLC cell proliferation. Furthermore, knockdown of FKBP3 significantly decreased histone deacetylase 2 (HDAC2) expression and increased p27 (a cell cycle inhibitor) expression. HDAC2 modulated the acetylation of histone H3K4 by directly binding to the p27 promoter. The proliferation-promoting effect of FKBP3 was dependent on HDAC2 and inhibited by p27. Also, FKBP3 induced HDAC2 promoter activity via inhibiting the ubiquitination of transcription factor Sp1. Additionally, we identified miR-145-5p as a regulator of FKBP3. miR-145-5p overexpression suppressed cell proliferation of NSCLC cells which was abrogated by FKBP3 overexpression. Taken together, our data clearly show that FKBP3/Sp1/HDAC2/p27 control cell proliferation during NSCLC development.
Abstract 1553: Delineating the role of multiple copies of RNA binding domains in human nucleolin and its homologs using a computational approach
Authors: Kamrun Begum, Ruchama Chaya Steinberg, Anjana Saxena, Shaneen Singh
Journal: Cancer Research (2017)

Abstract All eukaryotes have nucleoli, the sub-nuclear compartments where ribosomes synthesis occur. Nucleolin (NCL), an abundant RNA binding phosphoprotein,constitutes 5-10% of total nucleolar proteins. This multifunctional protein plays defined role/s in many critical cellular processes e.g. chromatin remodeling, ribosome biogenesis, transcriptional and translational regulation of various non-coding as well as coding RNAs. NCL binds to its target RNAs via two or multiple RNA binding domains (RBDs) to control gene expression during normal cell cycle as well as during cellular response to stress. A variety of tumors express elevated levels of NCL where NCL plays a direct role/s in increasing expressions of genes involved in cell survival, angiogenesis and metastasis. A comparison of NCL in various organisms shows that it is highly conserved, especially in its RNA binding domains that can vary in number (2 to 4 consecutive domains). Interestingly, the individual NCL-RBDs are more conserved across different species rather than within the same protein. RBDs are known to interact in pairs with RNA via RNA recognition motifs called RNP motifs, and complementary nucleic acid motifs or elements in RNA allow interaction with NCL. Vertebrate NCL proteins contains four RBDs, however most studies have focused only on the role/s of RDB 1,2; none probing the possible functional redundancy of the additional RBDs nor identifying any target-specificity for the RBD 3,4 in human NCL and other homologs. Earlier data from our lab suggested RBD 3,4 can bind RNA in a structurally analogous manner to RBD1,2 albeit with altered affinity. Here, we continue this research by investigating various homologs of human NCL to better understand the conserved mechanism of its interaction with RNA and whether the additional RBDs, are in fact, redundant in function. To test this hypothesis, RBDs from various homologs were modeled using template based methods and analyzed by a combination of sequence and structure analysis tools. We show that there are key residue differences in individual RBDs from various homologs that potentially manifest as differences in binding affinities. This study reveals new insights into NCL RBD function and describes the evolution of RBD function with respect to nucleic acid binding. Citation Format: Kamrun Begum, Ruchama Chaya Steinberg, Anjana Saxena, Shaneen Singh. Delineating the role of multiple copies of RNA binding domains in human nucleolin and its homologs using a computational approach [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 1553. doi:10.1158/1538-7445.AM2017-1553
Abstract 300: Taeumjowi-tang (TJ001) induces G2/M cell cycle arrest but not apoptosis in p53-mutant prostate cancer via up-regulation of p21WAF/CIP1
Authors: Soo-Yeon Kang, Hyo In Kim, Se Hyang Hong, Jin Mo Ku, Kangwook Lee, Myeong-Sun Kim, Yu-jeong Choi, Chunhoo Cheon, Youme Ko, Ching Wen Huang, Yui Sasaki, Sohyeon Kang, Hye-Sook Seo, Tai Young Kim, Ji Hye Kim, Yong Cheol Shin, Seong-Gyu Ko
Journal: Cancer Research (2017)

Abstract Taeumjowi-tang (TJ001) is a traditional Korean medicine that usually prescribed for Tae-um person to regulate stomach-related symptoms including headache, indigestion, and jaundice. Other studies on anti-obesity effect of TJ001 have also been researched, but have never been reported as a cure for cancer. In the present study, we investigated the molecular mechanism that TJ001 induces G2/M cell cycle arrest in DU145 (p53-mutant) prostate cancer cells. The missense mutation in human p53 gene (TP53) confers oncological effect to tumor suppressor p53-mutant protein. In prostate cancer, this gain-of-function of p53-mutant is associated with androgen-independence, increased angiogenesis, and metastasis. Our in vitro studies showed that a water extract of TJ001 induced G2/M cell cycle arrest via p53-mutant status and p21WAF/CIP1 up-regulation. Conventinally, p21WAF/CIP1 is induced by mediating p53 regulation, but, in experiments, handling the p53-dependent and -independent pathway. Although serine15-phosphorylated p53 and p53 proteins remained unchanged, p21WAF/CIP1 expression is induced and cyclin B1/Cdc2 complex is inactivated by a decrease of cyclin B1. In addition, in p53-independent pathway, the level of Cdc25C expression decreased and Serine-216 phosphorylated Cdc25C increased. Generally, concomitant with G2/M cell cycle arrest come the apoptosis cell death, but in the study, prolonged G2/M cell cycle arrest developed not apoptosis but cell senescence. Therefore, our data suggest that TJ001 is helpful for p53-mutant prostate cancer treatment. Citation Format: Soo-Yeon Kang, Hyo In Kim, Se Hyang Hong, Jin Mo Ku, Kangwook Lee, Myeong-Sun Kim, Yu-jeong Choi, Chunhoo Cheon, Youme Ko, Ching Wen Huang, Yui Sasaki, Sohyeon Kang, Hye-Sook Seo, Tai Young Kim, Ji Hye Kim, Yong Cheol Shin, Seong-Gyu Ko. Taeumjowi-tang (TJ001) induces G2/M cell cycle arrest but not apoptosis in p53-mutant prostate cancer via up-regulation of p21WAF/CIP1 [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 300. doi:10.1158/1538-7445.AM2017-300