bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1065: MMP sensitive liposomes followed by radiotherapy improves tumor control in head and neck cancer mice models
Authors: Brogaard Rikke Y. , Khoo Allison , Eliasen Rasmus , Melander Fredrik , Chadha Awalpreet , Aziz Kathryn , Krishnan Sunil , Andresen Thomas L. 
Published: July 2017

Abstract
Many cancers at advanced stages require a combination of chemotherapy and radiotherapy. A big challenge with this approach is accumulated toxicity because both of these treatment modalities are non-selective and inevitably damage non-target tissues. Nanoparticles such as liposomes provide the ability to differentiate between healthy and cancerous tissues and thus offer efficient delivery of chemotherapy to cancerous tissues. Recently, we developed a matrix metalloproteinase (MMP)-sensitive liposomal platform to carry anticancer agents to the tumor. High local expression of MMPs within the tumor microenvironment ensures bioavailability of the carried agent by converting a polyethylene glycol (PEG)ylated anionic liposome into a dePEGylated cationic liposome that is readily internalized by cells. Using oxaliplatin-loaded MMP-sensitive liposomes, we previously demonstrated great in-vivo efficacy in mice bearing CT26 tumors.
In the present study, we assessed the combinatorial effect of MMP-sensitive liposomes and radiotherapy in head and neck squamous cell carcinoma models. Using a clonogenic cell survival assay, we evaluated MMP-sensitive liposomes combined with radiotherapy. A slightly sensitizing effect was produced by oxaliplatin-loaded MMP-sensitive liposomes while free oxaliplatin produced an additive effect. Similarly, levels of platinum intercalated into DNA were three times higher in cells treated with oxaliplatin-loaded MMP-sensitive liposomes than in those treated with free oxaliplatin. The in-vivo efficacy of oxaliplatin-loaded MMP-sensitive liposomes combined with radiotherapy was studied in the same tumor models, FaDu and HN5, where zymogram gels confirmed an MMP-positive tumor microenvironment. MMP-sensitive liposomes and radiation had a much greater anti-tumor effect than any of the monotherapies or free oxaliplatin combined with radiation. In FaDu, the mean tumor size between liposomes + radiation and liposomes only were significantly different (p&lt;0.05). Thus, our preliminary results suggest that MMP-sensitive liposomes in combination with radiation hold a great potential for clinical translation. The MMP-sensitive liposome offers a valuable tool to deliver the payload in a controlled fashion into the tumor microenvironment, where radiation can potentially amplify the therapeutic index.
Note: This abstract was not presented at the meeting.
Citation Format: Rikke Y. Brogaard, Allison Khoo, Rasmus Eliasen, Fredrik Melander, Awalpreet Chadha, Kathryn Aziz, Sunil Krishnan, Thomas L. Andresen. MMP sensitive liposomes followed by radiotherapy improves tumor control in head and neck cancer mice models [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 1065. doi:10.1158/1538-7445.AM2017-1065
Abstract 1149: Targeting Rad6B suppresses melanomagenesis
Authors: Sarma Ashapurna , Petit Sarah , Liu Fangchao , Nangia-Makker Pratima , Mao Guangzhao , Shekhar Malathy 
Published: July 2017

Abstract
Active β-catenin signaling in melanoma is associated with aggressive disease. We have previously shown that Rad6B, an ubiquitin conjugating enzyme, is a positive regulator of β-catenin stability and transcriptional activity, and is itself a transcriptional target of β-catenin. This stabilization is mediated by Rad6B-induced K63-linked polyubiquitination of β-catenin that renders it insensitive to 26S proteasomal degradation. Immunohistochemical analysis of human cutaneous melanoma samples showed the first detectable expression of Rad6B in melanocyte hyperplasia and continued Rad6B and β-catenin overexpression in primary and metastatic melanomas. These data implicate a critical role for Rad6B in melanocyte transformation and a continuing role in melanoma progression. To analyze the role of Rad6B in melanomagenesis, we targeted Rad6B expression/activity in human M14 metastatic melanoma cells by using a Rad6-selective small molecule inhibitor SMI#9 and the CrispR/Cas9 gene editing system. Immunoblot analysis showed that compared to controls, M14 cells treated with SMI#9 showed decreased levels of β-catenin, and β-catenin driven transcriptional targets Rad6, vimentin, Mitf-M, and Melan A. Although Snail levels were not altered, SMI#9 treated cells showed increase in phosphorylated Snail. Immunocytochemical staining verified the western blot data and showed cytoplasmic relocalization of PCNA and Snail in SMI#9 treated cells which is consistent with increase in phosphorylated Snail. Concordant with the decrease in vimentin and unphosphorylated Snail levels, Rad6B-inhibited cells display poor capacity to migrate as compared to controls. Whereas Rad6B knockout cells were severely growth impaired, Rad6B edited clones showing partial expression (potentially from only one allele) similarly showed decreased levels of β-catenin, vimentin, and Mitf-M. Similar to Rad6B-inhibited cells, Rad6B edited cells were migration- and invasion-impaired. Whereas control cells produced robust tumors and overt lung metastases, the Rad6B gene edited cells were poorly tumorigenic. Rad6B gene edited clones showed complete loss of Melan A. Since Mitf-M is a transcriptional regulator of Melan A and a key player in melanocyte lineage specification, our data suggest that targeting Rad6B could potentially inhibit melanomagenesis by reprogramming melanoma cells. Supported by NIH CA178117 and 3Balls Racing.
Citation Format: Ashapurna Sarma, Sarah Petit, Fangchao Liu, Pratima Nangia-Makker, Guangzhao Mao, Malathy Shekhar. Targeting Rad6B suppresses melanomagenesis [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 1149. doi:10.1158/1538-7445.AM2017-1149
Abstract 1407: Translational regulation of RPA2 via IRES by UNR and eIF3a
Authors: Cui Jia-Jia , Wang Lei-Yun , Yin Ji-Ye 
Published: July 2017

Abstract
Purpose:
Translation is a critical step in the process of genetic information expression. Internal ribosome entry site (IRES) element is a RNA sequence with a complex structure, which plays an important role in cap independent translation regulation. The activation of RPA2 IRES element can cause its abnormal expression and finally effects DNA repair pathway. We conducted series of assays to explore the mechanism of translation initiation regulation of RPA2 via IRES by UNR and eIF3a
Methods:
Biotin pull down assay was taken to investigate the physical interaction between RPA2 IRES and UNR. UNR was knocked down and overexpressed in H1299, A549 and SK-MES cell lines. Western blot and real-time PCR were used to detect protein level and mRNA level respectively. For interaction of eIF3a with UNR, CO-IP assay and co-localization assay were conducted. And GST pull down assay was carried out to further identify their exact binding domains. RPA2 IRES-interacting domains of UNR and eIF3a were explored with EMSA assay.
Results:
UNR protein could directly bind to RPA2 IRES as well as to eIF3a, and UNR regulated the protein expression of RPA2 in H1299, A549 and SK-MES cells, while the mRNA level of RPA2 remained no change. UNR interacted with the first domain of eIF3a and with RPA2 IRES via its own first domain. However, we have not found a clue for the direct interaction of eIF3a with RPA2 IRES yet.
Conclusion:
UNR cooperated with eIF3a to regulate the RPA2 IRES activity and hence to regulate the RPA2 protein expression. This might be a regulation mechanism of cellular internal ribosomal entry site affecting translation initiation, the rate-limiting step of translation.
Citation Format: Jia-Jia Cui, Lei-Yun Wang, Ji-Ye Yin. Translational regulation of RPA2 via IRES by UNR and eIF3a [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 1407. doi:10.1158/1538-7445.AM2017-1407
Abstract 1702: Multimeric anti-DR5 IgM antibody displays potent cytotoxicity in vitro and promotes tumor regression in vivo
Authors: Wang Beatrice , Kothambalwala Tasnim , Hinton Paul , Ng Dean , Saini Avneesh , Baliga Ramesh , Keyt Bruce 
Published: July 2017

Abstract
Death receptor 5 (DR5) is a member of the TNF receptor superfamily that induces apoptosis upon receptor trimerization. It is expressed on many tumor types and has therefore been an important target for developing antibody based treatments of epithelial, solid tumors. However several agonistic Anti-DR5 IgG antibodies that have demonstrated efficacy in preclinical models have been unsuccessful in clinical trials, likely due to insufficient receptor crosslinking by bivalent IgGs. We have developed a multimeric anti-DR5 IgM antibody which has strong avidity for the receptor. The IgM binds Colo205 cells and triggers apoptosis, and is 1000-fold more potent than the respective IgG and 100-fold more potent than crosslinked IgG in vitro. Anti-DR5 IgM displays strong in vitro potency across a panel of tumor cell lines, including ones that are IgG-resistant. Anti-DR5 IgM causes tumor regression and delays tumor growth in various in vivo xenograft models including Colo205, HCT15 and MDA-MB231. These results support the development of an human anti-DR5 IgM therapeutic with the potential to treat solid tumors.
Citation Format: Beatrice Wang, Tasnim Kothambalwala, Paul Hinton, Dean Ng, Avneesh Saini, Ramesh Baliga, Bruce Keyt. Multimeric anti-DR5 IgM antibody displays potent cytotoxicity in vitro and promotes tumor regression in vivo [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 1702. doi:10.1158/1538-7445.AM2017-1702
Abstract 193: Inhibitors of MPS1: Discovery of CCT289346, a highly potent, selective and orally available preclinical candidate
Authors: Woodward Hannah L. , Innocenti Paolo , Cheung Kwai-Ming J. , Naud Sébastien , Hayes Angela , Henley Alan T. , Faisal Amir , Mak Grace , Box Gary , Westwood Isaac M. , Carter Michael , Valenti Melanie , Brandon Alexis De Haven , O’Fee Lisa , Saville Harry , Burke Rosemary , Montfort Rob van , Raynaud Florence , Eccles Suzanne A. , Linardopoulos Spiros , Blagg Julian , Hoelder Swen 
Published: July 2017

Abstract
MPS1 (also known as TTK), is a dual-specificity protein kinase and one of the main components of the spindle assembly checkpoint. Cancer cells heavily rely on MPS1 to cope with aneuploidy resulting from aberrant numbers of chromosomes and MPS1 has been found to be upregulated in a large number of tumor types. Extensive work by us and other groups has shown that MPS1 inhibitors are effective against a variety of cancers, particularly when used in combination with other drugs, for example, tubulin-targeting agents. We recently reported the structure-based design and discovery of a series of pyrido[3,4-d]pyrimidines inhibitors of MPS1 (1). Advanced compounds showed very potent inhibition of MPS1 in biochemical and cellular assays. However, these compounds suffered from high lipophilicity and pronounced metabolism in human liver microsomes preventing progression into preclinical development. Here we report the optimisation of this series ultimately yielding CCT289346, our preclinical candidate. CCT289346 shows excellent potency, kinase selectivity, and ADME properties including stability in human liver microsomes. The compound has been produced on a kilogram scale and is currently undergoing preclinical development. We will discuss our design approach and hypotheses leading to the discovery of CCT289346 and disclose in vivo efficacy data. References 1. Innocenti P et al. Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach. Journal of Medicinal Chemistry. 2016; 59(8):3671-88.
Citation Format: Hannah L. Woodward, Paolo Innocenti, Kwai-Ming J. Cheung, Sébastien Naud, Angela Hayes, Alan T. Henley, Amir Faisal, Grace Mak, Gary Box, Isaac M. Westwood, Michael Carter, Melanie Valenti, Alexis De Haven Brandon, Lisa O’Fee, Harry Saville, Rosemary Burke, Rob van Montfort, Florence Raynaud, Suzanne A. Eccles, Spiros Linardopoulos, Julian Blagg, Swen Hoelder. Inhibitors of MPS1: Discovery of CCT289346, a highly potent, selective and orally available preclinical candidate [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 193. doi:10.1158/1538-7445.AM2017-193
Abstract 2183: Targeted delivery of hyaluronic acid-labeled chitosan nanoparticles against CD44 overexpressed endothelial cell for tumor angiogenesis therapy
Authors: Kim Gahee , Han Heedong 
Published: July 2017

Abstract
Objective: RNA interference (RNAi)-based approaches hold great potential for cancer therapy. Here, we developed siRNA-incorporated chitosan nanoparticles coated with hyaluronic acid (HA-CH-NP/siRNA) to target CD44 receptor on the surface of tumor endothelial cells
Methods: Size and zeta potential of HA-CH-NP were measured by light scattering with a particle size analyzer and Zeta Plus. Morphology of HA-CH-NP was observed by atomic force microscopy (AFM). HA-based selective binding of HA-CH-NP on the CD44 positive cells was assessed by flow cytometry and immunohistochemistry (IHC) analysis. Therapeutic efficacy was examined in orthotopic mouse models of ovarian carcinoma. PLXDC1 mRNA was quantified using real-time reverse transcription-polymerase chain reaction (RT-PCR). Additionally, biological effect on angiogenesis (MCD), cell proliferation (Ki67), and apoptosis (TUNEL) in the tumor tissue were examined by IHC analysis.
Results: HA-CH-NP/siRNA was 185 ± 10 nm in size and zeta potential was 26.4 mV, respectively. The loading efficiency of siRNA into HA-CH-NP/siRNA was up to 60%. We confirmed selective binding efficiency of HA-CH-NP/siRNA with CD44+ tumor endothelial cells was increased 2.1-fold compared to CH-NP/siRNA. PLXDC1 silencing using HA-CH-NP/siRNA significantly inhibited tumor growth in A2780 tumor growth in A2780 tumor-bearing mice compared to control (p &lt; 0.0001), and mRNA expression of PLXDC1 was significantly decreased in HA-CH-NP/siRNA treated group. In addition, treatment with HA-CH-NP/siRNA resulted in significant inhibition of cell proliferation (p &lt; 0.05), microvessel density ( p &lt; 0.05), and increased cell apoptosis (p &lt; 0.05).
Conclusion: This study demonstrated that HA-CH-NP/siRNA was a novel and highly selective delivery system for siRNA with potential for broad applications for tumor angiogenesis therapy.
Citation Format: Gahee Kim, Heedong Han. Targeted delivery of hyaluronic acid-labeled chitosan nanoparticles against CD44 overexpressed endothelial cell for tumor angiogenesis 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 2183. doi:10.1158/1538-7445.AM2017-2183
Abstract 2186: Peptide-cleavable maytansinoid (ADCs) induce high bystander killing leading to improved anti-tumor activity in vivo
Authors: Widdison Wayne C. , Costoplus Juliet A. , Ponte Jose F. , Lanieri Leanne , Setiady Yulius , Dong Ling , Skaletskaya Anna , Wu Rui , Qiu Qifeng , Kovtun Yelena , Chari Ravi V. 
Published: July 2017

Abstract
Antibodies targeting surface antigens on cancer cells typically have progressively lower access to tumor cells that are further removed from blood vessels. Also, the antibody will not bind to cells in the tumor mass that do not express antigen, including stromal cells of the tumor, many of which reportedly aid in the survival or metastasis of cancer cells.
ADCs can bind to antigen positive cancer cells, after which they are internalized and catabolized to release one or more cytotoxic metabolite(s) that can kill the targeted cell. Metabolites that are membrane permeable may also diffuse into and kill neighboring cells, often called bystander cells, that would normally be less accessible.
The goal of this work was to design ADCs that would have increased bystander activity, which could result in greater killing of cancer cells and stromal cells in the tumor environment. We have prepared a new type of peptide-cleavable immolative ADC (PCI-ADC) that efficiently releases membrane permeable cytotoxic maytansinoid metabolites upon cleavage of the peptide linker, followed by immolation. Several PCI-ADCs were prepared that release metabolites having different degrees of hydrophobicity. As the hydrophobicity of the metabolite increased, the PCI-ADCs’ bystander activity also increased. The lead PCI-ADC generally displayed a similar degree of in vitro cytotoxicity as maytansinoid ADCs that utilize disulfide linkers, however the PCI-ADC induced significantly more bystander killing. In mice bearing large tumor xenografts (250 mm3) or tumor xenografts that express the target antigen heterogeneously, PCI-ADCs were found to be more efficacious than maytansinoid ADCs that use disulfide linkers, as well as our recently reported peptide-para-anilino maytansinoid ADCs. The nature of the amino acid residues in the peptide linker of the PCI-ADC was also altered so that the tolerability of the ADCs in mice could be increased without impeding efficacy.
In conclusion, we have developed a promising new type of maytansinoid ADC, one that provides a high degree of bystander killing, improved activity in homogeneous and heterogeneous tumor models in vivo, and has a different mechanism of metabolite release than current maytansinoid based ADCs.
Citation Format: Wayne C. Widdison, Juliet A. Costoplus, Jose F. Ponte, Leanne Lanieri, Yulius Setiady, Ling Dong, Anna Skaletskaya, Rui Wu, Qifeng Qiu, Yelena Kovtun, Ravi V. Chari. Peptide-cleavable maytansinoid (ADCs) induce high bystander killing leading to improved anti-tumor activity in vivo [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 2186. doi:10.1158/1538-7445.AM2017-2186
Abstract 2241: Diosmetin induces apoptosis in human prostate carcinoma cells via the Rictor pathway invitro and inhibits tumor growth in vivo
Authors: Patel Riddhi , Pakradooni Rebecca , Khalifa Ahmad , Bhaskaran Natarajan , Shukla Sanjeev 
Published: July 2017

Abstract
Cell growth is a fundamental biological process, where mTOR (mammalian target of rapamycin) pathway has its role, regulates cell growth by coordinating energy and nutrient signals with growth factor. mTOR protein kinase have two different complexes; complex-I contains major component raptor; a target of rapamycin and complex II; insensitive to rapamycin, has major component rictor. Rictor is important as it phosphorylates Ser-473 of Akt/PKB, which is essential for full Akt/PKB activation. Reports suggested that overexpression of mTOR in prostate cancer tissues, which may have potential role in prostate cancer progression. The known mTOR inhibitor rapamycin is not specific for mTOR-II complex, as it doesn’t inhibit main component Rictor. We need to have effective chemo-preventive agents, which can modulate Rictor signaling cascade to inhibit prostate cancer. Diosmetin (5, 7-Trihydroxy-4′-methoxyflavone), a natural flavonoid present in citrus plant, has anti-mutagenic and anti-allergic properties. Earlier we demonstrated growth factors Insulin-like growth factor-1 and cytokine (IL-6) induces Rictor expression, and phosphorylated Akt at Ser-473. Using diosmetin in concentration dependent fashion (5-40µM) to LNCaP and PC-3 cells down regulated phosphorylation of Rictor (Thr1135), Akt (Ser-473) and PKCα (Ser-657) expressions. This resulted in downregulation of survival molecules; Survivin and X-linked inhibitor of apoptosis protein, which induced apoptosis and inhibited cells growth. Luciferase tag PC-3 cells orthotopic implant in ventral prostate of nude mice represented significant decrease in tumor volume of diosmetin (20 and 50µg/animal/day) fed mice compared to control mice. Similarly bioluminescence imaging of orthotopically implanted mice represented decreased tumor luciferase activity after diosmetin feeding than control mice. Moreover, diosmetin feeding to tumor bearing nude mice reduced the phosphorylation of Rictor, (Thr1135), Akt (Ser-473) and PKCα (Ser-657) expressions and induced apoptotic events to inhibit tumor growth significantly. Based on results we may suggest diosmetin can be developed as an anticancer agent for prostate cancer.
Citation Format: Riddhi Patel, Rebecca Pakradooni, Ahmad Khalifa, Natarajan Bhaskaran, Sanjeev Shukla. Diosmetin induces apoptosis in human prostate carcinoma cells via the Rictor pathway invitro and inhibits tumor growth in vivo [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 2241. doi:10.1158/1538-7445.AM2017-2241
Abstract 2515: Understanding metabolic dysfunction in retinoblastoma development
Authors: Guha Nilanjan , Livi Carolina , Babu Vishnu Suresh , Winer Lisa , SA Deepak , Lateef Syed , Gundimeda Seetaraman , Padmanabhan Arunkumar , Dranka Brian , Ghosh Arkasubhra 
Published: July 2017

Abstract
Metabolic dysfunction or reprogramming is the underlying cause of many diseases including cancer. In this study, we looked into the transcriptomic and metabolomic profile of retinoblastoma (Rb), a pediatric eye cancer, from tumor and normal tissue, aqueous humor, vitreous humor and tear. The samples were collected from enucleated eyes of 9 subjects and 2 deceased controls, whose cause of death is not due to any eye related disease. The study was corroborated with cell line models of retinoblastoma, used for metabolic phenotyping. Combined pathway analysis of transcriptomics data from subject tissue samples and retinoblastoma cell line WERI-Rb-1 revealed a significant overlap in the differentially regulated genes belonging to both glycolysis and OXPHOS pathways. The results were correlated with Rb1 overexpressed and its respective control also. To better understand the implications of these two major pathways in the progression of retinoblastoma, metabolic study using Seahorse analyzer enables measurement of extracellular flux (oxygen consumption rate and extracellular acidification rate) to provide insight into mitochondrial function and glycolytic activity. Using a pharmacological approach, the contribution of glucose, glutamine and fatty acid oxidation pathways can be assessed. Overall the study demonstrates the value of using a multi-omics approach with functional metabolic profiling to understand the extent of metabolic dysfunction in retinoblastoma and also to identify implications of various biological pathways in Rb.
Citation Format: Nilanjan Guha, Carolina Livi, Vishnu Suresh Babu, Lisa Winer, Deepak SA, Syed Lateef, Seetaraman Gundimeda, Arunkumar Padmanabhan, Brian Dranka, Arkasubhra Ghosh. Understanding metabolic dysfunction in retinoblastoma development [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 2515. doi:10.1158/1538-7445.AM2017-2515