bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3508: Separate and combined effects of caloric restriction mimetics and autophagy inhibition on KRAS-driven pancreatic adenocarcinoma
Authors: Chen Xuewen , O'Flanagan Ciara H. , Coleman Michael , Der Channing J. , Hursting Stephen D. 
Published: August 2018

Abstract
Calorie restriction (CR) is one of the most effective dietary interventions for reducing cancer risk and progression. However, maintaining a dramatically reduced calorie intake over an extended time period is very challenging for most individuals. Thus a major effort is under way to identify mechanism-based pharmacologic approaches that mimic the anticancer effects of CR without the requirement of reduced calorie intake. We have established that CR exerts antitumor effects at least in part through altered metabolism, reduced circulating growth factors (such as insulin and IGF-1) and reduced signaling downstream of the insulin receptor and IGF-1R along the phosphoinositide 3-kinase/mTOR axis. We have previously shown CR reduced growth of KRAS-driven tumors in vivo, and the antitumorigenic effect was enhanced when combined with autophagy inhibition. Here we evaluated the effects of in vitro CR via glucose and serum modulation, as well as separate and combined effects of CR mimetics and autophagy inhibition on the KRAS-driven murine pancreatic adenocarcinoma (PDAC) cell line, FC1242. Glucose modulation alone via glucose restriction, metformin or AICAR treatment showed no effect on clonogenic growth of FC1242. In contrast, both cell viability and clonogenicity were significantly reduced by serum starvation, rapamycin treatment, IGF-1R/insulin receptor inhibition by BMS-754807, and sirtuin inhibition with nicotinamide, suggesting these cells are dependent on mTOR/IGF-1 signaling. The growth-suppressive effects of these CR mimetics were enhanced when combined with autophagy inhibition via chloroquine or verteporfin. Together, the study indicated the targeting of mTOR or IGF-1 signaling may most closely mimic the growth-suppressive effects of CR, and that co-treatment of these CR mimetics with autophagy inhibition may be an effective strategy for PDAC anticancer therapy.
Citation Format: Xuewen Chen, Ciara H. O'Flanagan, Michael Coleman, Channing J. Der, Stephen D. Hursting. Separate and combined effects of caloric restriction mimetics and autophagy inhibition on KRAS-driven pancreatic adenocarcinoma [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 3508.
Abstract 3532: Bitter melon extract suppresses triple-negative breast cancer growth by inhibiting ACAT1
Authors: Shim So Hee , Steele Robert , Ray Ratna 
Published: August 2018

Abstract
Breast cancer is the most common malignant cancer diagnosed in women worldwide each year. Triple-negative breast cancers (TNBC), defined by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), account for approximately 15% of breast cancers. Moreover, TNBC is usually more aggressive and metastatic with a worse prognosis. Bitter melon (Momordica charantia) is well known as a dietary supplement. Recently, we have shown an anti-cancer activity of bitter melon extract (BME) in breast cancer mouse models, although the mechanism is poorly understood. Furthermore, we became interested to understand the role of BME on cholesterol and lipid metabolism in TNBC. Our mass spectrometry data suggested that stored as a cholesteryl esters (CE) in Lipid droplets (LD) were much lower in BME treated TNBC cells. We found that not only CE but also LD was reduced in BME treated TNBC cells. The acyl-CoA:cholesterol acyl transferase-1 (ACAT-1) catalyzes the formation of CE from free cholesterols together with long-chain fatty acyl coenzyme A. Therefore, inhibition of ACAT-1 resulted in downregulation of CE, and upregulation free cholesterols. The attenuated CE is known to reduce cancer proliferation. Subsequent study demonstrated that BME treatment highly inhibited ACAT-1 in TNBC cells. The upregulated free cholesterol negatively regulates sterol regulatory element-binding proteins (SREBPs), which regulates lipogenesis protein such as fatty acid synthase (FASN) associated with cancer cell proliferation. We also observed that SREBP-1 and -2 were barely detectable, and FASN and low-density lipoprotein receptor (LDLR) were reduced in BME treated TNBC cells as compared to control cells. To our knowledge, this is the first report demonstrating that BME suppresses TNBC cell growth through ACAT-1 inhibition. BME supplement may potentially be an additional regimen in human breast cancer treatment.
Citation Format: So Hee Shim, Robert Steele, Ratna Ray. Bitter melon extract suppresses triple-negative breast cancer growth by inhibiting ACAT1 [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 3532.
Abstract 3641: Use of adjuvant interferon alfa-2b or ipilimumab 10 mg/kg for high-risk patients with melanoma, and associated adverse events and duration of therapy
Authors: Tarhini Ahmad , Gupte-Singh Komal , You Min , Gupta Amit , Kim Le Trong , Rao Sumati 
Published: August 2018

Abstract
OBJECTIVE: Adjuvant systemic therapy with interferon alfa-2b (IFN) or ipilimumab 10 mg/kg (IPI10) has been the standard for high-risk patients with melanoma who have undergone surgery; however, a high proportion of patients remain untreated. This analysis examines the adverse events (AEs) and duration of therapy (DoT) associated with IFN or IPI10. METHODS: A retrospective cohort study was conducted among each of the four US healthcare databases: OptumInsight, IMS PharMetrics, Truven Commercial, and Truven Medicare Supplemental. Patients receiving melanoma-related surgery (lymph node dissection) from July 1, 2006, to September 30, 2016, were identified. The study estimated the incidence rate (IR) per patient per year of AEs that commonly occur with IFN or IPI10 across different DoT levels among patients with melanoma following surgery. RESULTS: Of 46,401 eligible patients with melanoma surgery claims, 2423 (5%) were treated: 2316 with IFN and 107 with IPI10. Mean age was 51.7 years (60.5% male), and mean (standard deviation) Charlson comorbidity index score was 6.6 (2.8) and 7.5 (2.5) for patients prescribed IFN or IPI10, respectively. The DoT (median, mean (SD)) for IFN was 142, 182 (162) days and for IPI10 was 84, 73 (26) days. Similarly, the number of prescriptions (median, mean (SD)) for IFN were 20, 26 (28) and for IPI10 were 4, 3 (1). The overall AE IR per year was 4.4 in patients receiving IFN and 4.9 for those receiving IPI10. Among patients receiving IFN, the most common AEs were hepatitis, nausea, and fatigue (IRs: 0.92, 0.67, and 0.66, respectively). The most common AEs among IPI10-treated patients were fatigue, rash, nausea, and diarrhea (IRs of 0.95, 0.71, 0.66, and 0.63, respectively). AE rates were greater in patients with low DoT compared with those with a high DoT for most AEs in both IFN and IPI10 cohorts. CONCLUSION: Only 5% of high-risk patients with melanoma following lymph node dissection surgery were treated with adjuvant IPI10 or IFN, while the remaining were untreated. Patients treated with IPI10 or IFN had high AE rates impacting their ability to remain on therapy. Newer adjuvant treatments with more favorable AEs and DoT profiles are urgently needed for high-risk patients with melanoma.
Disclosure: This research was funded by Bristol-Myers Squibb.
Citation Format: Ahmad Tarhini, Komal Gupte-Singh, Min You, Amit Gupta, Le Trong Kim, Sumati Rao. Use of adjuvant interferon alfa-2b or ipilimumab 10 mg/kg for high-risk patients with melanoma, and associated adverse events and duration of therapy [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 3641.
Abstract 3659: Detection and validation of cancer immunotherapy biomarkers in blood
Authors: Xie Feng , Yu Jianjun , Jia Shidong 
Published: August 2018

Abstract
Immunotherapy response varies widely, making it difficult for physicians to know whether immunotherapy will be effective for a given patient. Indeed, ~80% or more patients with cancer fail to respond to checkpoint inhibitor immunotherapy. In addition to PD-L1 IHC staining, recent studies reported that patients with deleterious mutations in mismatch repair (MMR) genes, high tumor mutation burden (TMB) or microsatellite instability (MSI) are also associated with better clinical response. As tissue biopsy represents a practical challenge due to its insufficient quantity or lack of access, non-invasive molecular has emerged as an efficient complementary test and attracted increasing attention in clinical development of cancer immunotherapy.
With Predicine's gene RARDAR technology, we developed a blood-based PrediSeq NGS panel to capture genomic alterations in 180 cancer genes including tumor mutation burden (TMB) and microsatellite instability (MSI) and a Predi-CI (Cancer Immunotherapy) panel to measure dynamic expression change of 212 genes related to immune cells or immune responses.
Technical validation was performed to evaluate assay sensitivity, specificity and accuracy using reference samples with known genetic profiling. The panels have been further tested using tissue biopsy and plasma samples from cancer patients. The development of PrediSeq Panel and Predi-CI RNA gene expression tests offer a comprehensive solution to stratify and monitor cancer patients who may benefit from cancer immunotherapy.
Citation Format: Feng Xie, Jianjun Yu, Shidong Jia. Detection and validation of cancer immunotherapy biomarkers in blood [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 3659.
Abstract 3672: The three-dimensional (3D) spatial lamin A/C organization in normal lymphocytes, and in Hodgkin and Reed-Sternberg cells
Authors: Contu Fabio , Szczurek Aleksander , Vanni Roberta , Knecht Hans , Mai Sabine 
Published: August 2018

Abstract
Classical Hodgkin Lymphoma (HL) is a B-Cell lymphoma comprising mononucleated Hodgkin cells (H) and diagnostic bi- to multi-nucleated Reed Sternberg cells (RS). Genomic instability in HL is characterized by telomere dysfunction caused by critically short telomeres and telomere uncapping. Super resolution microscopy showed significant increases in the amount of DNA-poor nuclear spaces in HL compared to normal primary lymphocytes. A direct 3D interaction between telomeres and shelterin protein TRF2 is progressively disrupted from H to RS cells by either massive upregulation or downregulation of TRF2. TRF2 interacts with nuclear matrix protein lamin A/C in the maintenance of the 3D genome organization, which is disturbed in H and RS cells. Therefore we hypothesized that the TRF2- telomere-lamin A/C interaction is also disturbed in H and RS cells and leads to organizational alterations of the genome in HL. To this end, we analyzed lamin A/C expression levels of lymphocytes, H and RS cells and found that lamin A/C is upregulated in cancer cells compared to both activated and resting lymphocytes. The regular homogeneous and round shaped pattern found in lymphocytes was replaced in H and RS cells by a more irregular one, characterized by the presence of lamin A/C invaginations and septa that subdivide the nuclei into multiple smaller compartments. Our data show no co-localization between telomeres and lamin A/C in the DNA-poor spaces. Lamin A/C bordered the DNA-poor spaces but was never found inside them or in association with inner telomere fragments. 3D TRF-2 staining showed upregulation of the protein compared to normal lymphocytes, in correlation with the observation made in EBV-negative patients with clinically aggressive disease. The analysis of pre-treatment Hodgkin's patients' samples will allow to determine whether the TRF2-telomere-lamin A/C binding is different in patients with recurrent versus non-recurrent disease.
Citation Format: Fabio Contu, Aleksander Szczurek, Roberta Vanni, Hans Knecht, Sabine Mai. The three-dimensional (3D) spatial lamin A/C organization in normal lymphocytes, and in Hodgkin and Reed-Sternberg 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 3672.
Abstract 3705: Targeted anticancer drug delivery to Ewing's sarcoma using human anti-CD99 targeted hybrid polymerization liposomal nanoparticles
Authors: Kang Hyunggyoo , Nagy Jon , Triche Timothy 
Published: August 2018

Abstract
Most anticancer therapies are unspecific and therefore inevitably lead to off-target toxicity. To overcome these shortcomings, targetable hybrid polymerization liposomal nanoparticles (HPLNs) have been invented. Multiple innovative and proprietary technologies have been developed to enable creation of this unique form of nanoparticle therapy, including the use of cross linked lipids to improve both stability and bioavailability, modified polyethylene glycol (PEG) for both ‘stealthiness' (to prevent immune response to the nanoparticle) and for covalent attachment of targeting molecules such as tumor specific antibodies or peptides. Our present study showed the superior efficacy of human anti-CD99 targeted HPLNs in the treatment of Ewing sarcoma. Human monoclonal anti-CD99 antibody-targeted HPLNs encapsulating irinotecan (CD99-HPLN/Ir) can efficiently reach implanted Ewing sarcoma tumors in xenograft mice and dramatically reduce and/or eliminate the tumor burden. Complete tumor ablation has been observed at doses as low as 1 mg irinotecan/kg, treated twice per week. In other cases, animals who failed untargeted (HPLN/Ir) treatment showed complete tumor ablation after ‘salvage' treatment with CD99-HPLN/Ir. Our CD99 targeted HPLN/irinotecan formulation, termed NV103 showed much better efficacy than the commercial untargeted liposomal irinotecan (Onivyde™) and doxorubicin (Doxil™). Toxic side effects, normally associated with systemic administration of free irinotecan, were minimized or undetectable. Our nanoparticles showed excellent bioavailability. Even the untargeted HPLN/Ir improve drug bioavailability six-fold in a comparison experiment with the drug in liposome form (Onivyde™), with no discernable systemic toxicity. Antibody targeting of the HPLN irinotecan formulation (NV103) improves the efficacy 12-fold, over the untargeted liposome form. In conclusion, this formulation may be effective for treatment of other CD99-expressing tumors like certain leukemias, lymphomas and glioma. Ultimately, after development of other tumor-specific targeting agents and varied encapsulated therapeutics, this technology can be usefully adapted for the treatment of other cancers as well.
Citation Format: Hyunggyoo Kang, Jon Nagy, Timothy Triche. Targeted anticancer drug delivery to Ewing's sarcoma using human anti-CD99 targeted hybrid polymerization liposomal nanoparticles [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 3705.
Abstract 3770: Characterization of novel dual A2A/A2B adenosine receptor antagonists for cancer immunotherapy
Authors: Galezowski Michal , Wegrzyn Paulina , Bobowska Aneta , Commandeur Claude , Dziedzic Katarzyna , Nowogrodzki Marcin , Obara Alicja , Szeremeta-Spisak Joanna , Dzielak Anna , Lozinska Iwona , Dudek Marcelina , Janiga Anita , Reus Jacek , Wronowski Marek , Swirski Mateusz , Radzimierski Adam , Ziembik Magdalena , Mierzwicka Joanna , Wojcik-Jaszczynska Katarzyna , Gocek Elzbieta , Grycuk Karolina , Golas Aniela , Pierzchala Olga , Zachmann Julian , Nowak Mateusz 
Published: August 2018

Abstract
Adenosine is the key immunometabolite responsible for immune tolerance in tumors. It is present in normal tissue in low concentrations, having various physiological functions. In the tumor, its concentration increases rapidly, as a result of overexpression of enzymes producing adenosine, additionally enhanced by hypoxia and inflammation. Adenosine inhibits the biological functions of T lymphocytes infiltrating the cancer tissue by binding to the A2A receptor. The affinity to A2B receptor is believed to attenuate the response of dendritic cells and other parts of innate system. Thus blocking simultaneously the effects mediated by both receptor subtypes with dual inhibitor seems to be a viable approach to a single agent cancer immunotherapy or a combination with current immunotherapeutic agents.
We have discovered a novel series of potent and selective A2A/A2B inhibitors. Best compounds present subnanomolar activity in both in vitro recombinant cellular model and in primary human cells. Our antagonists dose-dependently restore the adenosine agonist-impaired functional activity of CD4+ and CD8+ human T-lymphocytes (cytokine release assays). We observe also the relieve of adenosine-related suppression in NK cells cytotoxicity. Most importantly tested compounds present improved primary pharmacological profile in comparison to A2A inhibitors currently tested in clinical trials. Further validation in in vivo models showed efficacy standalone and in combination with checkpoint inhibitors.
Citation Format: Michal Galezowski, Paulina Wegrzyn, Aneta Bobowska, Claude Commandeur, Katarzyna Dziedzic, Marcin Nowogrodzki, Alicja Obara, Joanna Szeremeta-Spisak, Anna Dzielak, Iwona Lozinska, Marcelina Dudek, Anita Janiga, Jacek Reus, Marek Wronowski, Mateusz Swirski, Adam Radzimierski, Magdalena Ziembik, Joanna Mierzwicka, Katarzyna Wojcik-Jaszczynska, Elzbieta Gocek, Karolina Grycuk, Aniela Golas, Olga Pierzchala, Julian Zachmann, Mateusz Nowak. Characterization of novel dual A2A/A2B adenosine receptor antagonists for 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 3770.
Abstract 3776: Generation and formatting of an Affimer® biotherapeutic for the inhibition of the PD-L1/PD-1 pathway: Proof of concept in mouse
Authors: Basran Amrik , Stanley Emma 
Published: August 2018

Abstract
We have generated a range of potent Affimer antagonists to both human and mouse programmed death-ligand 1 (PD-L1) and have demonstrated that when formatted, possess the necessary affinity, pharmacokinetics (PK) and tissue penetration to modulate the immune system and demonstrate efficacy in mouse models. Affimer biotherapeutics are a new protein scaffold with great potential for the generation of biotherapeutics. Based on the human protease inhibitor Stefin A, the scaffold is small (12kDa), lacks any post translational modifications such as disulphide bonds and glycosylation. Large diverse phage display libraries have been created by engineering in two 9 amino acid peptide loops into the scaffold backbone. Using phage display, we have identified competitive binders to both mouse and human PD-L1 which are low single digit nM in affinity as determined by Biacore. By ELISA we have shown that the Affimer molecules identified compete against PD-1 and CD80 for the binding site on PD-L1 and bind to the target on a range of human cancer cell lines (e.g. lung adenocarcinoma cells), as demonstrated by FACs. Following formatting of the lead Affimer protein to the N-terminal Fc region of an IgG, we showed that we could further improve the affinity to give a KD of &lt;40 pM as determined by Biacore. The PK properties of the Affimer-Fc fusion were determined in mouse dosed at 10 mg/kg and shown to have a terminal half-life of over 100 hours. When dosed in a tumor mouse model the Affimer-Fc fusion protein showed a statistically significant reduction in tumor volume when compared to a control antibody. We have demonstrated that the Affimer scaffold has all the necessary attributes to be developed as a therapeutic platform. The Affimer scaffold was well tolerated in vivo, demonstrated a potency and PK profile that ensured sufficient exposure in the animal to modulate the immune system to slow tumor progression in a relevant mouse model.
Citation Format: Amrik Basran, Emma Stanley. Generation and formatting of an Affimer® biotherapeutic for the inhibition of the PD-L1/PD-1 pathway: Proof of concept in mouse [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 3776.
Abstract 3794: CCL5 from tumor-associated macrophages/microglia (TAMs) regulates glioma migration and invasion via calcium-dependent matrix metalloproteinase-2
Authors: Wu Caren Yu-Ju , Chen Chia-Hua , Lin Chun-Yen , Feng Li-Ying , Lin Yung-Chang , Wei Kuo-Chen , Huang Chiung-Yin , Fang Jia-You , Chen Pin-Yuan 
Published: August 2018

Abstract
Tumor-associated macrophages/microglia (TAMs) are either macrophages of peripheral origin or brain-intrinsic microglia, and represent a considerable portion of the glioma mass, which facilitate gliomagenesis. Chemokine C-C motif ligand 5 (CCL5) is an inflammatory mediator produced by immune cells, and involves in tumor growth, and migration in serval cancers including glioma. However, the mechanism of how CCL5 facilitates glioma invasion remains largely unresolved. In this study, we demonstrate that CCL5 modulate human glioma cell lines, A172 and U87, migratory and invasive activities along with MMPs expression. In response to CCL5, glioma synchronized an increase of intracellular calcium levels, and kinase elevations including p-CaMKII, and p-Akt expressions in time and dosage manners. Importantly, glioma invasion along with MMPs elevation are dependent on CCL5-propogated p-CaMKII expression, and inhibition of p-CaMKII effectively reduced CCL5-directed glioma MMPs expression and invasion. Using three-dimensional cultures, we demonstrated that glioma cells tend to homing toward GM-CSF-activated TAM condition media. This homing effect associated with MMPs elevation which can be ameliorated either by controlling the intracellular and extracellular calcium levels or by CCL5 antagonism. Clinical results also reveal association of CCL5 with TAM activation, and patients' overall survival. Our results suggest that modulation of glioma CaMKII may restrict the effect of CCL5 on glioma migration and could be a potential therapeutic strategy for alleviating glioma invasion.
Citation Format: Caren Yu-Ju Wu, Chia-Hua Chen, Chun-Yen Lin, Li-Ying Feng, Yung-Chang Lin, Kuo-Chen Wei, Chiung-Yin Huang, Jia-You Fang, Pin-Yuan Chen. CCL5 from tumor-associated macrophages/microglia (TAMs) regulates glioma migration and invasion via calcium-dependent matrix metalloproteinase-2 [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 3794.