bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-131: Birinapant and carboplatin co-therapy can effectively target platinum resistant ovarian cancer initiating cells
Authors: La Vincent , Fujikawa Rachel , Janzen Deanna , Bainvoll Liat , Memarzadeh Sanaz 
Published: July 2016

Abstract
High-grade serous ovarian cancers (HGSOCs) contain CA125-negative cancer-initiating cells resistant to standard platinum therapy. High expression of cellular inhibitors of apoptosis proteins (cIAPs) in these platinum resistant HGSOC initiating cells causes resistance to apoptosis despite platinum-induced DNA damage. cIAPs can be degraded with the addition of birinapant, a SMAC-mimetic, sensitizing cancer initiating cells to carboplatin and resulting in their elimination. Using in vitro drug assays, we demonstrate that more than half of human HGSOCs (13/23 independent samples) can be targeted with birinapant and carboplatin co-therapy. Importantly, treatment with this co-therapy eliminated tumor cells irrespective of their clinically-defined platinum sensitivity suggesting that this therapeutic approach could be efficacious with patient who have platinum sensitive and/or resistant disease. Pre-clinical trials in mice bearing intra-peritoneal low-passage human-derived HGSOC cell lines demonstrate that birinapant and carboplatin co-therapy significantly improves overall survival. A vast majority of co-therapy treated mice are still alive, 5 months after all animals treated with vehicle or carboplatin monotherapy have succumbed to tumor. Given that co-therapy was efficacious in approximately 50% of HGOSCs, evaluation of biomarkers that can predict this response are clinically relevant. The expression of cIAP levels were quantified using western blot and then immunohistochemistry in the CA125 negative fraction of our 23 clinical samples. We found that expression of ≥24ng of cIAP in the CA125-negative HGSOC cell lysate could accurately predict response to co-therapy with 100 percent accuracy. Detection and quantification of cIAP in CA125 negative cells by immunohistochemistry (IHC) could also predict a response to co-therapy with 95 percent accuracy. We report on careful analysis of two sets of biomarkers specifically measuring druggable targets in ovarian cancer initiating cells that could predict a response to co-therapy with birinapant and carboplatin. This therapeutic approach, that can overcome platinum resistance in ovarian cancer initiating stem cells, will be tested in an upcoming clinical trial alongside our proposed companion diagnostic biomarkers of response.
Citation Format: Vincent La, Rachel Fujikawa, Deanna Janzen, Liat Bainvoll, Sanaz Memarzadeh. Birinapant and carboplatin co-therapy can effectively target platinum resistant ovarian cancer initiating cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-131.
Abstract LB-161: Exploiting non-canonical heterochromatin-mediated telomere protection mechanisms in human cells
Authors: Chow Tracy T. , Blackburn Elizabeth H. 
Published: July 2016

Abstract
Mammalian telomeres are inherently heterochromatic. While enhanced telomere maintenance is evident in malignant cancers, some cancers appear to maintain telomeres by neither the common telomerase nor the alternative telomere repeat recombination mechanisms. Specifically, the roles of epigenetic modifications in telomere protection are largely unknown in human cancers. I have combined newly developed cellular and molecular approaches to show that in some cancer cell types, experimentally enhanced heterochromatinization localized specifically at telomeres reduced damage-induced foci at telomeres, suggesting augmentation of telomere stability. These results lead to the intriguing hypothesis that manipulating the epigenetic status at telomeres may be exploited to elicit damage at the telomeres of cancer cells as a novel approach to fight cancer. My current work in progress focuses on identifying novel chromatin modifiers that weaken telomere protection by modulating telomere compaction. It is especially urgent to understand the plasticity and modes of telomere protection by which some human cancers escape the requirement of telomerase activation to sustain immortalization. Results from this work can potentially advance the development of novel combinatorial telomere-directed cancer treatments.
Citation Format: Tracy T. Chow, Elizabeth H. Blackburn. Exploiting non-canonical heterochromatin-mediated telomere protection mechanisms in human cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-161.
Abstract LB-195: The intronic DPYD variant rs75017182 correlates with a modest reduction in DPD enzyme activity
Authors: Shrestha Shikshya , Offer Steven M. , Diasio Robert B. 
Published: July 2016

Abstract
Nearly one-third of cancer patients that receive the commonly prescribed chemotherapy drug 5-fluorouracil (5-FU) experience severe (grade 3+) adverse toxicity related to treatment. Approximately 1,300 deaths are directly attributed to 5-FU toxicity annually in the U.S. While three deleterious genetic variations in the dihydropyrimidine dehydrogenase (DPD) gene (DPYD) are well-established predictors of severe toxicity (i.e., *2A, p.I560S, p.D949V), they only explain 30-35% of adverse cases of 5-FU toxicity. Recently, an intronic variant (rs75017182) has been suggested to contribute to 5-FU toxicity risk by promoting the alternative splicing of DPYD. However, recent clinical studies are conflicting as to the degree to which rs75017182 affects DPD enzyme function, and it remains unclear as to the extent to which DPYD splicing is affected in carriers. The primary aim of this study was to directly determine correlations between rs75017182, DPD enzyme function, and DPYD splicing. Genotyping for rs75017182, *2A, p.I560S, and p.D949V was performed on DNA obtained from 3950 healthy participants in the Mayo Clinic Biobank. Individuals carrying one or more of the genotyped variants, as well as matched non-carriers, were asked to provide an additional blood sample that was used to measure DPYD expression, DPYD splicing relevant to rs75017182, and DPD enzyme activity (n = 204). A moderate, but significant, reduction was noted in the expression of canonically spliced DPYD in rs75017182 carriers compared to non-carriers. DPD enzyme activity in peripheral blood mononuclear cells was similarly reduced in rs75017182 carriers. The degree to which DPD activity was reduced in rs75017182 carriers was not as severe as was noted for carriers of the toxicity-associated variants *2A, p.I560S, or p.D949V. Collectively, our data support a model in which rs75017182 leads to alternative splicing of a fraction of primary transcripts that harbor the variant, which in turn causes a modest reduction in the levels of functional DPD enzyme. The modest phenotypes noted may partially explain some of the discrepant results noted between various clinical studies that have attempted to evaluate the variant.
Citation Format: Shikshya Shrestha, Steven M. Offer, Robert B. Diasio. The intronic DPYD variant rs75017182 correlates with a modest reduction in DPD enzyme activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-195.
Abstract LB-208: First-in-class steroidal leukemia inhibitory factor (LIF) inhibitor in targeted cancer therapy
Authors: Nair Hareesh B. , Santhamma Bindu , Viswanadhapa Surya , Nickisch Klaus J. 
Published: July 2016

Abstract
The leukemia inhibitory factor (LIF), an IL-6 family member, is a pleotropic cytokine has been demonstrated as an oncogene and involved in multiple cellular mechanisms during the initiation and progression of various human malignancies. Overexpression of LIF was significantly correlated with advanced tumor stage, larger tumor size and worse relapse free survival rate. In the present study EC330, a novel steroidal LIF inhibitor showed cytotoxicity in various cancer cell lines and NCI-60 cell line panel at low nano-molar range. EC330 blocked formation of colonies in soft agar and inhibited angiogenesis (tube formation) in human umbilical vein endothelial cells. EC330 binds to LIF/LIFR complex by insilico docking studies and reduced the STAT3 phosphorylation in a dose dependent manner through blocking LIF-JAK-STAT signaling. EC330 showed marked specificity in MCF-7 cells overexpressing LIF verses MCF-7 cells. The compound further showed cytoskeletal disruption and targeting cancer associated fibroblasts (CAFs). EC330 treatment (0.5 and 2.5mg/kg) dose dependently reduced tumor burden in ovarian (IGROV-1) and triple negative breast cancer (MDA-MB-231) cell xenografted mouse models. These findings establish EC330 as a novel LIF inhibitor having targeted therapeutic perspectives for patients with aggressive primary tumors. LIF targeting may result in the blockade of cancer fibroblast associated pro invasive tumor microenvironment in regular as well as therapy resistant tumors.
Citation Format: Hareesh B. Nair, Bindu Santhamma, Surya Viswanadhapa, Klaus J. Nickisch. First-in-class steroidal leukemia inhibitory factor (LIF) inhibitor in targeted cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-208.
Abstract LB-231: An optide (optimized knottin-peptide) that inhibits tumor cell growth In vitro and accumulates in sarcoma flank tumors in vivo
Authors: Sottero Theo , Girard Emily J. , Correnti Colin , Stroud Mark R. , Kier Brandon L. , Mhyre Andrew J. , Olson James 
Published: July 2016

Abstract
Antibody-drug conjugates (ADCs) have been FDA approved for the targeted delivery of chemotherapy to cancer. However, ADCs are limited for solid tumors and brain cancer by their poor penetration and inability to cross the blood-brain-barrier. A number of groups have shown that cystine-knot peptides (knottins) can be modified in ways that allow them to target cancer cells. Our lab demonstrated that an optide (optimized knottin-peptides) conjugate such as chlorotoxin-Cy5.5 are able to accumulate throughout tumors and cross an intact blood-brain barrier. However, chlorotoxin-Cy5.5 accumulates in mouse liver - a potential liability if used as a peptide-drug conjugate. We sought to identify a novel peptide that is capable of delivering chemotherapy selectively to tumor cells in vitro and in vivo.
Our group has developed a mammalian protein expression system that is able to produce &gt;20mg scale, endotoxin-free knottins and can rapidly generate variants of those peptides. We went in vivo to investigate if there was selective accumulation of our novel peptide-dye conjugates in sarcoma flank xenografts. Mice were injected intravenously with conjugate and accumulation was quantified in a number of tissues using IVIS imaging. We identified a novel peptide that accumulated in sarcoma flank tumors &gt;10-fold relative to liver. We tested the ability of this peptide to deliver cytotoxic chemotherapy in vitro as a peptide-drug conjugate. We identified a novel conjugate capable of efficiently inhibiting the growth of a number of tumor cell lines in vitro. We tested the ability of various endocytosis inhibitors to prevent the uptake of this peptide and showed that inhibitors of GPI-anchored protein endocytosis prevented this accumulation. To verify tumor accumulation in preparation for efficacy studies we tracked the distribution of a radiolabeled form of the peptide in a whole body autoradiography model and observed sustained tumor uptake.
Our novel peptide-conjugate is able to potently inhibit the growth of a number of tumor cell lines in vitro and the endocytosis of GPI-anchored proteins is involved in this accumulation. Additionally, this peptide accumulates in tumor tissue in vivo. Optide-drug conjugates may offer enhanced tumor penetration over antibody-drug conjugates and therefore increase the therapeutic index in delivering cytotoxic chemotherapy.
Citation Format: Theo Sottero, Emily J. Girard, Colin Correnti, Mark R. Stroud, Brandon L. Kier, Andrew J. Mhyre, James Olson. An optide (optimized knottin-peptide) that inhibits tumor cell growth In vitro and accumulates in sarcoma flank tumors in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-231.
Abstract LB-237: BMS-986012, a fully human anti-fucosyl-GM1 antibody has potent in vitro and in vivo antitumor activity in preclinical models of small cell lung cancer
Authors: Chen Bing , Pan Chin , Ponath Paul , Oyasu Miho , Menezes Daniel , Cardarelli Pina 
Published: July 2016

Abstract
Fucosyl-GM1, is a sphingolipid monosialoganglioside and tumor-associated antigen with a high prevalence in human small cell lung cancer (SCLC), while its expression is minimal in most normal tissue. Here, we report results of our preclinical studies with BMS-986012, a novel fully human, non-fucosylated, IgG1 monoclonal antibody that specifically binds to FucGM1. The binding affinity of BMS-986012 was evaluated in Biacore® and cell-based assays. BMS-986012 binds with a high affinity to FucGM1 and demonstrates no significant binding to other closely related gangliosides. The antibody was engineered in a non-fucosylated IgG1 format, resulting in a 40-fold increased affinity for FcγRIIIa (CD16). In in vitro assays, BMS-986012 binds to FucGM1 on cancer cells and activates antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-mediated phagocytosis (ADCP). The antitumor activity of BMS-986012 was profiled in a panel of SCLC lung cancer models in immunodeficient mice with varying FucGM1 target expression levels qualified using immunohistochemistry. Dose-dependent antitumor activity was observed in a panel of SCLC xenograft models with tumor regressions occurring at BMS-986012 doses greater than 0.3 mg/kg against DMS79 tumors. BMS-986012 efficacy generally correlated with FucGM1 target expression in tumor models. In mice, the antibody was well tolerated, with no adverse events observed in long term efficacy studies. Preclinical studies also explored combinations of BMS-986012 with standard-of-care (SOC) chemotherapeutics, including cisplatin, etoposide, topotecan and irinotecan. Combination therapy of BMS-986012 with SOC resulted in significantly enhanced antitumor activity compared to monotherapy. Finally, studies conducted with BMS-986012 in combination with anti-CD137 antibody resulted in significant improvement in efficacy. These data provide preclinical support for evaluation of BMS-986012 in SCLC. BMS-986012 is currently in a phase I trial.
Citation Format: Bing Chen, Chin Pan, Paul Ponath, Miho Oyasu, Daniel Menezes, Pina Cardarelli. BMS-986012, a fully human anti-fucosyl-GM1 antibody has potent in vitro and in vivo antitumor activity in preclinical models of small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-237.
Abstract LB-253: Control of tumor growth in vivo by a synthetic multi-antigen DNA immune therapy for prostate cancer
Authors: Ferraro Bernadette , Walters Jewell N. , Reuschel Emma L. , Balakrishnan Amritha , Morrow Matthew P. , Khan Amir S. , Sardesai Niranjan Y. , Humeau Laurent M. , Weiner David B. 
Published: July 2016

Abstract
Prostate cancer (PCa) is one of the leading causes of cancer deaths among men with limited treatment options. Accordingly, new approaches, such as immunotherapy, may represent important approaches for PCa treatment. Electroporation (EP) delivered DNA vaccines has recently shown promising results for therapeutic immunotherapy strategies has been limited to single antigen and epitope targets with limited success. We hypothesized that a broader collection of antigens adjuvanted by plasmid encoded IL-12 would bypass immune tolerance and improve the breadth and effectiveness of a PCa immunotherapy approach. We tested this hypothesis in NHP for immune tolerance effects as well as in the highly relevant TRAMP-C2 challenge model. We developed highly optimized DNA vectors encoding consensus antigens for important PCa targets prostate-specific antigen (SynCon PSA), prostate-specific membrane antigen (SynCon PSMA), and human six-transmembrane epithelial antigen of the prostate (STEAP). In mice the vaccines demonstrated potent IFNγ production by ELISpot (2740 SFU) and robust immune responses in the CD4+ (0.53%) and CD8+ (3.0%) T cell compartments. Further, sera from immunized mice reacted in ELISA with relevant targets and specifically stained LNCaP cells, a human PCa cell line, as well as human PCa tumor sections, supporting that the vaccine antigens induced relevant antibody responses. Vaccination of Rhesus Macaques, which share greater than 98% identity with humans, showed robust anti-PSA, PSMA and STEAP IFNγ production (612 SFU), potential for cytotoxic T cell function, and antigen specific seroconversion supporting the ability of these constructs to break tolerance. The therapeutic potential of PSMA, STEAP, and the combination of PSMA and STEAP, alone or with the molecular adjuvant IL-12, was evaluated in mice in the TRAMP-C2 tumor model. Alone, PSMA, STEAP or PSMA+STEAP demonstrated prolonged survival and a modest impact on tumor growth. However, the combination of synthetic vaccine antigens with IL-12 resulted in 100% efficacy in treatment and clearance of tumors resulting in 100% survival. These data support further study of this novel immune therapy of PCa.
Citation Format: Bernadette Ferraro, Jewell N. Walters, Emma L. Reuschel, Amritha Balakrishnan, Matthew P. Morrow, Amir S. Khan, Niranjan Y. Sardesai, Laurent M. Humeau, David B. Weiner. Control of tumor growth in vivo by a synthetic multi-antigen DNA immune therapy for prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-253.
Abstract LB-271: Targeting fatty acid metabolism regulates the immunosuppressive activity of myeloid-derived suppressor cells
Authors: Al-Khami Amir A. , Hossain Fokhrul , Wyczechowska Dorota , Zheng Liqin , Rodriguez Paulo , Ochoa Augusto C. 
Published: July 2016

Abstract
Myeloid-derived suppressor cells (MDSC) play a major role in the immune defects associated with cancer. Although several mechanisms have been suggested as critical for MDSC-induced T cell suppression, there are no current therapies to block the accumulation and/or function of MDSC. Recent studies have highlighted the role of specific energy metabolic pathways in the activation and function of immune cells. However, the metabolic programs of tumor-associated MDSC (T-MDSC) remain unknown. Herein, we found that T-MDSC, but not splenic MDSC or normal myeloid cells, activated fatty acid oxidation (FAO). T-MDSC increased mitochondrial mass and function, key FAO enzymes, and oxygen consumption rate. Of interest, Inhibition of FAO blocked the immunosuppressive mechanisms and functions in T-MDSC and decreased their production of immunosuppressive cytokines. FAO inhibition also resulted in a T cell-dependent decrease in tumor growth and synergized with low-dose chemotherapy and cellular immunotherapy. Furthermore, targeting fatty acid uptake decreased the regulatory activity of T-MDSC. Human MDSC exhibited similar metabolic characteristics. These data support the possibility of targeting fatty acid metabolism as a novel approach to block MDSC and enhance cancer therapy.
Citation Format: Amir A. Al-Khami, Fokhrul Hossain, Dorota Wyczechowska, Liqin Zheng, Paulo Rodriguez, Augusto C. Ochoa. Targeting fatty acid metabolism regulates the immunosuppressive activity of myeloid-derived suppressor cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-271.
Abstract LB-275: Single cell analysis identified LY6D as a novel marker of castration-resistant multipotent luminal progenitors
Authors: Linn Douglas E. , Barros-Silva João , Guo Guoji , Brown Michael , Ashton Garry , Clarke Noel W. , Yuan Guo-Cheng , Orkin Stuart H. , Baena Esther , Li Zhe 
Published: July 2016

Abstract
The cellular origin of castration-resistant prostate cancer (CRPC) remains largely unsolved. We compared single-cell expression profiles of prostate cells sorted from hormone-naïve and castrated mice. Our single-cell analysis reveals that the prostate luminal lineage is highly heterogeneous. A subset of prostate cells in the luminal lineage characterized by high expression levels of luminal lineage markers including cytokeratin 8 (Krt8) and androgen receptor (Ar) genes, as well as prostate stem/progenitor marker genes (e.g., Trop2/Tacstd2, Sca1/Ly6a), and intermediate levels of basal genes (e.g. Trp63, Krt5), is enriched upon castration. We validated LY6D as a novel marker of castration-resistant (CR) multipotent luminal progenitor. Organoid culture revealed that LY6D+ prostate cells, including LY6D+ prostate luminal cells, were enriched with multipotent organoid-forming cells under androgen-deprivation. Lineage-tracing using Krt8-CreER mice revealed that in wild-type mice, LY6D+ CR luminal cells appeared to produce LY6D- luminal cells upon regeneration; however, when under the Pten-loss background, LY6D+ Pten-null luminal cells gave rise to LY6D+ luminal cancer cells. Furthermore, upon induced loss of Pten, prostate cancers originating from Krt8+ CR luminal cells were LY6D+ high-grade and were more advanced than those originating from hormone-naïve luminal cells. Lastly, in prostate cancer patients, LY6D amplification/upregulation correlates with advanced disease. Overall, our results uncover the luminal lineage heterogeneity and identify LY6D as a novel tumor-initiating cell marker of CRPC.
Citation Format: Douglas E. Linn, João Barros-Silva, Guoji Guo, Michael Brown, Garry Ashton, Noel W. Clarke, Guo-Cheng Yuan, Stuart H. Orkin, Esther Baena, Zhe Li. Single cell analysis identified LY6D as a novel marker of castration-resistant multipotent luminal progenitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-275.