bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5278: Separate and combined effects of metabolic reprogramming interventions, autophagy inhibition, and carboplatin on murine triple-negative breast cancer cells
Authors: Cozzo Alyssa J. , Coleman Michael F. , O'Flanagan Ciara H. , Pearce Jane B. , Rainey Magdalena A. , Hursting Stephen D. 
Published: August 2019

Abstract
Triple-negative breast cancers (TNBC) are an aggressive BC subset currently lacking targeted therapies. TNBCs exhibit aberrant fuel metabolism, including increased flux through glycolysis and the pentose phosphate pathway, increased lactate production (Warburg metabolism), and elevated dependence on glutamine (glutaminolysis). While dietary interventions such as caloric restriction, intermittent fasting, or ketogenic diets have demonstrated benefits (e.g, reduced tumor incidence, progression, and sensitization to some chemotherapeutic agents) in preclinical BC models, translation to humans has proven challenging, and concerns remain regarding tolerance and long-term safety of extreme diets in cancer patients. We hypothesized that targeted disruption of select metabolic pathways could recapitulate the beneficial effects of the aforementioned dietary interventions and improve the efficacy of carboplatin, part of first-line chemotherapy for primary and metastatic TNBCs. Moreover, we posited that blocking autophagy would further enhance the anticancer effects of metabolic reprogramming interventions (MRIs) alone and in combination with carboplatin. To test these hypotheses, we are using a high-throughput screening approach employing several MRIs with or without the addition of chloroquine and/or carboplatin in vitro. Serum starvation (an in vitro model of caloric restriction), rapamycin, BMS-754807 (a dual IGF-1R/insulin receptor), and nicotinamide significantly reduced cell viability (assessed by MTT assay) and clonogenicity (assessed by colony formation assay) of M-Wnt and M6 cells, both well-characterized TNBC cell lines derived from mammary tumors of MMTV-Wnt-1 and C3-TAg transgenic mice, respectively. The growth suppressive effects of these MRIs were further enhanced when combined with autophagy inhibition via chloroquine (CQ). Treatment of M-Wnt and M6 cells with CQ (20-80 µM) also increased in vitro cytotoxicity of carboplatin. Ongoing analyses and planned in vivo studies will confirm whether co-treatment with MRIs and/or CQ are an effective strategy for increasing the efficacy of carboplatin in TNBC cells.
Citation Format: Alyssa J. Cozzo, Michael F. Coleman, Ciara H. O'Flanagan, Jane B. Pearce, Magdalena A. Rainey, Stephen D. Hursting. Separate and combined effects of metabolic reprogramming interventions, autophagy inhibition, and carboplatin on murine triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5278.
Abstract 5280: Branched chain amino acids represent indispensible metabolic substrates in glioblastoma
Authors: Prabhu Antony H. , Kant Shiva , Kesarwani Pravin , Chinnaiyan Prakash 
Published: August 2019

Abstract
Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options. Considerable advances have been made in understanding the genetic alterations driving these tumors, however, the metabolic alterations and mechanisms underlying these aggressive phenotypes remain unclear. We performed global metabolomic profiling of patient derived low-grade astrocytoma (LGA, n= 28) and GBM (n=80). Hierarchical clustering (HC) identified amino acid (AA) metabolism as a dominant metabolic node in GBM compared to LGA. Considerable inter-tumoral heterogeneity of AA metabolism was observed in GBM, with HC identifying two clearly distinct metabolic subtypes consisting of increased and decreased concentrations of AA and their metabolic intermediates. VIP analysis identified the accumulation of branched chain amino acids (BCAA)- leucine, valine and isoleucine as the top ranked metabolites differentiating these subtypes. Based on this, GBMs were classified as BCAA-high and BCAA-low. BCAA-high GBM was enriched with mesenchymal and classical subtypes while BCAA-low GBM was enriched with proneural and neural subtypes. Integrative analysis coupling these metabolic signatures with gene expression profiling performed on matched tissue demonstrated upregulation of BCAA metabolism-associated genes in BCAA-high GBM, along with global transcriptional programs designed to activate cell cycle progression. When extended into molecular subtype specific preclinical models, we demonstrated that BCAA were indispensible for survival of mesenchymal GBM cells, which was independent of the presence or absence of other non-essential and essential amino acids. Further, these cells were able to maintain long-term survival in a dormant state when grown in media devoid of all essential and non-essential AA other than BCAA and glutamine. Knockdown of key enzymes in BCAA metabolism led to robust cytotoxicity in this model, underscoring the importance of BCAA in GBM survival. Ongoing studies are designed to determine the biologic consequence and intermediary metabolism of BCAA in GBM. Collectively these results identify BCAA metabolism as a therapeutic target in GBM.
Citation Format: Antony H. Prabhu, Shiva Kant, Pravin Kesarwani, Prakash Chinnaiyan. Branched chain amino acids represent indispensible metabolic substrates in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5280.
Abstract 5294: The PanNET-related histone H3.3 chaperone Daxx regulates lineage specification and tissue homeostasis in the pancreas
Authors: Sposito Teresa , Tu Marie-Sophie Nguyen , Rutter Guy A. , Novelli Marco , Thirlwell Chrissie , Salomoni Paolo 
Published: August 2019

Abstract
Progressive age-dependent replacement of canonical H3.1/2 with H3.3 in post-mitotic cells is a crucial mechanism for maintaining genome integrity at heterochromatic sites. The histone chaperone DAXX cooperates with the chromatin remodeller ATRX for the deposition of the non-canonical histone H3.3 at heterochromatin, while it prevents the expression of endogenous retroviral elements in another complex involving the SETDB1 methyltransferases. Loss of function mutations affecting ATRX/DAXX and MEN-1 have been recently identified as a subgroup of pancreatic neuroendocrine tumours (PanNETs) leading to poor prognosis and more aggressive phenotype compared to the ATRX/DAXX and MEN-1 wild-type counterparts. We developed a mouse model for conditional Daxx inactivation in mouse islets to understand the impact of DAXX loss on pancreas homeostasis and PanNETs development. We found that loss of Daxx in the endocrine pancreas, using the Insulin-1Cre driver, leads to aberrant glucose metabolism with the development of hyperglycemia and consequently insulin resistance in mice. We have also shown that loss of DAXX is linked to increased expression of α-cell lineage genes upon glucose stimulation of isolated islets in vitro, resembling the recently reported phenotype of PanNETs harboring ATRX/DAXX or MEN1 mutations. Nonetheless, loss of Daxx was not sufficient to lead to PanNET development. We are currently investigating the chromatin and transcriptional perturbations caused by Daxx loss and how these could be linked to the aberration of cell lineage specification and tissue dysfunction in the pancreas. More generally, this work will provide new insight into how epigenetic alterations contribute to misregulation of developmental programmes and cancer development in the pancreas.
Citation Format: Teresa Sposito, Marie-Sophie Nguyen Tu, Guy A. Rutter, Marco Novelli, Chrissie Thirlwell, Paolo Salomoni. The PanNET-related histone H3.3 chaperone Daxx regulates lineage specification and tissue homeostasis in the pancreas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5294.
Abstract 5298: Finding new molecules to bypass the tumor suppressor gene TP53 and restore cell cycle checkpoint control
Authors: Moore Henry , Blackburn Jessica 
Published: August 2019

Abstract
The tumor suppressor gene, tumor protein 53 (TP53), has been shown to be mutated in more than half of all human cancer cases. p53 controls the G1/S phase checkpoint of the mitotic cell cycle, protecting the fidelity of DNA and inducing apoptosis in cells with irreparable DNA damage. Mutations in TP53, which are often missense mutations that interfere with p53 DNA binding activity or protein folding, result in protein inactivation and loss of checkpoint control, allowing cells with potentially oncogenic mutations to survive and proliferate. TP53 mutations have been shown to enhance tumor progression, increase metastatic potential, and mediate chemotherapy resistance. Because of the importance of p53 in cancer, many studies have aimed to identify small molecules that can “reactivate” mutated p53 protein in cell culture, although this has met with little success thus far. The aim of this research is to identify the extent to which the effects of non-functioning p53 can be completely bypassed, and cell cycle checkpoint restored, using already-established FDA approved compounds in a zebrafish model of p53 loss.
Zebrafish were genetically engineered to have their entire TP53 locus removed using TALEN (Transcription activator-like effector nuclease), rendering them unable to produce the p53 protein. p53 deficient and wild-type zebrafish larvae were then subjected to gamma-irradiation to induce DNA damage. An apoptotic cell staining assay was then performed to allow for the qualitative and quantitative analysis of apoptosis levels throughout the larvae. As expected, TP53 null fish had significantly less apoptotic cells than control after DNA damage. We are in the process of testing 770 FDA approved compounds for their effects in inducing an apoptotic response in p53 null larvae after gamma-irradiation. Positive hits will be carried forward to human cancer cells with TP53 mutation, and the mechanism of action of the drug will be determined using biochemical approaches. These results could identify novel pathways that work in concert with p53 and will allow us to harness new mechanisms of DNA damage induced apoptosis to kill cancer cells. Repurposing FDA-approved drugs can also rapidly translate to clinical benefit in a wide number of cancers driven by TP53 mutation.
Citation Format: Henry Moore, Jessica Blackburn. Finding new molecules to bypass the tumor suppressor gene TP53 and restore cell cycle checkpoint control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5298.
Abstract 530: Phosphatidylserine-targeting antibody combined with chemoradiation enhances systemtic anti-tumor immunity
Authors: Wang Yifan , Liu Zhigang , Deng Weiye , Kim Betty Y. , Lin Steven H. , Jiang Wen 
Published: August 2019

Abstract
The discovery of immune checkpoint blockades have resulted in significant clinical benefits for patients with metastatic cancers including non-small cell lung cancer (NSCLC). Nevertheless, a large proportion of patients do not respond to such therapy. Strategies to enhance the therapeutic efficacy of cancer immunotherapy among a larger group of patients are urgently needed. Increasing the recognition of cancer cells by immune system may enhance response to immunotherapies. Tumor-associated macrophage (TAM) is the most abundant immune cell in most solid tumors, and is critical in bridging innate and adaptive immune system functions. Cancer cells overexpress multiple immune suppressive molecules including phosphatidylserine (PS) to inhibit immunological functions of TAMs. PS expression can be enhanced by cancer therapeutics such as radiation to induce immune suppression. Our results show that radiation increased expression of PS on lung cancer cells. The combination of PS blocking antibody with radiation decreased immune-suppressive phagocytosis and enhanced antigen presentation of macrophages. In murine lung cancer models, combination treatment of PS blockade and chemoradiation more effectively controlled tumor growth and prolonged survival than each treatment used alone. In a bilateral lung cancer tumor model, addition of PS blockade to chemoradiation promoted cytotoxic T cell infiltration and induced tumor growth inhibition of the non-irradiated tumors. Together, our results demonstrate that PS-targeting antibodies may be combined with chemoradiation to enhance intrinsic tumor immunogenicity and activate systemic anti-tumor immune responses. This approach may provide new routes for improving the efficacy of modern immunotherapeutics.
Citation Format: Yifan Wang, Zhigang Liu, Weiye Deng, Betty Y. Kim, Steven H. Lin, Wen Jiang. Phosphatidylserine-targeting antibody combined with chemoradiation enhances systemtic anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 530.
Abstract 5300: LIN9 as a potential negative regulator of the glioblastoma stem cell state
Authors: Farkouh Farid , Chheda Milan G. , Jash Arijita 
Published: August 2019

Abstract
Introduction: Glioblastoma (GBM) is the most lethal primary brain tumor. The GBM stem cells are treatment-resistant cells. We performed an RNAi screen to identify genetic drivers of the GSC state. LIN9 suppression scored strongly in the opposite direction: LIN9 suppression led to a significant increase in neurosphere size and number. In other cellular contexts, LIN9 interacts with pRB and cooperates to promote differentiation. It also inhibits DNA synthesis and oncogenic transformation. The purpose of this study is to better understand the role of LIN9 in GBM.
Methods: Lentivirus for suppression and overexpression of LIN9 was produced via transfection of 293T cells. We transduced patient-derived 0308 GSCs. qRT-PCR was used to determine the expression of various genes.
Results: LIN9 suppression in 0308 GSCs results in increased sphere formation and increased cell proliferation but not increased cell size. Additionally, LIN9 suppression results in upregulation of Sox2 in human astrocytes. In contrast, LIN9 overexpression in 0308 cells results in decreased sphere formation and decreased proliferation. Further ongoing experiments will determine if suppression and overexpression of LIN9 have an effect on the expression of stem cell markers (ex. SOX2, Nestin, OLIG2) and differentiation markers (ex. GFAP, MAPK2, GAL4). We expect LIN9 suppression will result in an increase in the expression of stem cell markers and a decrease in expression of differentiation markers. We also expect the opposite results for LIN9 overexpression.
Conclusions: LIN9 is a potentially important negative regulator of the glioblastoma stem cell state.
Citation Format: Farid Farkouh, Milan G. Chheda, Arijita Jash. LIN9 as a potential negative regulator of the glioblastoma stem cell state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5300.
Abstract 533: The immune landscape in colon cancer and its changes after radiotherapy
Authors: Nigro Cristiana Lo , Sangiolo Dario , Ricci Vincenzo , Garrone Ornella , Abbona Andrea , Falletta Antonella , Merlotti Anna , Varamo Chiara , Aglietta Massimo , Gammaitoni Loretta , Bertetto Oscar , Merlano Marco 
Published: August 2019

Abstract
Background: The TRANSLATE project started in 2016 to test the immune effects on circulating immune cells and cytokines of metronomic Cyclophosphamide (CTX), daily low-dose IL-2 administered every other week, and radiotherapy (RT). The rationale is based on self vaccination induced by RT, T cells expansion by IL-2 treatment and selective Tregs down regulation by low dose cyclophosphamide administration.
Materials/Methods: Treatment consisted of CTX 50/mg tab daily continuously until progression or unacceptable toxicity, 8 Gy single fraction on one metastatic lesion given day 8 from CTX start and IL-2, 500.000 UI twice a day i.v. day 1 to 5 every other week, starting the day after RT. We enrolled patients with end-stage for colon, breast, kidney and prostate cancer. Analysis was performed at baseline, the day after RT, after 28 days from treatment start and at disease progression. Assay focused on Tregs, CD8+, NK, MDSC, CD3-PD1, IL-2, IL-4, IL-5, IL- 6, IL-10, IL-12, IL-13, IL-17a, TNFα, IFNγ, TGFβ. We report baseline and post-RT data separately in patients with colon cancer (CC) and other patients (non-CC).
Results: We report data from 8 pts with left colon, 6 with breast, 2 with kidney and 3 with prostate cancer. At baseline, cytokine expression was similar in CC and non-CC except IFNγ and IL-13, both less represented in CC. After RT, TNFα increased in both groups, but more evidently in CC. A clear increase in IL-10 and IFNγ occurred only in non-CC, while IL-2 increased only in CC. Cumulatively, CC and non-CC reacted differently to RT in terms of positive or negative changes of the analyzed cytokines. On the contrary, we did not observe clear differences in immune cells between CC and non-CC neither at baseline nor after RT.
Discussion: The limited number of patients reduced the interpretation of the study. The differences observed are numerical, but not statistically significant. Colon cancer shows some peculiarities, including the low IL-13 and IFNγ value and a different response to RT. Further analyses investigations are in progress.
Citation Format: Cristiana Lo Nigro, Dario Sangiolo, Vincenzo Ricci, Ornella Garrone, Andrea Abbona, Antonella Falletta, Anna Merlotti, Chiara Varamo, Massimo Aglietta, Loretta Gammaitoni, Oscar Bertetto, Marco Merlano. The immune landscape in colon cancer and its changes after radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 533.
Abstract 563: A biparatopic agonist antibody for OX40 that exhibits superior activity without secondary crosslinking
Authors: Hammer Bonnie , Bawadekar Mandar , Bissen Matthew , Painter John , Lehmann Lauren , Li Francis Qufei , Bailey Lucas , Glaser Bryan , Green Roland 
Published: August 2019

Abstract
The development of agonistic antibodies that activate T-cell co-stimulatory pathways represents a therapeutic strategy with significant clinical potential. However, challenges remain for the translation from in vitro efficacy to clinical success. OX40 and other tumor necrosis factor receptor (TNFR) superfamily members are notorious for requiring high-order receptor clustering in order to achieve full activity. For monoclonal antibodies, this high-order clustering is generally achieved through secondary cross-linking strategies. In vivo, this secondary cross-linking is often supplied through internal immune effector cells via Fc engagement. Bispecific and biparatopic antibodies represent an emerging class of drug molecules that enable unique mechanisms of action relative to their monoclonal counterparts. Here, we describe the use of our bispecific platform for the generation of large panels of biparatopic antibodies which enabled high-throughput screening for the discovery of an array of OX40 agonistic molecules. We have optimized these multivalent antibodies that exceed the potency of the OX40 ligand in NFkB activation without the need for secondary cross-linking. These agonist antibodies have additionally been characterized using primary T cell assays to monitor the kinetics of growth proliferation and cytokine secretion, outperforming cross-linked antibodies currently being tested in clinical trials. In co-culture systems, these agonist antibodies were effective in inhibiting immuno-suppressive properties of Tregs. Our lead OX40 agonist antibody has been optimized for activity and developability and has entered stable cell line development to further support pre-clinical activities.
Citation Format: Bonnie Hammer, Mandar Bawadekar, Matthew Bissen, John Painter, Lauren Lehmann, Francis Qufei Li, Lucas Bailey, Bryan Glaser, Roland Green. A biparatopic agonist antibody for OX40 that exhibits superior activity without secondary crosslinking [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 563.
Abstract 577: Optimization of methods for the analysis of class I MHC peptides by mass spectrometry
Authors: Ford Michael J. , Jones Richard C. , Amunugama Ravi , Allen David , Rizzo Paul Del , Mobley James , Pisano Michael 
Published: August 2019

Abstract
Immuno-oncology describes therapeutic approaches exploiting the body's immune system to fight cancer. One approach involves educating the immune-system to recognize and destroy tumor cells by targeting tumor-specific neoantigens. Neoantigens are antigens presented by tumors but not recognized by the immune-system. Identification of Neoantigens is therefore an active area of research and development. The major histocompatibility complex (MHC) plays a crucial role in antigen presentation. Peptides generated by protein degradation in the cytosol are presented, non-covalently bound to MHC Class I molecules, on the surface of cells for inspection by T-lymphocytes. Cytotoxic T lymphocytes (CTL) recognize peptides presented by MHC Class I. The recognition of peptide antigens presented by MHC Class I results in the destruction of the presenting cell by the CTL. Characterization of peptides associated with MHC Class I molecules requires a targeted protein complex enrichment, an unbiased peptide elution and finally a peptide analysis method. Here we present the latest results from our work optimizing and performing a workflow for the analysis of peptides associated with Class I MHC molecules.
Citation Format: Michael J. Ford, Richard C. Jones, Ravi Amunugama, David Allen, Paul Del Rizzo, James Mobley, Michael Pisano. Optimization of methods for the analysis of class I MHC peptides by mass spectrometry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 577.