bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A13: Anti-CD38-attenukine: A myeloma-targeting immunocytokine containing an engineered IFNα that provides &gt;10,000-fold enhanced tumor-specific activity compared to native IFNα.
Authors: Pogue Sarah , Taura Tetsuya , Bi Mingying , Mikesell Glen , Yun Yong , Sho Angela , Sanchez Eric , Chen Haiming , Berenson James , Behrens Collette , Stevens Maxwell , Domagala Teresa , Sokolovsky Maya , Hallak Hussein , Rosenstock Moti , Doyle Anthony , Wilson David 
Published: August 2015

Abstract
Multiple myeloma (MM) remains an incurable disease despite recent approvals of novel therapies. Treatments which utilize alkylating agents, corticosteroids, proteasome inhibitors and immunomodulatory drugs have provided significant survival benefits; however, tumor relapse eventually occurs with the use of these agents. The cytokine, interferon-α (IFNα), has been used clinically to treat MM for over 30 years. IFNα exerts good anti-myeloma tumor activity but durable responses are rarely achieved due to dose limiting toxicities. Tumor specificity can be modestly increased by attaching IFNα to an anti-CD38 antibody, thus targeting the cytokine to MM cells. However, by introducing an attenuating mutation to the IFNα portion of this fusion protein, the activity of the cytokine is dramatically reduced on CD38 negative cells while exhibiting a similar potency to native IFNα on CD38+ MM cells. As a result, the anti-CD38-attenuated IFNα, referred to as anti-CD38-attenukine™, has over 10,000-fold greater myeloma-specificity than native IFNα in vitro. In vivo, even though the off-target activity is decreased, anti-CD38-attenukine™ has profound anti-tumor effects in murine MM and NHL xenograft models. Treatment with this fusion protein can cure mice with large (&gt;700mm3) tumors—an effect not observed with any other MM agents tested. Here we report that in a Velcade (bortezomib) refractory, IFNα-insensitive primary MM xenograft model, the combination of Velcade with anti-CD38-attenukine™ has potent anti-tumor activity, resulting in tumour elimination and curing of mice. Our findings indicate that anti-CD38-attenukine™ may be a well tolerated, potent anti-MM treatment that may be utilized alone or in combination with Velcade.
Citation Format: Sarah Pogue, Tetsuya Taura, Mingying Bi, Glen Mikesell, Yong Yun, Angela Sho, Eric Sanchez, Haiming Chen, James Berenson, Collette Behrens, Maxwell Stevens, Teresa Domagala, Maya Sokolovsky, Hussein Hallak, Moti Rosenstock, Anthony Doyle, David Wilson. Anti-CD38-attenukine: A myeloma-targeting immunocytokine containing an engineered IFNα that provides &gt;10,000-fold enhanced tumor-specific activity compared to native IFNα. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A13.
Abstract A17: Non-RGD-based strategies to target the thyroid hormone receptor-integrin αvβ3: Lessons from myeloma cells.
Authors: Cohen Keren , Ellis Martin , Davis Paul J. , Hercbergs Aleck , Ashur-Fabian Osnat 
Published: August 2015

Abstract
Introduction. Integrin αvβ3 is a plasma membrane structural protein expressed/activated in tumor cells and dividing blood vessel cells. The extracellular domain of αvβ3 has an Arg-Gly-Asp (RGD) recognition site that enables the integrin to bind specific extracellular matrix (ECM) proteins that contain the RGD sequence and to transduce the binding into discrete intracellular signals. Such ECM proteins have pivotal roles in solid tumors and the RGD site has been tested as a chemotherapeutic target. Recently, a receptor for thyroid hormone (L-thyroxine, T4; 3, 5, 3'-triiodo-L-thyronine, T3) has been described on αvβ3 that is distinct from the RGD recognition site and has been shown to mediate proliferative effects of T4 and T3 on solid tumor cells via the MAPK pathway. We have recently shown that similar T4- and T3-induced proliferation occurs in multiple myeloma (MM) cells. Actions of T4 and T3 at the non-RGD site can be blocked by tetraiodothyroacetic acid (tetrac), a naturally-occurring deaminated T4 analog. In addition, tetrac has anti-tumor effects that are independent of blockade of actions of T4 and T3. In this report, we define mechanisms of tetrac action in MM cells.
Methods. MM cell lines (CAG, RPMI 8226, ARK, ARP-1, U266) and primary cultures of marrow cells from MM patients were grown with T4/T3 and with/without tetrac (100 nM-50 μM). Harvested cells were subjected to the following analyses: cell counts (FACS, CyQuant), viability (WST-1), cell cycle (FACS, PI), cell death (Annexin-PI ± pan-caspase inhibitor, ZVAD, FACS; cleaved caspase-3, cleaved PARP, western blots), DNA damage response (pATM and PARP, western blots) and transcription of apoptosis-relevant genes (RT-PCR).
Results. Early (4-8 h) and late (24 h) effects of tetrac were observed. In the early phase, tetrac reduced cell proliferation (p &lt;&lt;0.05) and induced a DNA damage response (ATM and PARP) and apoptosis (cleaved caspase-3 and cleaved PARP). After 24 h, tetrac significantly (p &lt; 0.05) reduced cell number and viability and induced apoptotic cell death, with a parallel increase in pro-apoptotic gene expression.
Conclusion. The thyroid hormone-binding (non-RGD) site on integrin αvβ3 in myeloma cells appears to be a novel target for chemotherapy with tetrac.
Citation Format: Keren Cohen, Martin Ellis, Paul J. Davis, Aleck Hercbergs, Osnat Ashur-Fabian. Non-RGD-based strategies to target the thyroid hormone receptor-integrin αvβ3: Lessons from myeloma cells. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A17.
Abstract A21: Inhibition of USP7 for the treatment of multiple myeloma and other malignancies.
Authors: Nicholson Benjamin , Kodrasov Matthew P. , LaRocque James P. , Eddins Michael J. , Kumar Suresh , Chauhan Dharminder , Anderson Kenneth C. , Mattern Michael R. 
Published: August 2015

Abstract
The conjugation and deconjugation of ubiquitin controls the stability, localization and activity of many cellular proteins. Deconjugation of ubiquitin is performed by a family of ~80 deubiquitylating enzymes (DUBs) including USP7 which specifically removes ubiquitin from HDM2, Foxp3, claspin and other therapeutically relevant substrates. Importantly, USP7 is overexpressed in human multiple myeloma cells and the expression level of USP7 inversely correlates with prognosis in multiple myeloma patients. Previously, we reported the discovery and characterization of P0005091 a USP7 inhibitor which exhibited anti-tumor activity in in vitro and in vivo models of multiple myeloma. Additionally, we reported that P0005091 inhibits USP47 a closely related DUB which is an emerging oncology target in its own right. Furthermore, a structural analog of P0005091, P0022077 has recently been reported by another research group to inhibit neuroblastoma growth in an orthotopic mouse model suggesting that in addition to hematological tumors, solid tumors may be treatable via inhibition of USP7. To obtain additional starting points for a USP7 or a USP7/USP47 specific drug discovery program we recently performed a new screening campaign. By utilizing a biophysical assay platform we were able to exclude compounds that bind to the active site of USP7 thus increasing the possibility of identifying allosteric modifiers of USP7 activity. Hits from this screen are currently the subject of hit to lead optimization and will be evaluated in biophysical and biochemical assays as well as in vitro and in vivo models of hematological malignancies. Data will be presented describing these results.
Citation Format: Benjamin Nicholson, Matthew P. Kodrasov, James P. LaRocque, Michael J. Eddins, Suresh Kumar, Dharminder Chauhan, Kenneth C. Anderson, Michael R. Mattern. Inhibition of USP7 for the treatment of multiple myeloma and other malignancies. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A21.
Abstract A26: Cancer-associated mutations impair the functional association of ETO/MTG family members with E proteins.
Authors: Acharya Pankaj , Hiebert Scott W. 
Published: August 2015

Abstract
MTG8 and MTG16 are disrupted by the t(8;21) and t(16;21) chromosomal translocations respectively, yielding a fusion protein containing the N-terminal DNA-binding domain of RUNX1 fused to almost all of the MTG8 or MTG16. The t(8;21) is responsible for up to 15% of de novo AML cases, however, t(16;21) is relatively rare and has been liked to therapy-related AML. MTG16 is also disrupted by the inv(16)(p13.3q24.3) in 27% of non-Downs syndrome acute megakaryocytic leukemia (AMKL). This translocation fuses the first 3/4th of MTG16 to GLIS2. That two different ETO/MTG family members are disrupted by frequent translocations highlights the key regulatory role of this gene family, but we are just beginning to understand how ETO/MTG8 and MTG16/ETO2 act in transcriptional control and tumorigenesis. Proteomic studies suggest that these proteins link DNA binding proteins such as the “E proteins” E2A and HEB to the transcriptional machinery that controls RNA polymerase II transcriptional initiation and elongation. E-proteins also play a critical role in B- and T-cell development. Here, we have tested mutations uncovered by The Cancer Genome Atlas (TCGA) project in solid cancers that we predicted would affect the association between MTGs and E proteins. We found that the majority of these changes are silent in our assays but selected alterations impaired MTG-dependent interference with E2A-dependent transcriptional activation. This was also true in complementation assays in vivo. Furthermore, the mutations also affected E-protein-MTG interactions. These results suggest that inactivating mutations in MTG family members may contribute to solid cancers in specific instances, and also deregulate normal B- and T-cell development.
Citation Format: Pankaj Acharya, Scott W. Hiebert. Cancer-associated mutations impair the functional association of ETO/MTG family members with E proteins. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A26.
Abstract A43: Opposing roles of the 19S regulatory- and 20S core-proteasomal subunits in controlling sensitivity of multiple myeloma cells to proteasome inhibition.
Authors: Acosta-Alvear Diego , Kampmann Martin , Cho Min Y. , Wild Thomas , Choudhary Chunaram , Shuman Marc A. , Weissman Jonathan S. , Walter Peter 
Published: August 2015

Abstract
Multiple myeloma (MM) remains a devastating incurable disease. Because of their secretory nature, MM cells heavily rely on proteostasis networks to maintain homeostasis. Indeed, paraprotein production by MM cells imposes a protein-folding burden that provides an opportunity for therapeutic intervention: because protein production in MM cells can exceed the buffering capacity of the cell for protein degradation, they are exquisitely sensitive to proteasome inhibitors. While successful, standard-of-care proteasome inhibitors, like bortezomib, remain not curative, as patients ultimately become refractory, suggesting the selection of genetic escape routes. Employing an ultra-complex shRNA library, we performed pooled shRNA screens in RPMI-8226, U-266, and JJN-3 MM cells, and in K-562 leukemia cells, and identified genes whose diminished function impact the cell's response to proteasome inhibition. Unexpectedly, we found that, contrary to knockdown of subunits in the 20S proteasome core-particle, the genetic ablation of subunits within the 19S regulatory-particle led to partial desensitization towards bortezomib. Proteome-wide analyses of in vivo ubiquitylated sites in K562 cells, in which we constitutively ablated a component of the 19S regulatory-particle, revealed potential candidate substrates that were differentially degraded in knockdown cells. We are investigating the mechanistic basis for this differential degradation to pinpoint key substrates mediating proteasome inhibitor resistance. Our results reveal potential escape routes in MM tumor cells to proteasome inhibitors, suggesting new promising targets to pre-empt resistance.
Citation Format: Diego Acosta-Alvear, Martin Kampmann, Min Y. Cho, Thomas Wild, Chunaram Choudhary, Marc A. Shuman, Jonathan S. Weissman, Peter Walter. Opposing roles of the 19S regulatory- and 20S core-proteasomal subunits in controlling sensitivity of multiple myeloma cells to proteasome inhibition. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A43.
Abstract A44: p53 protects against MG132-induced apoptosis in a cell state-dependent manner.
Authors: Legesse-Miller Aster , Cheng Jacky Ho Wa 
Published: August 2015

Abstract
Proteasome inhibition is an important strategy for treating many types of cancer. While proteasome inhibitors induce apoptosis in certain rapidly proliferating cancer cells, some cells enters quiescence and survives. The mechanism by which quiescent cells become resistant to proteasome inhibitors is unknown. The tumor suppressor protein p53 plays an essential role in establishing and maintaining quiescence in human cells. It also regulates several cell survival mechanisms, such as cell cycle arrest, autophagy, and activation of detoxifying enzymes. Here, we investigate the role of p53 in establishing resistance against proteasome inhibitors in quiescent cells. We found that MG132 (a known proteasome inhibitor) treatment induces the accumulation of p53 and its downstream target p21 more in quiescent than in proliferating primary human fibroblasts. shRNA-mediated down-regulation of p53 sensitizes both proliferating and quiescent fibroblasts to MG132-mediated apoptosis and cell death, suggesting that p53 plays a protective role in all cell states. Additional experiments demonstrated that proliferating fibroblasts are susceptible to inhibition of cytoplasmic p53 activity, whereas quiescent fibroblasts are sensitive to inhibition of either nuclear or cytoplasmic p53 activity. These findings suggest that proliferating and quiescent cells depend on different p53-induced survival mechanisms to be protected from proteasome inhibition. Autophagy, an alternative degradation pathway regulated by p53, is also induced in both cell states upon MG132 treatment. Identification of p53-mediated regulatory mechanisms that are activated in quiescent cells in response to proteasome inhibition may help to suggest strategies for improving the effectiveness of proteasome inhibitors in treating cancer.
Citation Format: Aster Legesse-Miller, Jacky Ho Wa Cheng. p53 protects against MG132-induced apoptosis in a cell state-dependent manner. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A44.
Abstract A46: Real time niche tracking of cancer stem cell cycle kinetics using a novel bi-cistronic lentiviral reporter.
Authors: Pineda Gabriel , Lennon Kathleen M. , Lambert-Fliszar Florence , Riso Gennarina L. , Jamieson Catriona 
Published: August 2015

Abstract
Human leukemia stem cells (LSC) are quiescent self-renewing cells that drive leukemic transformation of myeloproliferative neoplasms and myelodysplastic syndromes. Currently, there are few methods to quantitatively visualize cell cycle progression in (LSC) and to interrogate stem cell cycle gene regulatory networks in live cells. Human LSC are characterized as quiescent self-renewing cells and current methods require sequential transduction and clonal selection. These methods and conditions are not feasible for studying primary patient samples and LSC, which are generally limited in cell numbers. To alleviate this challenge, we generated a lentiviral biscistronic vector encoding FUCCI2 (fluorescent ubiquitination-based cell-cycle indicator) probes. We characterized the fidelity of the cell cycle by confirming normal cell division and distinct nuclear staining of either green or red fluorescence in both transiently and stably transduced 293 cells. Further, analysis by flow cytometry of 293 cell confirmed that S/G2/M and G1/G0 phases of cell cycle correlate with expression of fluorescent reporters expressed from the bicistronic lentiviral vector and recapitulate FACS based analysis using traditional Ki67 and 7AAD staining. Recently, using this lentiviral biscistronic reporter we succeeded in tracking cell cycle progression in CD34+ cells from CML primary patient samples co-cultured with SL/M2 cells. Time-lapse confocal imaging of these samples reveals distinct differences within the population of CML cells. In summary using this new Dual FUCCI2 lentiviral reporter makes it possible to track real time cell cycle kinetics in cancer stem cells. Future studies will include measuring LSC, cell cycle gene regulatory networks in live cells at different stages of the cell cycle.
Citation Format: Gabriel Pineda, Kathleen M. Lennon, Florence Lambert-Fliszar, Gennarina L. Riso, Catriona Jamieson. Real time niche tracking of cancer stem cell cycle kinetics using a novel bi-cistronic lentiviral reporter. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A46.
Abstract B04: Investigating the use of tyrosine kinase inhibitors in Ph-like ALL.
Authors: Roberts Kathryn G. , Yang Yung-Li , Payne-Turner Debbie , Harvey Richard C. , Chen I-Ming , Gastier-Foster Julie M. , Loh Mignon L. , Willman Cheryl L. , Hunger Stephen P. , Mullighan Charles G. 
Published: August 2015

Abstract
This abstract is being presented as a short talk. A full abstract is printed in the Proffered Abstracts section (PR02) of the Conference Proceedings.
Citation Format: Kathryn G. Roberts, Yung-Li Yang, Debbie Payne-Turner, Richard C. Harvey, I-Ming Chen, Julie M. Gastier-Foster, Mignon L. Loh, Cheryl L. Willman, Stephen P. Hunger, Charles G. Mullighan. Investigating the use of tyrosine kinase inhibitors in Ph-like ALL. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B04.
Abstract B08: eIF4E3 forms a novel cap-binding complex for mRNA translation initiation.
Authors: Landon Ari L. , Muniandy Parameswary A , Houng Simone , Shetty Amol , Becker Kevin , Borden Katherine , Gartenhaus Ronald B. 
Published: August 2015

Abstract
Dysregulation of mRNA translation can alter the cellular phenotype leading to cancer initiation, maintenance, progression, invasion or metastasis. Cap-dependent translation is the primary mechanism of mRNA translation in eukaryotic cells. The conventional cap-binding complex, eIF4F consists of three components including eIF4A, eIF4G and eIF4E1. eIF4E1 binds the 7-methyl-guanosine-cap (cap) structure in the mRNA and functions to bridge mRNA to the ribosome. eIF4E3 is another member of the eIF4E family that has been recently shown to bind cap using biophysical approach. We explored the biological function of eIF4E3 in a diffuse large B-cell lymphoma model. We found that in the absence or lack of eIF4E1 phosphorylation, eIF4E3 expression is enhanced, and this increases the cap-binding ability of eIF4E3. We find that eIF4E3 also physically associates with the components of the cap-binding complex eIF4A and eIF4G, essentially forming a novel cap-binding complex. We interrogated the functional capacity of the eIF4E3-mediated translation by analyzing the translatome and transcriptome of eIF4E3 expressing cells. eIF4E3 and eIF4E1 mutually regulate a high fraction of total mRNA transcripts, while exclusively modulating translation of select messages. Interestingly, we identified selective motif enrichments in the 5'UTR that may facilitate transcript selection by eIF4E1 or eIF4E3. Together, we have identified a novel cap-binding complex consisting of eIF4A, eIF4G and eIF4E3, which can initiate mRNA translation of select messages.
Citation Format: Ari L. Landon, Parameswary A Muniandy, Simone Houng, Amol Shetty, Kevin Becker, Katherine Borden, Ronald B. Gartenhaus. eIF4E3 forms a novel cap-binding complex for mRNA translation initiation. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B08.
Abstract B24: Delineating the roles of lysine 27 methylation-associated epigenetic modulators in T cell leukemia.
Authors: Ntziachristos Panagiotis , Welstead Grant , Trimarchi Thomas , Bakogianni Sofia , Xu Luyao , Vlierberghe Pieter Van , Prinjha Rab , Ferrando Adolfo , Jaenisch Rudolf , Mullighan Charles , Iannis Aifantis 
Published: August 2015

Abstract
This abstract is being presented as a short talk. A full abstract is printed in the Proffered Abstracts section (PR03) of the Conference Proceedings.
Citation Format: Panagiotis Ntziachristos, Grant Welstead, Thomas Trimarchi, Sofia Bakogianni, Luyao Xu, Pieter Van Vlierberghe, Rab Prinjha, Adolfo Ferrando, Rudolf Jaenisch, Charles Mullighan, Aifantis Iannis. Delineating the roles of lysine 27 methylation-associated epigenetic modulators in T cell leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B24.