Newswise — Researchers from The Cancer Institute at NYU Langone Medical Center will present at the 52nd Annual American Society of Hematology (ASH) Meeting and Exposition on December 4-7, 2010 in Orlando, Florida. They will be available for interviews during the conference about the following abstract presentations:
Abstract #118: The Novel Kinesin Spindle Protein Inhibitor SB-743921 Exhibits Marked Activity In In Vivo and In Vitro In Models of Aggressive Diffuse Large B-Cell Lymphoma Sunday, December 5, 2010: 5:15 PM Authors: Danielle C. Bongero and Owen A. O'Connor, MD, PhD, NYU Cancer Institute
Researchers investigated the efficacy of SB-743921 in aggressive B-cell lymphomas to evaluate effectiveness and tolerability in germinal center (GCB) and post germinal center (ABC) diffuse large B-cell lymphomas (DLBCL). Researchers concluded that SB-743921 is promising as a single agent for treatment of DLBCL both in vitro and in vivo. Disclosures: O'Connor: Millennium Pharmaceuticals, Inc.: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Learn more: http://ash.confex.com/ash/2010/webprogram/Paper32996.html
Abstract # 435: Synergistic Combinations of Histone Deacetylase Inhibitors and Decitabine Induce a Unique Gene Expression and Epigenetic Profile in Models of Diffuse Large B-Cell Lymphoma Monday, December 6, 2010: 11:00 AM Authors: Matko Kalac, MD, PhD, and Owen A. O'Connor, MD, PhD, NYU Cancer Institute
Researchers hypothesized that the combination of Histone deacetylase inhibitors (HDACI) and DNMT inhibitors (DNMTI) in DLBCL may be active only in combination and not as single agents. Researchers examined the interaction between a broad range of HDACI and DNMTI using in vivo and in vitro models of DLBCLs, clearly confirming that these agents are in fact synergistic with decitabine. Researchers also analyzed the molecular basis for this synergistic effect by evaluating the global gene expression and methylation using microarrays on the cells treated with the single agents and combination in DLBCL. The contribution to the gene expression phenotype of the combination was greater from the HDACI than with DNMTI. Surprisingly, differentially expressed genes and networks identified by each of the treatment conditions and by combination therapy were unique with few overlapping genes. Taken together, integrative genomic analysis has provided insights into the relative contribution of independent epigenetic therapies to the combination phenotype and these findings may provide important leads in identifying unique biomarkers. Disclosures: O'Connor: Millennium Pharmaceuticals, Inc.: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Learn more: http://ash.confex.com/ash/2010/webprogram/Paper31320.html
Abstract # 1787: Interim Results of a Phase 1 Trial of an Oral Histone Deacetylase Inhibitor Belinostat In Patients with Lymphoid Malignancies Saturday, December 4, 2010: 5:30 PM-7:30 PMAuthors: Jasmine M. Zain, MD and Owen A. O'Connor, MD, PhD, NYU Cancer Institute
Belinostat (Bel) is a histone deacetylase inhibitor with broad preclinical activity. A phase I study of oral Bel in patients with solid tumors found a recommended dose for day (d) 1-14, q3w, of 750 mg QD, with allowance for intra-patient dose escalation if limited toxicity. The current study was initiated to assess if the same dose could be utilized in patients with lymphoma. The study found that Oral Bel can be administered safely with in patients with lymphoma at a daily dose higher than what has been established for patients with solid tumors. Final evaluation will include additional patients and possible dose escalation. The safety profile and early tumor shrinkage noted by the researchers warrants continued evaluation of Bel, especially in combination with other active compounds. Disclosures: L O'Connor: Allos Therapeutics, Inc.: Research Funding. Learn more: http://ash.confex.com/ash/2010/webprogram/Paper33728.html
Abstract # 3937: The Combination of Histone Deacetylase Inhibitors and Hypomethylating Agents Exhibits Marked Synergy in Preclinical Models of T-Cell Lymphoma Monday, December 6, 2010: 6:00 PM-8:00 PM Authors: Enrica Marchi, MD, PhD and Owen A. O'Connor, MD, PhD, NYU Cancer Institute
Histone deacetylase inhibitors (HDACIs) are epigenetic agents known to be active in T-cell lymphoma. Recently romidepsin (R) was approved for patients with relapsed or refractory CTCL. Both romidepsin (R) and belinostat (B) are being investigated in patients with relapsed or refractory PTCL. Researchers have previously shown that hypomethylating agents as decitabine (D) produce synergistic interactions with HDACIs in B-cell lymphomas. Researchers investigated the in vitro and in vivo activity of decitabine (D) , romidepsin (R) and belinostat (B) alone or in combination in different T-cell lymphoma and leukemia cell lines including CTCL (H9, HH), and T- acute lymphoblastic leukemia (T-ALL) lines resistant to gamma-secretase inhibitors (GSI) (P12, PF-382). Collectively, the data suggest that the combination of a hypomethylating agent like D and a HDACI (B and R) are synergistic in in vitro models of human T-cell lymphoma, and may lead to a new platform for the treatment of these diseases. Disclosures: O'Connor: Millennium Pharmaceuticals, Inc.: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Learn more: http://ash.confex.com/ash/2010/webprogram/Paper31322.html
Abstract # 3940: Generation and Characterization of a Novel CD19-CherryLuciferase (CD19CL) Mouse Model: A New Fluorescent/Bioluminescent Model for the Study of B-Cell Development and Lymphomagenesis Monday, December 6, 2010: 6:00 PM-8:00 PM Authors: Luigi Scotto, PhD, and Owen A. O'Connor, MD, PhD, NYU Cancer Institute
Existing mouse models available to study the effects of new treatment strategies for lymphoma almost exclusively rely on xenograft models of the disease. These models, while informative, do not mirror the natural history of a disease that arises in the bone marrow or lymphatic system, as seen in patients. The prospect of integrating both fluorescence and bioluminescence detection capabilities into a single genetically engineered mouse (GEM) model may offer a unique opportunity to assess this biology in a more realistic, cost-effective, and efficient manner. In this study, a bioluminescent signal in double transgenic affected animals allowed tracking of B-cell lymphoma growth during a 4 week time period and evaluation of the response of an established B-cell lymphoma to a drug therapy. The possibility of sequential measurements of tumor growth as a function of an intervention allows essentially real time assessment and identification of micro- and macro-metastases in the living animals. At present there are no other models that allow in vivo imaging of spontaneously generated lymphoma and the mouse model described in this study is intended to be used to hasten translational studies of novel agents in lymphoma, with the intent that understanding the relevant pharmacology prior to clinical study will hasten successful development in clinical studies. Learn more: http://ash.confex.com/ash/2010/webprogram/Paper31588.html
Abstract # 4151: Post Transplant Lymphoproliferative Disorders: Prognostic Features and Rituximab Impact In a 120 Case Single Institution Series Monday, December 6, 2010: 6:00 PM-8:00 PM Authors: Francesca Montanari, MD and Owen A. O'Connor, MD, PhD, NYU Cancer Institute
Post-transplant lymphoproliferative disorder (PTLD) is a broad spectrum of lymphoproliferative disorders that can occur after solid organ transplant or hematopoietic stem cell transplant. It represents a serious and potentially life threatening complication, with reported mortality rate up to 40-50%. Researchers analyzed the prognosis and clinical characteristics of 120 patients diagnosed and treated with PTLD over a 19-year period (from 1990 to 2009). To the best of our knowledge, this is the largest series of PTLD to be reported by a single Institution. In the group of adult patients with DLBCL PTLD and pPTLD (61 total), researchers analyzed the impact on overall survival of Rituximab treatment, as single agent or in combination with chemotherapy, compared to chemotherapy or immunosuppressant tapering alone. This series proposed a new prognostic model for patients with PTLD, based on ECOG score, age and CD 20 expression. Interestingly, in a homogeneous population of adult patients with DLBCL and p-PTLD, the use of rituximab as single agent or in combination, compared to chemotherapy and immunosuppression tapering, did not show a survival benefit. Disclosures: O'Connor: Allos Therapeutics, Inc.: Research Funding. Learn more: http://ash.confex.com/ash/2010/webprogram/Paper30573.html
Abstract # 3233: High Throughput Transcriptome Sequencing of Pediatric Relapsed Acute Lymphoblastic Leukemia (ALL) Identifies Relapse Specific Mutations and Expression Monday, December 6, 2010: 6:00 PM-8:00 PM Authors: Julia A. Meyer, BSc and William L. Carroll, MD, NYU Cancer Institute
Relapsed ALL carries a very poor prognosis despite intensive therapy, indicating the need for new insights into disease mechanisms. To create an integrated genomic profile of ALL, researchers have now focused on high throughput RNA sequencing to detect changes in the transcriptome from diagnosis to relapse. Researchers sequenced 6 matched diagnosis/relapse pairs (i.e. 12 marrow samples) from B-precursor ALL patients enrolled on Children’s Oncology Group (COG) P9906 and AALL0232 trials. Researchers observed a total of 119,000 genetic variants across all samples, with comparable overall mutational burden at relapse and diagnosis. To identify candidate lesions that may indicate a selection for common chemoresistance pathways, researchers focused analysis on relapse-enriched, non-synonymous variants. 8,486 non-synonymous variants were identified that occurred more often at relapse compared to diagnosis. While, isoform specific expression was shared amongst patients at relapse, all relapse specific mutations were private and data to date indicate that a diversity of mechanisms contribute to relapsed disease. Further sequencing analysis of the researchers expanded cohort of samples will determine the mutation and isoform expression prevalence, as well as the functional significance and the potential therapeutic relevance. Learn more: http://ash.confex.com/ash/2010/webprogram/Paper31425.html
Abstract # 3630: Vorinostat Reverses Relapse-Specific Drug Resistance Gene Expression Signatures In Childhood Acute Lymphoblastic Leukemia (ALL) Monday, December 6, 2010: 6:00 PM-8:00 PM Authors: Teena Bhatla, MD, and William L. Carroll, MD, NYU Cancer Institute
Despite significant improvements in outcome for childhood ALL, prognosis is dismal for the 20-25% of patients who relapse. Poor outcomes of relapsed ALL warrant new therapeutic approaches. Researchers previously used gene expression profiling of pediatric ALL diagnosis–relapse paired patient samples to identify the underlying biological pathways that mediate drug resistance. Researchers searched the Connectivity Map (cmap), a database of over 7,000 gene expression profiles from cell lines treated with 1309 compounds, to identify novel agents that could “reverse” the relapse-specific signature and potentially restore chemosensitivity. The histone deacetylase (HDAC) inhibitor, vorinostat, also known as SAHA emerged as a top candidate agent which could potentially endow a chemosensitive gene expression profile. Gene expression based chemical genomics identifies the HDAC inhibitor, vorinostat, as a potential agent which can reverse the relapsed ALL signature and hence reverse drug resistance. Evaluation in ALL cell lines shows that vorinostat is additive to synergistic with chemotherapy, when administered sequentially. Vorinostat applied before conventional chemotherapy may be a promising approach to the treatment of relapsed ALL. Learn more: http://ash.confex.com/ash/2010/webprogram/Paper31471.html
About NYU Langone Medical CenterNYU Langone Medical Center is one of the nation's premier centers of excellence in healthcare, biomedical research, and medical education. For over 170 years, NYU physicians and researchers have made countless contributions to the practice and science of health care. Today the Medical Center consists of NYU School of Medicine, including the Smilow Research Center, the Skirball Institute of Biomolecular Medicine, and the Sackler Institute of Graduate Biomedical Sciences; and the NYU Hospitals Center, including Tisch Hospital, a 705-bed acute-care general hospital, Rusk Institute of Rehabilitation Medicine, the first and largest facility of its kind, and NYU Hospital for Joint Diseases, a leader in musculoskeletal care, a Clinical Cancer Center and numerous ambulatory sites.
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