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|PRE-CONFERENCE SHORT COURSE
Monday, October 20 - 9:00am-12:00pm
(SC3) Advances in DNA Methylation Analysis
DNA methylation refers to the addition of methyl groups catalyzed by the enzyme DNA methyltransferase to cytosines in CpG dinucleotides. This biochemical event has now come to be recognized as an important epigenetic phenomenon that affects gene expression. In recent years this field has been an area of intense activity and several new methodologies and applications for DNA methylation analysis have rapidly emerged. This course will cover the basics underlying the various techniques that have been developed and the context in which they have been successfully used. The advantages and limitations of the various methodologies will be discussed and appropriate case studies will be presented to demonstrate their use in biological, medical and epidemiological studies. The course will be offered in an informal, interactive setting to enable a free exchange of ideas and information. more>>>
WEDNESDAY, OCTOBER 22
7:00am – 6:00pm Registration Open
Progress in the Clinic
2:00pm Chairperson’s Remarks
Peter Atadja, Group Leader, Novartis Institutes for Biomedical Research
2:10 Clinical Development of a Novel Pan-Histone Deacetylase (HDAC) Inhibitor, Romidepsin, from Phase I through Registrational Studies in a Range of Hematopoietic Tumors
Jean Nichols Ph.D., President and Chief Operating Officer, Gloucester Pharmaceuticals
Romidepsin is a unique bicyclic peptide that has been identified as a novel pan-HDAC inhibitor. More than 600 cancer patients have received romidepsin as a single agent or in combination with other agents in clinical studies conducted around the world. Romidepsin has activity and is well tolerated in patients with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), and multiple myeloma.
2:40 Development of the Pan-DAC Inhibitor Panobinostat (LBH589) in Anti-Cancer Therapy
Peter Atadja, Ph.D., Group Leader, Novartis Institutes for Biomedical Research
The highly potent pan-deacetylase (DAC) inhibitor panobinostat (LBH589) has shown evidence of clinical activity in the treatment of both solid tumors and hematologic malignancies. However, the specific mechanisms underlying the anti-cancer effects of panobinostat remain to be elucidated. Panobinostat induces gene expression, protein hyperacetylation and significant anti-proliferative and anti-cancer effects in a number of cancer cell lines and in vivo tumor models, including lymphomas, multiple myeloma, and small-cell lung cancer. We have undertaken preclinical screening for panobinostat sensitivity to predict tumor types with potential clinical response and to discern the molecular events mediating the anti-cancer effects of panobinostat.
3:10 Progress in the Development of Vorinostat
Victoria Richon, Ph.D., Senior Director, Cancer Biology and Therapeutics, Merck Research Labs
Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a nanomolar inhibitor of Class I and II HDAC activity. Vorinostat induces growth arrest, differentiation or apoptosis in a wide variety of transformed cells. The anti-proliferative effects of vorinostat are believed to be due to drug-induced accumulation of acetylated proteins, including the core nucleosomal histones and other proteins (e.g., bcl6, alpha-tubulin and Hsp90). Results from clinical trials show that vorinostat can inhibit its target enzyme, HDAC, in peripheral mononuclear cells and tumors, at doses that are well-tolerated. Anti-tumor activity has been seen in patients with both hematological and solid tumors. Vorinostat was approved by the FDA in 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. Vorinostat is currently undergoing evaluation as a single agent and in combination in clinical trials in both hematological and solid cancers.
3:40 Networking Refreshment Break in the Exhibit Hall
4:20 Overcoming Resistance to Targeted Therapies with Entinostat (SNDX-275) - The Oral, Class 1 Selective HDACi
Peter Ordentlich, Ph.D., Director, Scientific Affairs, Syndax Pharmaceuticals
Resistance to targeted therapies in cancer can be de novo (i.e. absence of target) and can also be acquired (i.e. cell growth becomes independent of target). Both scenarios represent significant challenges to effectively extending the benefit of targeted therapies Two cases will be presented in which SNDX-275 is used to restore sensitivity to a targeted agent and the clinical applications of these findings will be highlighted. The first relates to resistance to epidermal growth factor receptor (EGFR) inhibitors in non-small cell lung cancer (NSCLC) and the second to resistance to anti-estrogen therapy in breast cancer.
4:50 Technology Watch
Sky Biotech Puritin™ and RedSee™ – Unique Tandem-Affinity Tags for Protein Production
Scott Gridley, Ph.D., Director of Protein Sciences, Blue Sky Biotech, Inc.,
Recombinant protein production continues to be challenged by difficulties in achieving satisfactory solubility and purity with many different target classes. Here we describe two unique tags developed by Blue Sky Biotech – the Puritin™ and RedSee™ tags. The Puritin™ tagging system is a novel tandem tag incorporating polyhistidine and a mammalian biotinylation domain that provides for rapid, parallel high-affinity purification. We have expressed SHIP2 with a standard polyhistidine tag or with our Puritin™ tag in insect cells, with and without co-expression of mammalian protein biotin ligase. While HIS-SHIP2 is predominantly insoluble and binds weakly to nickel-chelating resin, Puritin™ tagged SHIP2 binds with high affinity. Further, we demonstrate efficient in vivo biotinylation of the target protein which is dependent on co-expression of the mammalian protein biotin ligase. Currently, we are expanding the application of this tag to include rapid association of recombinant proteins with streptavidin-conjugated matrix, easily facilitating further protein purification or protein-protein interaction studies. The RedSee™ tag is a chromophoric tag that binds a commercially-available chromatography resin, thereby enabling visual tracking of protein purification during affinity chromatography. Furthermore, RedSee™ has been observed to enhance solubility of several enzymes expressed in E. coli. As a leading collaborative research service provider, Blue Sky Biotech continues to provide increased value to our clients through technological innovation.
5:05 Technology Watch (Sponsorship available)
5:20 JNJ-26481585 - a novel second-generation oral pan-HDAC inhibitor
Janine Arts, Ph.D., Section Head Cancer Biology Department, Research Fellow, Ortho Biotech Oncology Research & Development
5:50 Belinostat (PXD101): A Versatile Oral and IV HDAC Inhibitor for Both Solid Tumours and Haematological Malignancies
James Ritchie, Ph.D., Belinostat Preclinical Project Manager, TopoTarget A/S
Belinostat is a low MW hydroxymate class I and II HDAC inhibitor. In a wide range of preclinical models, belinostat has shown potent growth-inhibitory activity when used as a monotherapy and in combination with a variety of cancer therapeutics. Belinostat clinical development is focused on maximizing patient exposure and optimizing administration schedules when used in combination with other treatments. Oral, intravenous and continuous infusion schedules are under investigation with efficacy being demonstrated as a monotherapy, and in combination, against hematological malignancies and solid tumors. In addition, preliminary evidence for re-sensitization by belinostat of tumors refractory to chemotherapy will be presented.
6:20pm End of Day
Pre-Conference Short Courses