Day 1 :
University of Rochester, USA
Time : 10:00-10:45
Henry M Sobell completed his studies at Brooklyn Technical High School (1948-1952), Columbia College (1952-1956), and the University of Virginia School of Medicine (1956-1960). Instead of practicing clinical medicine, he then went to the Massachusetts Institute of Technology (MIT) to join Professor Alexander Rich in the Department of Biology (1960-1965), where, he had a Helen Hay Whitney Postdoctoral Fellowship where he learned the technique of single crystal X-ray analysis. He then joined the Chemistry Department at the University of Rochester, having been subsequently jointly appointed to both the Chemistry and Molecular Biophysics departments (the latter at the University of Rochester School of Medicine and Dentistry), becoming a full tenured Professor in both departments (1965-1993). He is now retired and living in the Adirondacks in New York, USA.
Premeltons are examples of emergent structures (i.e., structural solitons) that arise spontaneously in DNA due to the presence of nonlinear excitations in its structure. They are of two kinds: B-B (or A-A). Premeltons form at specific DNA-regions to nucleate site-specific DNA melting. These are stationary and, being globally non-topological, undergo breather motions that allow drugs and dyes to intercalate into DNA. B-A (or A-B) premeltons, on the other hand, are mobile, and being globally topological, act as phase-boundaries transforming B- into A- DNA during the structural phase-transition. They are not expected to undergo breather-motions. A key feature of both types of premeltons is the presence of an intermediate structural-form in their central regions (proposed as being a transition-state intermediate in DNA-melting and in the B- to A- transition), which differs from either A- or B- DNA. The so called beta-DNA, this is both metastable and hyperflexible–and contains an alternating sugar-puckering pattern along the polymer-backbone combined with the partial-un-stacking (in its lower energy-forms) of every other base-pair. Beta-DNA is connected to either B- or to A- DNA on either side by boundaries possessing a gradation of nonlinear structural-change, these being called the kink and the anti-kink regions. The presence of premeltons in DNA leads to a unifying theory to understand much of DNA physical-chemistry and molecular-biology. In particular, premeltons are predicted to define the 5’ and 3’ ends of genes in naked-DNA and DNA in active-chromatin, this is having important implications for understanding physical aspects of the initiation, elongation and termination of RNA-synthesis during transcription. For these and other reasons, the model will be of broader interest to the general audience working in these areas. The model explains a wide variety of data, and carries within it a number of experimental predictions –all readily testable – as will be described in my talk.
1. Sobell H M (2016) Premeltons in DNA. Journal of Structural and Functional Genomics 17:17-31.
2. Sobell H M (2009) Premeltons in DNA. A unifying polymer-physics concept to understand DNA physical-chemistry and molecular-biology. Explanatory publications, Lake Luzerne, NY, ISBN 978-0-615-33828-6.
3. Sobell HM (2013) Organization of DNA in Chromatin. Rather than bending uniformly along its length, nucleosomal DNA is proposed to consist of multiple segments of B- and A- DNA held together by kinks when forming its left-handed toroidal superhelical structure. Explanatory publications, Lake Luzerne, NY, ISBN 978-0-692-01974-0.
Dr. Margarete Fischer Bosch-Institute of Clinical Pharmacology, Germany
Time : 10:45-11:30
Hiltrud Brauch has completed herPhDat the University of Heidelberg, Germany, and postdoctoral studies as a Fogarty International Visiting Fellowat the National Institutes of Health (NIH), National Cancer Institute (NCI), Frederick, Maryland, USA. She is the deputy director of Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology in Stuttgart, a non-profit private research institute of the Robert Bosch Foundation. She has published more than 250 papers in reputed journals and has been serving as an editorial board member of Pharmacogenetics and Genomics as well as Pharmacogenomics and Personalized Medicine.
Breast cancer is a global health burden with 1.7 million newly diagnosed patients and more than half a million patients dying from the disease each year. The large majority (75%) of breast cancers express the estrogen receptor (ER) making them amenable to targeted endocrine therapy. Standard of care is the blockade of estrogen signaling via long-term estrogen deprivation. Two proven treatment options are available: tamoxifen, a selective ER modulator which blocks 17ß-estradiol binding to ER to stop tumor growth, and aromatase inhibitors (AI), which block the aromatase enzyme that prevents the conversion of androgens to estrogens. Despite the well-established effectiveness of endocrine treatments every other patient displays de novo or acquired resistance which ultimately leads to disease progression and death. Based on its well-known metabolism and drug action, tamoxifen has been in the spotlight of pharmacogenomics investigations within the past decade. The goal is to identify biomarkers that can predict tamoxifen outcome and facilitate personalized treatment schemes in order to avoid drug failure. Tamoxifen failure has been in part attributed to a lack of bio-activation towards its active metabolite, endoxifen. Pharmacological and pharmacogenetics evidence strongly support the view that in vivo endoxifen formation is mainly mediated from the primary metabolite N-desmethyl-tamoxifen by the polymorphic cytochrome P450 (CYP) 2D6 enzyme. Distinct genetically determined functional CYP2D6 variants are present in the general population and inter-individual differences in enzyme activities can be grouped into the four CYP2D6 phenotypes ultra-rapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizers. We and others provided strong evidence that tamoxifen treated EM breast cancer patients have high levels of endoxifen and that they are likely to benefit from the treatment. In contrast, PM patients have low endoxifen levels and a significant risk to relapse. Thus, CYP2D6 polymorphism and plasma endoxifen levels have a great potential as suitable tamoxifen outcome predictors. However, due to controversies from negative studies, the translation into the clinic has been hampered. In my talk, I will discuss the current status of the debate and emphasize the need for uniform study design, technology and statistical procedures in the conduct of pharmacogenomics analyses in order to avoid shortcomings and delay in clinical implementation. Moreover, I will present a way forward towards the clarification of the CYP2D6 tamoxifen pharmacogenomic issue via a novel strategy for the optimization of endoxifen plasma levels in CYP2D6 compromised breast cancer patients currently investigated in our ongoing phase II clinical trial.