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Abstract Book ABSTRACT BOOK CONTENTS Plenary lectures 4 Invited sessions 11 Poster sessions 72 P.1 Preclinical research – Neurobiology 72 P.2 Preclinical research – Neuropsychiatry 101 P.3 Preclinical research – Other themes 108 P.4 Preclinical research – Biotechnology 117 P.5 Preclinical research – Medicinal Chemistry 121 P.6 Preclinical research – Nanomedicine 143 P.7 Clinical research 149 3 PLENARY LECTURES PL. 1 (Inaugural lecture) Personalized therapies for CNS diseases: needs and approaches Kalpana Merchant, PhD, TransThera Consulting Co., Portland, OR, USA CNS diseases, both psychiatric and neurological disorders, represent significant unmet medical needs and associated societal burden. The age-associated chronic, progressive, neurodegenerative disorders are of particular concern in light of the expected exponential increase in the worldwide aging population. From a drug discovery and development perspective, CNS disorders have been one of the most challenging areas, with perhaps the highest rate of clinical failure. The primary factor underlying the failures has been the lack of meaningful efficacy in patients. This is despite the fact that advances in genomic and drug discovery technologies have identified many novel molecular targets as well as potent and safe drug-like clinical candidates. This talk will highlight major reasons associated with the attrition rate of CNS drugs and approaches to address these issues. Specifically, the focus will be on translational approaches that could result in dissecting syndromic CNS disorders into molecularly-defined disease states in individual patient populations. An important first step if to reform the current practice of diagnosing CNS diseases, which relies largely on blunt clinical instruments that are frequently based on patient-reported symptoms and clinical outcomes. These classifications fail to take into account the tremendous heterogeneity in the etiology and pathophysiology underlying a disorder as well as allostatic molecular changes that are known to occur within a patient over time. On the bright side, advances in genomic, imaging and other analytical “omics” technology platforms offer an unprecedented opportunity to derive insights into molecular mechanisms associated with CNS disorders. These insights could enable, on the one hand, re-classification of CNS diseases on the basis of objective biomarkers, and on the other hand, provide targets for therapeutic interventions that target pathophysiologic mechanisms in individual patient populations; i.e., personalized therapies. The power of this approach is evident in the recent emergence of transformative therapies in the oncology area. Although CNS diseases have their unique set of challenges, specific examples from published literature will be discussed to demonstrate that it is possible to develop personalized therapies for CNS diseases. 4 PL. 2 Hereditary breast and ovarian cancers Jan Lubinski, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland Hereditary breast and ovarian cancers are a group of syndromes that involve high predisposition to above cancers and an autosomal dominant with high penetrance pattern of inheritance. Genetic factors and risk assessment Breast and ovarian cancer among carriers of BRCA1 / BRCA2 mutations Among BRCA1 carrier the average cumulative risk of breast cancer by 80 yrs of age is 70% and of ovarian cancer 45%. Among BRCA2 carriers these average cumulative risks are 70% and 10% respectively. After a first breast cancer, BRCA1 and BRCA2 carriers have also a substantial risk of contralateral breast cancer. 70% of breast cancers that develop in BRCA1 carriers are “triple negative”. BRCA2 carriers are “triple negative” in 15% only. Serous ovarian cancers predominate in both types of carriers. Risk of breast or ovarian cancer is higher among carriers with a positive family history, however for ~40% of carriers breast/ovarian cancer family history is negative although the risk of these cancers is substantially increased. By 70 yrs of age, the cumulative risk of breast cancer is ~7% among men with BRCA2 mutations. Hereditary breast and ovarian cancer due to genes other than BRCA1 and BRCA2 High (>20-25%) lifetime risk of breast cancers has been reported also in carriers of mutations in such genes like PALB2, CHEK2, PTEN, TP53, STK11, CDH1 and, recently, RECQL. Hereditary breast and ovarian cancer without an identified genetic cause At present, majority of persons with a suspected hereditary predisposition to breast and ovarian cancer have not been found to have a mutation that is pathogenic. For these patients, integrating estimates of cancer risks according to family history with other clinical factors, are recommended. The most popular tools include BOADICEA (ccge.medschl.cam.ac.uk/boadicea/), BRCAPro and Tyrer-Cuzick model (www.cancertechnology.co.uk/ibis-software-tyrer-cuzick-model). Screening for mutations Next generation sequencing (NGS) NGS analyses are now available which allow BRCA1 and BRCA2 sequencing for 200 USD. With such cost it seems that NGS of BRCA1/BRCA2 should be considered by all women, because, actually, it is life-saving procedure. In addition to BRCA testing NGS panels of other cancer risk genes are also available now. This cost is only slightly higher than NGS of BRCA1/BRCA2 Founder mutations For several countries / ethnic groups genetic testing is much more cost-effective because of high prevelance of founder mutations. It is the well known effect in Israel, Slavic countries, French Canadians, Iceland, Cyprus and others. 5 5 Management in hereditary breast and ovarian cancer syndromes BRCA1/BRCA2 Surveillance Screening for breast cancer should include an annual MRI examination because of its high sensitivity (85-90%) in detection of early cancers. Mammography and USG of the breast performed together are showing sensitivity 2 times lower. USG and CA125 are detecting no more than 10% of early ovarian / fallopian tube cancers. Prevention Two the strongest procedures to reduce the risk of cancers among BRCA1/2 carriers are mastectomy – protection approaches 100% and adnexectomy - 5-fold protection. Preventive adnexectomy is associated also with ~80% reduction of all-cause mortality. Other procedures include: long breast feeding, delay of menarche, tubal ligation and tamoxifen. A very important is to do not use oral contraceptives (OC) at age under 25 yrs (increased risk of breast cancer diagnosed at age under 40 yrs) but to apply OC at women at age above 35 yrs (not increased risk of breast but lower of ovarian cancer). Treatment The 10-year survival rate among women with breast cancer and a BRCA1 mutation is much improved after adnexectomy – the risk of death is decreased by up to 70%. Tamoxifen in breast cancers in carriers is reducing by 50% the risk of contralateral breast cancer even in patients with ER(-), PR(-) tumours. Breast cancers in carriers are poorly responding to taxanes, but are highly sensitive to cis-platin. Ovarian cancers in carriers which are sensitive to platin, have longer progression free survival (PFS) after applying PARP inhibitor – olaparib. References: Agnese DM, Pollock RE. Breast Cancer Genetic Counseling: A Surgeon's Perspective. Front Surg. 2016; 3: 4. Cybulski C, et al, Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncol. 2015; 16(6):638-44. Cybulski C, et al, Germline RECQL mutations are associated with breast cancer susceptibility. Nat Genet. 2015; 47(6):643-6. Economopoulou P, Dimitriadis G, Psyrri A. Beyond BRCA: new hereditary breast cancer susceptibility genes. Cancer Treat Rev. 2015;41(1):1-8. Finch AP, Lubinski J, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol. 2014; 32(15):1547-53. Hartmann LC, Lindor NM., The Role of Risk-Reducing Surgery in Hereditary Breast and Ovarian Cancer. N Engl J Med. 2016; 374(5):454-68. Huzarski T, et al, Ten-year survival in patients with BRCA1-negative and BRCA1-positive breast cancer. J Clin Oncol. 2013; 31(26):3191-6. Kotsopoulos J, et al, Timing of oral contraceptive use and the risk of breast cancer in BRCA1 mutation carriers. Breast Cancer Res Treat. 2014; 143(3):579-86. Narod SA, BRCA mutations in the management of breast cancer: the state of the art. Nat Rev Clin Oncol. 2010, 7, 702-707. Pederson HJ, Padia SA, May M, Grobmyer S. Managing patients at genetic risk of breast cancer. Cleve Clin J Med. 2016; 83(3):199-206. Stuckey AR, Onstad MA. Hereditary breast cancer: an update on risk assessment and genetic testing in 2015. Am J Obstet Gynecol. 2015; 213(2):161-5. Wittersheim M, Büttner R, Markiefka B. Genotype/Phenotype correlations in patients with hereditary breast cancer. Breast Care (Basel). 2015; 10(1):22-6. 6 PL. 3 Personalizing treatment of the schizophrenia spectrum through endophenotypes, rational pharmacology, and pharmacogenomics Herbert Y. Meltzer, MD Professor of Psychiatry and Behavioral Sciences, Pharmacology and Psychiatry, Northwestern University, Feinberg School of Medicine, Chicago, IL USA The atypical antipsychotic drugs, of which clozapine is the prototype, are now widely used to treat not only schizophrenia and schizoaffective disorder, but also bipolar disorder, treatment resistant depression (regardless of the presence of psychosis) behavioral disturbances of dementia, aggression, and suicide. All of the atypical antipsychotic drugs were introduced to treat schizophrenia but became more widely prescribed,
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