Learning from Cancer to Advance Neurodegeneration Drug Discovery and Development

Learning from Cancer to Advance Neurodegeneration Drug Discovery and Development

Thursday, June 11, 2015

The New York Academy of Sciences

Does having cancer decrease your risk of developing neurodegenerative diseases? Why do many cancer drug targets overlap with targets for neurodegeneration? This interdisciplinary meeting seeks to answer these questions and help attendees learn from the mechanistic insight and years of research on cancer biology to advance new therapeutic development for neurodegenerative diseases. Speakers will address how their research relates to both cancer and neurodegeneration and what we can learn about cell biology and function from these seemingly disparate diseases. Talks will also discuss cancer drug repurposing opportunities for Alzheimer's and related dementias.

*Reception to follow.

This event will also be broadcast as a webinar.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City when possible.

Registration and Webinar Pricing

Member$30
Student / Postdoc Member$15
Nonmember (Academia)$65
Nonmember (Corporate)$85
Nonmember (Non-profit)$65
Nonmember (Student / Postdoc / Resident / Fellow)$45

 

Presented by

  • Alzheimer's Drug Discovery Foundation
  • The New York Academy of Sciences

The Brain Dysfunction Discussion Group is proudly supported by



Mission Partner support for the Frontiers of Science program provided by Pfizer

Agenda

* Presentation titles and times are subject to change.


Thursday, June 11, 2015

8:00 AM

Registration and Continental Breakfast

8:45 AM

Welcome and Opening Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Howard Fillit, MD, The Alzheimer's Drug Discovery Foundation

Plenary Address

9:00 AM

Inverse Association between Cancer and Neurodegenerative Disease: Review of the Epidemiologic and Biological Evidence
Jane A. Driver, MD, MPH, Brigham and Women's Hospital

Session I: Common Molecular Mechanisms Underlying Cancer and Neurodegeneration

9:40 AM

Chaperones and Homeostasis in Neurodegeneration and Cancer
Stuart K. Calderwood, PhD, Harvard Medical School

10:10 AM

TFEB-mediated Intracellular Clearance as a Potential Therapy for Alzheimer's Disease
Hui Zheng, PhD, Baylor College of Medicine

10:40 AM

Networking Coffee Break

11:10 AM

Understanding and Drugging the Epigenome
Claes Wahlestedt, MD, PhD, University of Miami Miller School of Medicine
(* The 11:10 am slides will not be broadcast as part of the live webinar.)

11:40 AM

Genetic Determinants of Cancer and Neurodegenerative Disease: Two Sides of the Same Coin?
David M. Roy, PhD, Memorial Sloan Kettering Cancer Center

12:10 PM

Networking Lunch Break and Poster Session

All poster presenters should stand by their posters 12:30 PM–1:30 PM

Session II: Learning from Cancer Drug Development—Clinical Trial Designs and Repurposing Opportunities for Neurodegenerative Disease

1:30 PM

Improving Synaptic Connections and Reducing Inflammation with the Fyn Inhibitor Saracatinib
Stephen M. Strittmatter, MD, PhD, Yale University School of Medicine

2:00 PM

The Lysine Specific Demethylase LSD1 in Oncological and Neurodegenerative Disease
Tamara Maes, PhD, Oryzon Genomics S.A.
(* The 2:00 pm slides will not be broadcast as part of the live webinar.)

2:30 PM

Repurposing Nilotinib to Promote Autophagy for Alzheimer's Disease and Parkinson's Disease
Raymond Scott Turner, MD, PhD, Georgetown University

3:00 PM

Networking Coffee Break

3:30 PM

The Utilization of Microtubule-Stabilizing Drugs for the Treatment of Tauopathies
Kurt Brunden, PhD, University of Pennsylvania

4:00 PM

A Randomized Controlled Study to Evaluate the Effect of Bexarotene-an RXR Agonist-on β-Amyloid and Apolipoprotein E Metabolism in Healthy Subjects
Gary Landreth, PhD, Case Western Reserve University

4:30 PM

Therapeutic Strategies for Epigenetic Alterations and Cellular Dysfunction
Li Huei Tsai, PhD, Massachusetts Institute of Technology

5:00 PM

Closing Remarks
Howard Fillit, MD, The Alzheimer's Drug Discovery Foundation

5:10 PM

Networking Reception

6:00 PM

Symposium Adjourns

Speakers

Organizers

Howard Fillit, MD

The Alzheimer's Drug Discovery Foundation

Howard Fillit, MD, a geriatrician, neuroscientist and a leading expert in Alzheimer's disease, is the founding Executive Director of the Alzheimer's Drug Discovery Foundation (ADDF). The ADDF's mission is to accelerate the discovery and development of drugs to prevent, treat and cure Alzheimer's disease, related dementias and cognitive aging. Dr. Fillit has had a distinguished academic medicine career at The Rockefeller University and The Mount Sinai School of Medicine where he is a clinical professor of geriatrics and medicine and professor of neurobiology. He is a co-author of more than 250 scientific and clinical publications, and is the senior editor of the leading international Textbook of Geriatric Medicine and Gerontology. Previously, Dr. Fillit was the Corporate Medical Director for Medicare at New York Life, responsible for over 125,000 Medicare managed care members in five regional markets. Dr. Fillit has received several awards and honors including the Rita Hayworth Award for Lifetime Achievement. He also serves as a consultant to pharmaceutical and biotechnology companies, health care organizations and philanthropies.

Diana Shineman, PhD

The Alzheimer's Drug Discovery Foundation

Diana Shineman, PhD is the Director for Scientific Affairs at the Alzheimer’s Drug Discovery Foundation, where she develops and manages the Foundation’s drug discovery and development grant programs and strategic initiatives. Combining scientific and business expertise, the ADDF manages its research funding portfolio to balance risk, stage of development, and drug target mechanism of action, ensuring that grants meet key milestones before securing follow-on funding. As a measure of success, projects funded by the ADDF have gone on to garner nearly $2 billion in follow-on funding. The ADDF also works strategically with foundations, government and industry partners to tackle unmet needs in the field. As an example of such an initiative, Dr. Shineman led an interdisciplinary effort to standardize animal model study design to improve research efficiency and translatability. Diana joined the ADDF in 2008. She earned a PhD in Cell and Molecular Biology from the University of Pennsylvania working in the Center for Neurodegenerative Disease Research led by Drs. Virginia Lee and John Trojanowski. She also worked as an Editorial Intern for the Journal of Clinical Investigation and was an active member of the Penn Biotechnology Group. Diana received a BA in Biology with a Nutrition concentration from Cornell University, where she was named a Howard Hughes Undergraduate Research Scholar. In addition to maintaining various professional memberships, Diana has also authored numerous articles and peer-reviewed publications.

Sonya Dougal, PhD

The New York Academy of Sciences

Keynote Speaker

Jane A. Driver, MD, MPH

Brigham and Women's Hospital

Jane A. Driver, MD, MPH is a member of the Geriatrics Research Education and Clinical Center (GRECC) at VA Boston Healthcare System the Division of Aging, Brigham and Women’s Hospital, and the Division of Medical Oncology, Dan Farber Cancer Institute. She is an Assistant Professor at Harvard Medical School. Trained as both a geriatrician and an oncologist, her research focuses on the epidemiology, prediction and prevention of cancer and neurodegenerative disease. She is currently investigating the link between cancer and Alzheimer’s disease, as well as new methods of early diagnosis of Alzheimer’s disease. With her collaborator Dr. Ping Lu, she is investigating the role of the enzyme Pin1 in the development of cancer and Alzheimer’s disease. She is currently examining the role of metabolic therapies in the prevention of both families of diseases. Dr. Driver has received research grants from the Department of Veterans Affairs, Hartford Foundation, the Parkinson’s Disease Foundation and Harvard Medical School. In addition to her research work, Dr. Driver cares for vulnerable elderly Veterans with memory disorders and is co-director of the Older Adult Hematologic Malignancy Program at the Dana Farber Cancer Institute. She teaches medical students, medical residents, geriatric fellows, and provides research mentorship for trainees and young faculty in both geriatrics and oncology.

Speakers

Kurt R. Brunden, PhD

University of Pennsylvania

Dr. Kurt R. Brunden is Director of Drug Discovery and a Research Professor in the Center for Neurodegenerative Disease Research (CNDR) at the University of Pennsylvania, where he oversees drug discovery programs in the areas of Alzheimer’s disease (AD), frontotemporal lobar degeneration and Parkinson’s disease. Prior to joining CNDR in 2007, Dr. Brunden was an executive in the biotechnology sector, where he served as VP of Research at Gliatech, Inc. and later as Sr. VP of Drug Discovery at Athersys, Inc. In these positions, he initiated and managed drug discovery programs in AD, cognitive enhancement, schizophrenia, inflammation, metabolic disease and cancer. Prior to his time in industry, Dr. Brunden was an NIH-funded faculty member within the Biochemistry Department at the University of Mississippi Medical Center, with a research focus on the regulation of myelination. He obtained his BS degree (magna cum laude) from Western Michigan University, with dual majors of Biology and Health Chemistry, and his Ph.D. in Biochemistry from Purdue University, with a post-doctoral fellowship at the Mayo Clinic. Dr. Brunden has over 85 scientific publications, and multiple issued and pending U.S. and PCT patents.

Stuart K. Calderwood, PhD

Harvard Medical School

Dr. Calderwood obtained his PhD from the University of Newcastle-upon-Tyne, England in 1978. He subsequently carried out postdoctoral fellowships studying the mammalian stress response at Newcastle (1978-1980) and Stanford University (1980-1984). He was recruited to The Dana Farber Cancer Institute, Harvard Medical School as an Assistant Professor in 1985, carrying out studies on mechanism of transcription of molecular chaperone genes. He became Associate Professor in 1991. Dr. Calderwood then became Director of the Molecular Stress Response Center and Professor of Medicine, Boston University (2002-2003). In 2003 Dr Calderwood became Director of Molecular and Cellular Biology and Professor of Radiation Oncology at Beth Israel Deaconess Medical Center Harvard Medical School and remains so until today. Dr. Calderwood has published extensively on regulation of molecular chaperone gene expression in cancer and aging as well as the immune properties of heat shock proteins leading to over 200 publications in peer reviewed journal and books and speaking engagements at local, national and international meetings. Dr. Calderwood’s research has been continuously funded through the NCI since1986. He has been a charted member of multiple NIH study sections since 1989.

Gary Landreth, PhD

Case Western Reserve University

Dr. Landreth received his undergraduate degree in Chemistry and Biochemistry from the University of Kansas in 1972. He then completed a PhD in the Neurosciences Program at the University of Michigan, including a year of study at the National Institute of Medical Research in London. He did postdoctoral work in the Department of Neurobiology at Stanford. Dr. Landreth was appointed to the faculty of the Medical University of South Carolina, where he worked for 9 years. He moved to Case Western Reserve University and the Alzheimer Research Laboratory in 1989 and is currently a professor in the Department of Neurosciences. His work over the past 25 years has focused on investigation of Alzheimer’s disease and the development of new drugs for its treatment.

Tamara Maes, PhD

Oryzon Genomics S.A.

Dr. Tamara Maes is Chemist by training with a Biotechnology specialty at the University of Ghent (Belgium). She received her PhD in Biotechnology from the University of Ghent, Belgium working on developmental genetics. Afterwards, she was a European Union postdoctoral fellow and worked in the CSIC of Barcelona, Spain. In 2000, she founded Oryzon, where she has been since then the Chief Scientific Officer and the responsible for the programs and products of the company. She has produced many scientific papers and patents internationally and has developed innovative HTS methods for functional genomics. Under her supervision, the company identified biomarkers for minimally invasive detection of endometrial cancer in post-menopausic women and she was responsible for developing the discovery stages and the clinical and regulatory development for GynEC-Dx, the first marketed product (in the Diagnostics area) of the company. Also under her supervision, the company identified early human biomarkers in several neurodegenerative disorders and in 2008 proposed to the board to start a drug discovery program on LSD1. This program was soon split in two branches: molecules designed for CNS uses and molecules optimized for oncological indications. This oncological program yielded ORY-1001, this molecule got the orphan drug status from the European Medicine Agency and is currently in clinical Phase I/IIA for acute leukemia and has been licensed recently to Roche in a multimillion dollar deal. The CNS program yielded ORY-2001 a dual LSD1-MAOB inhibitor expected to enter in clinic for the treatment of Alzheimer’s disease by the end of 2015.

David M. Roy, PhD

Memorial Sloan Kettering Cancer Center

David Roy is in his final year at Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program in New York. While in medical school, he completed a two-year HHMI research fellowship studying the role of PTPRD in cancer. He later received his PhD in 2015 from Weill Cornell Medical College under the supervision of Dr. Timothy Chan at Memorial Sloan Kettering Cancer Center. His graduate work focused on studying genomic alterations in glioma and developing computational strategies to identify driver genes involved in malignant transformation and metastasis. Currently, he is exploring the role of arm-level copy number alterations in cancer progression.

Stephen M. Strittmatter, MD, PhD

Yale University School of Medicine

Stephen M. Strittmatter, MD, PhD, was born in St. Louis, MO and earned his undergraduate degree from Harvard College, summa cum laude. He completed MD and PhD training at Johns Hopkins in 1986 with mentorship from Solomon H. Snyder, MD.  He then moved to Massachusetts General Hospital for a medical internship and an Adult Neurology residency. While at MGH, he worked as a Research Fellow with Mark Fishman, MD exploring the molecular basis of axonal guidance. He joined the faculty of Yale University in 1993. He is currently holds the Vincent Coates Professorship of Neurology at Yale and is a Founding Director of the Yale Cellular Neuroscience, Neurodegeneration and Repair Interdepartmental Program. He is also Director of the Yale Memory Disorders Clinic. Over 20 years, his laboraotry work has contributed to defining a molecular basis for axonal guidance during development, and neural repair after adult injury. More recently, his laboratory has also explored ligand-receptor interactions in degenerative dementias. In analyzing Amyloid–beta oligomer toxicity, his work has defined a pathway from PrPC to mGluR5 to Fyn. Dr. Strittmatter’s research has been recognized by the Ameritec Award, John Merck Scholar Award, Donaghue Investigator Award, McKnight Foundation Brain and Memory Disorders Award, Alzheiemr's Association Zenith Fellow Award, and Senator Jacob Javits Award in the Neurosciences. 

Li-Huei Tsai, PhD

Massachusetts Institute of Technology

Dr. Tsai is the Director of the Picower Institute for Learning and Memory at MIT and Picower Professor of Neuroscience. She is interested in the mechanisms of neurological disorders accompanied by learning and memory impairments, represented both by neurodegenerative disorders such as Alzheimer's disease (AD), and also by neurodevelopmental disorders. In the past two decades, Dr. Tsai's laboratory has contributed to the study of neuronal development and function in both the developing and adult brain, and how neuronal function and circuitry may be dysregulated in disorders of cognitive impairment. Her early work demonstrated p35 to be a neuron-specific activator of the serine/threonine kinase Cdk5, and that the Cdk5/p35 complex plays a critical role in cortical development. Her work showed that dysregulation of Cdk5 causes neuronal demise, and found that a mouse model of Cdk5 hyperactivation exhibits AD-like neurodegeneration and memory impairment. She also found that promoting chromatin remodeling using HDAC inhibitors ameliorates cognitive deficits, even after the onset of neurodegeneration. Her lab identified histone deacetylase 2 (HDAC2) as a key negative regulator of genes implicated in activity regulation, synaptogenesis, and synaptic plasticity. The lab also studies genomic integrity in neurons and have identified a novel mechanism involving DNA double strand breaks in regulating gene expression in neurons.

Raymond Scott Turner, MD, PhD

Georgetown University

Dr. Turner is a Professor of Neurology and Director of the Memory Disorders Program at Georgetown University Medical Center, Washington, DC. Previously, he was Chief of the Neurology Service at the VA Ann Arbor Healthcare System and Associate Professor and Associate Chair in the Department of Neurology, University of Michigan, Ann Arbor. He was awarded MD and PhD degrees from Emory University, Atlanta, and completed internship, residency, and fellowship training at the University of Pennsylvania, Philadelphia. He is Board-Certified in psychiatry and neurology. Turner has received prestigious awards including a research fellowship from the Howard Hughes Medical Institute, a Paul Beeson Scholarship, and a Washington Monuments Award from the Alzheimer’s Association, National Capital Chapter. Turner lectures widely, serves as a reviewer for granting agencies and biomedical journals, and has published more than 75 peer-reviewed papers, editorials, and book chapters. Turner is directing clinical studies sponsored by industry, the NIH, or both, at Georgetown University. Most recently, he was the PI of a multi-center, randomized, double-blind, placebo-controlled Phase 2 trial of resveratrol for individuals with mild-moderate Alzheimer’s disease - in collaboration with the NIA-funded Alzheimer’s Disease Cooperative Study (ADCS). For more information, see memory.georgetown.edu.

Claes Wahlestedt, MD, PhD

University of Miami Miller School of Medicine

Claes Wahlestedt, MD, PhD is Leonard M. Miller Professor at the University of Miami Miller School of Medicine and is working on a range of drug discovery and translational efforts in his roles as Associate Dean and Center Director for Therapeutic Innovation. The author of 200+ papers with 30,000+ citations, his ongoing research projects concern epigenetics, mammalian transcriptomics, noncoding RNAs, cancer, neuroscience, and drug discovery across several therapeutic areas. A native of Sweden, Dr. Wahlestedt obtained his MD and PhD degrees from Lund University, and then went on to develop an international career in academia as well as in the pharmaceutical industry. Prior to joining the University of Miami, Dr. Wahlestedt was a professor and director of neuroscience at the new Florida campus of The Scripps Research Institute (2005-2011). Before that he was an endowed professor of pharmacogenomics and chair of the Department for Genomics and Bioinformatics at the Karolinska Institute in Stockholm (1997-2005). He has also directed large drug discovery and biotechnology teams in the pharmaceutical industry for Astra-Zeneca, Pharmacia & Upjohn, and Pharmacia Corporation. His most recent biotechnology start-ups are CURNA Inc. (focusing on noncoding RNAs; acquired by OPKO Health in 2011) and Epigenetix Inc. (focusing on chromatin regulators).

Hui Zheng, PhD

Baylor College of Medicine

Dr. Hui Zheng gained research experience on Alzheimer’s disease both from industry (Merck Research Laboratories, 1991-1999) and academia (Baylor College of Medicine, 1999-present). She has a long-standing track record in understanding the biological and pathophysiological functions of the amyloid precursor protein and presenilins. Her work revealed APP as a synaptic adhesion protein and identified an intriguing role of presenilins in skin tumorigenesis. Recently, Dr. Zheng expanded her research effort to investigate the neuron-glia signaling pathways and intracellular clearance mechanisms in neuronal health and Alzheimer’s disease. Dr. Zheng holds the Huffington Foundation Endowed Chair and is Director of the Huffington Center on Aging at Baylor College of Medicine. She serves on the Cellular & Molecular Biology of Neurodegeneration (CMND) Study Section, and is a member of the BrightFocus Foundation Scientific Advisory Committee and the Alzheimer’s Association Medical & Scientific Advisory Council. 

Sponsors

For sponsorship opportunities please contact Perri Wisotsky at pwisotsky@nyas.org or 212.298.8642.

Promotional Partners

ALZForum

American Federation for Aging Research

American Society of Clinical Oncology

Alzheimer's Association

Dana Foundation

Elsevier

Journal of Alzheimer's Disease

Leaders Engaged on Alzheimer's Disease (LEAD)

Nature

Society for Neuroscience

 

Presented by

  • Alzheimer's Drug Discovery Foundation
  • The New York Academy of Sciences

The Brain Dysfunction Discussion Group is proudly supported by



Mission Partner support for the Frontiers of Science program provided by Pfizer

Abstracts

Inverse Association between Cancer and Neurodegenerative Disease: Review of the Epidemiologic and Biological Evidence
Jane A. Driver, MD, MPH, Brigham and Women’s Hospital, Boston VA Medical Center, Harvard Medical School

There is converging evidence of a complex but intriguing association between cancer and certain neurological conditions, particularly age-related neurodegenerative diseases. Cancer survivors have a 20-50% lower risk of developing Parkinson’s and Alzheimer’s disease, and patients with these conditions have a substantially lower incidence of cancer. On the other hand, cancer and neurodegeneration share key pathophysiological features, including metabolic and mitochondrial dysfunction, oxidative stress, and abnormal entry into the cell cycle. We will review the epidemiologic, genetic and biological evidence for the unusual association between these two families of diseases, which is intimately linked to the teleology of neurons and dividing cells. The known genetic and metabolic connections between cancer and neurodegeneration generally fall along two axes. The first includes shared genes and pathways such as Pin1 and the ubiquitin proteasome system that are dysregulated in opposite directions to promote one disease or the other. Careful manipulation of these pathways is already leading to new classes of drugs for both AD and a number of cancers. The second axis includes common drivers of both conditions. Drugs and interventions that promote DNA integrity and metabolic health, such as exercise and metformin, show great promise for treatment and prevention of both cancer and neurodegeneration. There is also evidence that some anti-neoplastic agents may have a neuroprotective effect. We will illustrate examples of these biological links and their implications for developing new approaches to prevention and treatment.
 

Chaperones and Homeostasis in Neurodegeneration and Cancer
Stuart K. Calderwood, PhD, Harvard Medical School

Neurodegeneration and cancer, diseases which are both associated with advancing age appear to be opposite in many attributes: cancer is characterized by a group of cells that have abandoned many aspects of the adult state and are instead growing and recapitulating stages of early development, while in neurodegeneration the population is static and non-dividing and the vital forces that prompted survival of the adult tissue become lost, presumably to the eroding power of time on cellular homeostasis. This difference is reflected in the relative power of the cells to respond to protein folding challenges. Cancer cells in general have markedly elevated levels of heat shock protein (HSP) molecular chaperones while neurons, cells  which even in their prime possess relatively feeble capacity to synthesize HSPs, show an age -related  decline in HSP synthesis as well as reduced capacity to degrade damaged proteins. In both diseases cells are presented with problems in protein folding: in cancer cells, overexpression of oncogenes, increased somatic mutation and polyploidy increase the pressure on the protein folding systems. In neurodegenerative diseases, presence of proteins with a dominant tendency to aggregate such as amyloid-b peptide, a-synuclein and polyglutamine tract-containing proteins pose problems in folding that are not met. The rationale behind these differences in the disease types is not clear although the ability of the expanding cancer cell population to evolve strategies to overcome cell regulation, compared to the static neuronal cell population is likely an important contributor.
 

TFEB-mediated Intracellular Clearance as a Potential Therapy for Alzheimer’s Disease
Hui Zheng, PhD, Baylor College of Medicine

Tauopathies consist of a group of diseases, including frontotemporal dementias and the most common form Alzheimer’s disease, and are characterized by the accumulation of intracellular neurofibrillary tangles (NFTs) composed of aggregates of hyperphosphorylated and misfolded Tau protein and extensive neurodegeneration. Tau is normally localized to the neuronal axons where it binds and stabilizes the microtubules. Aberrant Tau phosphorylation leads to its dissociation from the microtubules followed by aggregation and redistribution to cell bodies and dendrites. Accumulating evidence has implicated impaired autophagy-lysosome pathway in neurodegenerative diseases including Alzheimer’s disease. Recently, the Transcription Factor EB (TFEB) was discovered as a master regulator of cellular clearance through coordinated expression of autophagy and lysosomal target genes. We investigated the role of TFEB in AD mouse models. We report that mild TFEB expression has no untoward side effects on wild-type mice. In contrast, TFEB is highly efficacious in reducing the neurofibrillary tangle pathology and rescuing the behavioral and synaptic deficits and neurodegeneration in the rTg4510 mouse model of tauopathy. TFEB specifically targets the hyperphosphorylated and misfolded Tau species present in both soluble and aggregated fractions while leaving the normal Tau intact. The specificity and efficacy of TFEB in mediating the clearance of toxic Tau species and the fact that its activity can be modulated through kinase inhibition make TFEB an attractive therapeutic target for treating diseases of tauopathy including AD.
 

Understanding and Drugging the Epigenome
Claes Wahlestedt, MD, PhD, University of Miami Miller School of Medicine

Much of the mammalian genome is transcribed into long and small noncoding RNAs of different categories. This lecture will in part be concerned with noncoding RNAs which regulate gene expression through several distinct mechanisms including modulation of chromatin regulator protein complexes. Attention will also be given to more conventional epigenetic regulation which involves modification of proteins that are important for transcription, notably histones. Indeed, many protein families affect epigenetic processes through the acetylation and methylation of histones, including histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins and proteins that bind to methylated histones. These latter protein families are small molecule druggable classes of enzymes. Examples of BET bromodomain inhibitor efficacy in disease models will be given.
 

Genetic Determinants of Cancer and Neurodegenerative Disease: Two Sides of the Same Coin?
David M. Roy, PhD, Memorial Sloan Kettering Cancer Center

Recent advances in genomics have allowed the comprehensive exploration of altered genetic landscapes, shedding new light on underlying mechanisms of disease.  Remarkably, massive efforts to identify genetic culprits in either cancer or neurodegenerative disease have uncovered several areas of overlap. Genes that have been implicated in both include PTPRD, PARK2, PTEN, ATM, APP, and mTOR. It is believed that these proteins regulate vital cellular processes including autophagy, cell cycle regulation, cell-cell signaling, and DNA repair. For example, we have shown that the E3 ubiquitin ligase PARK2 is inactivated through mutation and deletion in several malignancies, including glioma.  PARK2 mutations have also been documented in early-onset Parkinson disease. Inactivation of PARK2 results in accumulation of both cyclin D and cyclin E, resulting in cell cycle progression in cancer. In neurons however, this results in cell death. Similarly, the tyrosine phosphatase PTPRD is widely inactivated in cancer and predicts worse survival in glioma. Intriguingly, PTPRD also plays a role in axonal growth and differentiation and has been implicated in restless legs syndrome, a neurological disorder. Despite obvious challenges presented by phenotypic differences in cancer and neurodegenerative disease, it is likely that advances in either field can synergistically clarify causal mechanisms and reveal new therapeutic vulnerabilities.
 

Improving Synaptic Connections and Reducing Inflammation with the Fyn Inhibitor Saracatinib
Stephen M. Strittmatter, MD, PhD, Yale University School of Medicine

Alzheimer’s disease is characterized by Amyloid-ß (Aß) accumulation, with soluble oligomers (Aßo) being the most synaptotoxic. Once formed, Aßo acts to impair synpases through PrPC and mGluR5 via activation of the Fyn tyrosine kinase, a Src-related enzyme. We sought to repurpose a Src family kinase inhibitor oncology compound AZD0530 (saracatinib) for AD. The Fyn kinase inhibitor enters the brain and potently inhibits both Aßo-induced signaling and downstream phosphorylation of the AD risk gene product, Pyk2, and of NR2B Glu receptors in brain slices. After a month of treatment, Fyn kinase inhibitor dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Aß metabolism. In addition, the AZD0530 treatment reduced microglial activation.  In triple transgenic mice, the compound reduced Tau phosphorylation and aggregation. Overall, Fyn inhibition reverses the effects of Aßo through the PrPC–mGluR5 complex at the synapse, and rescues transgenic mouse models of AD.
 

The Lysine Specific Demethylase LSD1 in Oncological and Neurodegenerative Disease
Tamara Maes, PhD, Oryzon Genomics

The lysine specific demethylase (LSD1/KDM1A) demethylates H3K4me2/1 and is a modulator of gene expression. LSD1 plays an important role in hematopoiesis and is a necessary co-factor for important transcriptional regulator. LSD1 inhibitors were shown to promote the differentiation and to selectively abrogated the clonogenic potential of acute myeloid leukemia cells with MLL translocations, sparing the repopulating potential of normal hematopoetic stem cells. We have developed ORY-1001, an enantiomerically pure LSD1 inhibitor that is >1000x stronger than tranylcypromine, highly selective over related FAD dependent amine oxidases. ORY-1001 reduces leukemic stem cell potential, potently inhibits colony formation, overcomes the differentiation block in AML cell lines, and induces apoptosis / inhibits proliferation at sub-nanomolar EC50 values in selected AML cell lines, and is currently in a Phase I trial in recurrent in relapsed or refractory acute leukemia. In solid tumors, LSD1 over-expression has been associated with unfavorable prognosis, and small cell lung cancer cells have shown particular sensitivity to treatment with LSD1 inhibitors. The potential use of LSD1 inhibitors is not limited to oncological disease. LSD1 forms part of regulatory networks affected in different neurological or neurodegenerative conditions, and LSD1 inhibitors have the potential to modulate gene expression and modify the disease course. For example, ORY-2001, a novel brain penetrable dual inhibitor of LSD1 and monoamine oxidase-B (MAO-B), prevented the development of memory deficit in SAMP-8 mice, a model for accelerated aging and Alzheimer’s disease. ORY-2001 is currently undergoing regulatory toxicology studies, and is expected to reach Phase I by the end of 2015.
 

Repurposing Nilotinib to Promote Autophagy for Alzheimer’s Disease and Parkinson’s Disease
Raymond Scott Turner, MD, PhD, Georgetown University

The two defining pathologies found in Alzheimer’s disease (AD) brain are neurofibrillary tangles (NFTs) comprised primarily of phosphorylated Tau (pTau) and Ab/amyloid plaques. Ab/amyloid and pTau/NFTs accumulation with aging may be due to impaired autophagic clearance resulting in proteostasis and neuronal toxicity. Thus, promotion of autophagy may degrade Ab and pTau to prevent or slow progressive cognitive decline. Activation of the tyrosine kinase Abl is associated with increased pTau in animal models of AD and in human AD brain tissues. The Bcr-Abl inhibitor nilotinib (TASIGNA®) is FDA-approved for the treatment for chronic myeloid leukemia (CML). Our data with nilotinib treatment of animal models of neurodegenerative disease demonstrate that the drug penetrates the blood-brain barrier, promotes autophagic degradation of Ab/amyloid and pTau/NFTs, attenuates neuroinflammation, and improves cognition. We hypothesize that Nilotinib will alter CSF Ab and pTau181 levels, modulate blood and CSF immune markers, and improve or stabilize cognitive function in subjects with mild to moderate AD. Specifically, we propose a 6-month randomized, double-blind, placebo-controlled trial of oral Nilotinib for AD. Primary outcomes will be CSF Ab40, Ab42, total Tau, and pTau181. Secondary and exploratory outcomes will include safety and tolerability, change in amyloid PET, inflammatory markers in CSF, serum, and plasma, and cognitive function. This novel treatment strategy may also be safe and effective for individuals with Parkinson’s disease and other neurodegenerative disorders of aging defined by proteostasis and impaired autophagy.
 

The Utilization of Microtubule-Stabilizing Drugs for the Treatment of Tauopathies
Kurt R. Brunden, PhD, University of Pennsylvania, Perelman School of Medicine

A group of neuro­degenerative dis­eases referred to as tauopathies, which include Alz­heimer’s dis­ease (AD) and frontotemporal lobar degene­ration, are characterized by the accu­mulation within neu­rons of ag­gre­gates comprised of hyper­phos­phorylated forms of the micro­tubule-as­so­ci­ated pro­tein, tau. Tau normally stabilizes axonal microtubules, and the dis­engagement of hyper­phos­phorylated tau from micro­tubules in tauopathies is thought to lead to microtubule deficits that reduce axonal transport and impair neuronal function in the brain. This has led to the hypothesis that small molecule microtubule-stabilizing agents, such as those that reduce cancer cell division through alteration of the mitotic spindle, might have utility in the treatment of tauopathies. We have identified and char­acter­ized multiple brain-penetrent, small mole­cule micro­tubule-stabilizing molecules that might serve to normalize micro­tubule func­tion in tauopathies, including the natural product epothilone D, which was shown to enhance micro­tubule density, increase axonal trans­port, and re­duce neu­ronal death in trans­genic mouse models of tauopathy. Epothilone D subsequently advanced to Phase 1b clinical testing in Alz­heimer’s dis­ease patients. More recently, we have iden­tified ad­di­tional natural product and non-natural product micro­tubule-stabilizing molecules that are enter the brain and enhance micro­tubule stabilization. The concept of microtubule-stabilization as a therapeutic strategy for tauopathies, and data supporting this approach, will be discussed during this presentation.
 

A Randomized Controlled Study to Evaluate the Effect of Bexarotene – an RXR Agonist – on β-Amyloid and Apolipoprotein E Metabolism in Healthy Subjects
Gary Landreth, PhD, Case Western Reserve University

The nuclear receptors LXR:RXR and PPAR:RXR are ligand-activated transcription factors which act to stimulate the expression of ApoE and its lipid transporters. In murine models of AD, oral administration of the RXR agonist bexarotene (TargretinTM) resulted in reduced levels of soluble forms of Abeta and improved memory and cognition through an ApoE-dependent mechanism. Bexarotene is an FDA–approved drug for the treatment of cutanteous T-cell lymphoma. We have performed a proof of mechanism study in normal subjects using stable isotope labeling kinetics and absolute quantitation using C13-leucine. Bexaraotene (n=6) or placebo (n=6) was administered orally at 225 mg/kg BID for 5 days. On the morning of day 4 the subjects were administered C13-leucine. The plasma and CSF were sampled hourly for 48 hrs. We report that plasma levels of bexarotene were approximately 1-2 microM, reaching maximal levels approximately 5 hrs following dosing. However, CSF levels of bexarotene were at or below the level of detection (<20nM), with average plasma:CSF ratio of 80:1, reflecting poor CNS penetrance. Absolute CSF ApoE levels were elevated approximately 25% in drug treated subjects, but there was no change in the fractional synthesis or clearance rates of ApoE. There were no significant changes in the synthesis, clearance of total Abeta levels or of Abeta40 elicited by drug treatment. We conclude that bexarotene engaged its targets, but poor CNS penetrance limited the magnitude of the response and its effects on CSF Abeta. Thus, a primary endpoint of the study was not met.
 

Therapeutic Strategies for Epigenetic Alterations and Cellular Dysfunction
Li-Huei Tsai, PhD, Massachusetts Institute of Technology

Following the completion of the Human Genome Project, much of biology's focus has shifted from the raw sequence of genes to their regulation, both over time and in response to environmental stimuli. Like books on a shelf, genes do not exert effects by their mere presence, rather, the pages of the book (i.e. the chromatin) need to be opened so that the words (i.e. the genes) can be read and interpreted correctly. The epigenetic regulation of gene expression refers precisely to this process. To date, an increasing body of evidence indicates that various neurodevelopmental, neurodegenerative, and psychiatric disorders are, in part, caused by aberrant epigenetic modifications. Fortunately, research from several fields has demonstrated that pathological epigenetic modifications are readily amenable to pharmacological interventions, and thus have raised justified hopes that the epigenetic machinery provides a powerful new platform for therapeutic approaches against these diseases. I will present recent evidence supporting a critical role for dysregulated epigenetic gene regulation in age-related cognitive decline, including Alzheimer's disease, the most devastating health problem facing modern society. Potential strategies to reverse disease-associated gene expression programs and repair the nervous system will be discussed.
 

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