2017 Archived Content
Autophagy is a highly regulated and complex process of destroying damaged proteins and organelles under stressful conditions. Stemming from the pioneering work of Professor Yoshinori Ohsumi, who was awarded the 2016 Nobel Prize in Physiology and Medicine, dysregulation of the autophagy process has been established to play a role in neurodegenerative diseases and cancers. Consequently, the discovery of novel therapeutic agents targeting various stages along this process has emerged as a promising new approach for drug developers.
Cambridge Healthtech Institute’s Inaugural Targeting Autophagy symposium will bring together academic and industry leaders to network, collaborate and discuss advances in autophagy drug discovery.
Final Agenda
Monday, September 25
7:00 am Registration Open and Morning Coffee
7:55 Welcome Remarks
Kip Harry, Senior Conference Director, Cambridge Healthtech Institute
8:00 Chairperson’s Opening Remarks
Nicholas Cosford, Ph.D., Associate Director, Translational Research & Professor, Cancer Metabolism and Signaling Networks Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute
8:10 KEYNOTE PRESENTATION: Targeting Autophagy in Cancer
Eileen White, Ph.D., CSO, Deputy Director & Associate Director, Basic Science, Rutgers Cancer Institute of New Jersey
Macroautophagy (autophagy) degrades proteins, other macromolecules, and organelles, in lysosomes and recycles the breakdown products to promote survival in stress and starvation. Autophagy is upregulated in some cancers and promotes survival and malignancy, suggesting that targeting autophagy in cancer may be therapeutically advantageous. Autophagy promotes tumor cell autonomous cancer in preclinical models by suppressing p53, apoptosis, senescence, and immune responses, and also by promoting metabolism and proliferation.
9:10 A Membrane-Associated Signaling Complex for Controlling Peroxisome Fate
Vlad Denic, Ph.D., Professor, Molecular and Cellular Biology, Harvard University
Eukaryotic cells maintain the quality of their organelles by controlling organelle turnover by autophagy. Recent work has shown that autophagy receptor proteins induce organelle destruction by triggering local autophagosome initiation upon activation by cytosolic kinases. It has remained unclear, however, how receptor activation is regulated. We hypothesized that receptor activation is controlled locally by organelle resident proteins to enable quality control decisions. I will present our evidence for this hypothesis in the context of selective autophagy of peroxisomes in the budding yeast S. cerevisiae and discuss implications of this work for drug targeting of mammalian pexophagy associated with certain Zellweger Spectrum disorders.
9:40 Networking Coffee Break with Poster Viewing
10:10 Context-Specific Regulation and Function of Autophagy, Therapeutic Food for Thought
Eric H. Baehrecke, Ph.D., Professor, Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School
Autophagy is an important cellular response to stress, and plays essential roles in development, immunity, cancer and neurodegeneration. Thus, autophagy is considered a promising target for disease therapies. Pioneering studies of yeast led to the identification of conserved core factors that regulate autophagy, but the role of autophagy in specific cell contexts within multi-cellular organisms has not been rigorously studied. Recent studies of how autophagy is regulated and contributes to distinct cell fates will be presented.
10:40 Selected Poster Presentation
11:10 Enjoy Lunch on Your Own
1:10 pm Chairperson’s Remarks
Eric H. Baehrecke, Ph.D., Professor, Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School
1:20 The Investigation of Autophagy in Cancer Using Chemical Biology
Nicholas Cosford, Ph.D., Associate Director, Translational Research & Professor, Cancer Metabolism and Signaling Networks Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute
Despite recent breakthroughs in the understanding of how ULK1 is activated by nutrient deprivation, how ULK1 promotes autophagy remains poorly understood. Using various chemical biology approaches, we identified and characterized a potent ULK1 small molecule inhibitor. The compound SBI-0206965 is a highly selective ULK1 kinase inhibitor in vitro and suppresses ULK1-mediated phosphorylation events in cells, regulating autophagy and cell survival. This presentation will describe our efforts to date on the validation of autophagy inhibition.
1:50 Targeting Autophagy in Cancer
Jeff MacKeigan, Ph.D., Professor, College of Human Medicine, Michigan State University
In recent years, autophagy has emerged as an important therapeutic target. In response to environmental, therapeutic, and oncogenic stress, cancer cells upregulate autophagy and also demonstrate an increased dependence upon this intracellular recycling process. Many cancers still lack targeted therapeutic options, and autophagy inhibitors are a promising and emerging anti-cancer target. We present the therapeutic development of autophagy inhibitors from early lysosomotropic agents to next-generation lysosome-targeted drugs to kinase-directed targets.
2:20 Targeting the Lysosome in Cancer
Ravi Amaravadi, M.D., Associate Professor, Medicine, University of Pennsylvania
The anti-tumor efficacy of the second-generation dimeric chloroquine Lys05 has now been demonstrated by a number of laboratories. A new series of third-generation longer linkered dimeric chloroquines such as DC661 demonstrate substantial improvements in potency compared to Lys05. Finally the dimeric quinacrine DQ661 concurrently inhibits mTOR and autophagy. The molecular target of dimeric chloroquine derivatives was pulled down using multiple DC and DQ-photoaffinity probes. This lysosomal enzyme could play a critical role in multiple oncogenic pathways.
2:50 Networking Refreshment Break with Poster Viewing
3:30 Inhibitors of Vps34 in Cancer Treatment
Jessica Martinsson, Ph.D., Vice President, Medicinal Chemistry, Sprint Bioscience AB
We have developed potent and selective inhibitors of Vps34 with excellent drug properties. The compounds are potent inhibitors of autophagy, affecting cellular metabolism and oxygen consumption. With these compounds, we have shown the relevance of autophagy inhibition in TNBC and investigated its role in immune response.
4:00 Discovery of Novel TAOK2 Inhibitor Scaffolds from High-Throughput Screening
Malia B. Potts, Ph.D., Assistant Member, Cell and Molecular Biology, St. Jude Children’s Research Hospital
A synthetic lethal screen performed using a NSCLC (non-small cell lung cancer) cell line, and a second screen identifying potential modulators of autophagy have implicated TAOK2 as a potential cancer therapeutic target. Using a 200,000 compound high throughput screen, we identified three specific small molecule compounds that inhibit the kinase activity of TAOK2. These compounds also showed inhibition of autophagy. Based on SAR (structure-activity relationship) studies, we have predicted the modifications on the reactive groups for the three compounds.
4:30 Targeting Autophagy for Cancer Therapy
Natalie Roy D’Amore, Ph.D., Director, Early Discovery Oncology, Takeda Pharmaceuticals
5:00 Close of Symposium
5:00 Pre-Conference Dinner Short Course Registration
Click here for details on short courses offered.