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Edison Liu, M.D. Integrated Translational Science Center Dave Tuveson M.D., Ph.D. and Larry Baker D.O. CSHL-JAX-SWOG-HOPE September 15, 2016 Our ITSC: Education and Research • SWOG Meetings • • • • Translational Summer Workshop • • • Introductory sessions and office hours with ITSC Leadership Eagle II Reception - Thursday September 15, 2016 (for all workshop participants and pilot project awardees). Translational dinner, talks and networking session is being planned for Spring 2017 SWOG group meeting Alternating years at CSHL or JAX 12 SWOG Clinical Investigators, 12 basic scientists from JAX, 12 basic scientists from CSHL Pilot Projects • • ~ 4 awarded per year (1 year award, $100,000 in direct costs) Must have one clinical and one basic scientist as co-PIs. Translational Workshop SWOG/Integrated Translational Science Center The forum provides an opportunity for: • CSHL & JAX scientists to present the technology platforms • SWOG clinicians to discuss clinical questions that need to be addressed Goal is to pair SWOG clinicians with CSHL/JAX scientists to propose pilot projects using technologies to tackle clinical questions ITSC Translational Workshops: • Banbury Conference Center, CSHL (June 18-20, 2015) • Highseas Conference Center, JAX (Aug 31-Sept 2, 2016) • Banbury Conference Center, CSHL (2017, date tba) • Highseas Conference Center, JAX (2018, date tba) Pilot Projects SWOG/Integrated Translational Science Center Goals: • Support collaborative projects between SWOG investigators with coPI from Cold Spring Harbor Laboratory or The Jackson Laboratory • Use technology platforms – THE DISCOVERY ENGINE - available at CSHL and JAX to obtain preliminary data that can then be used as the basis for grant funding or development of clinical protocols 2014 (Year 1): 4 Letters of Intent and 4 full applications requested; 2 funded 2015 (Year 2): 16 Letters of Intent and 10 full applications requested (7 from workshop participants); 6 Funded (4 from SWOG clinicians who attended the workshop) 2016 (Year 3): 7 Letters of Intent Received. Plan to fund 4 pilots SWOG Discovery Engine: CSHL and JAX Clinical Cancer Genomics: Computational Modeling RNA,DNA,Epigenome Single Cell Genomics Gene Editing Genome Engineering Cell-based Screens Patient Derived Xenografts Humanized NSG Xenografts Conditional Reprogrammed Progenitor Cells Cancer Organoids 6 SWOG Discovery Engine: CSHL and JAX US SWOG-CSHL-JAX Discovery Genomics Cell Engine Models PDX Models YOU Important Clinical Question SWOG Impactful Clinical Trial EVERYONE Improved Patient Outcome ITSC Pilots with SWOG-JAX PIs SWOG PI JAX PI Title Gandara, Mack Bult, Keck Testing novel therapies for EGFR mutant lung cancer in PDX models Algazi Keck Testing immune modulators that target human squamous cell carcinoma of the head & neck (HNSCC) in hu-NSG mice Burack, Casulo Hasham The AID-RAD51 axis as a better biomarker in follicular lymphoma Hassan Hasham, Bult Determining the role of AICDA in development of T790M mutation in lung cancer PDX models Hu-Lieskovan Robson Tumor microenvironment profiling to identify biomarkers of anti-PD-1 therapy Pusztai Chuang Genomic analysis of inflammatory breast cancer (IBC) 8 ITSC Pilot Project 2015: Lajos Pusztai (Yale) and Jeff Chuang (JAX) Landscape of somatic mutations in inflammatory breast cancer whole-genome sequences Paired-end whole genome sequencing (WGS) of 20 IBC vs. 23 non-IBC Age, race and ER and HER2 matched, from TCGA for comparison. 9 10 ITSC Pilot Project 2015: Lajos Pusztai (Yale) and Jeff Chuang (JAX) Landscape of somatic mutations in inflammatory breast cancer whole-genome sequences Recurrent mutations were detected in the coding region of GRIN2A gene in 15% IBC samples, vs. 1.7% previously reported in breast cancers). Other significant mutations in coding regions included GRHL1, PIK3R2, ESR1, and FLG2. Contributions of mutational signature 9, that is associated with polymerase , were significantly higher in IBC cohort than non-IBC cohort (p-value=0.056). To be presented at the San Antonio Breast Cancer Con 11 Pilot Projects - Awarded 2014 Pilots Induced Cytidine Deaminase as a Biomarker in Follicular Lymphoma (Owen O’Conner, MD/PhD; & Kevin Mills, PhD, JAX) Neutrophil Extracellular DNA Traps and Breast Cancer Metastasis (Anne Schott, MD, Univ Michigan; Mikala Egeblad, PhD, CSHL) 2015 Pilots The AID-RAD51 Axis as a Better Biomarker in Follicular Lymphoma (Kevin Mills, PhD, JAX; Richard Burack, MD/PhD and Caral Casulo, MD, Univ Rochester) Genomic Analysis of Inflammatory Breast Cancer (IBC) in SWOG S0800 Clinical Trial Tissues to Identify Molecular Alterations that Underlie the Aggressive Biology of IBC and Could Lead to the Development of New Diagnostic Tests and Therapeutic Interventions (Lajos Pusztai, MD/PhD and Mark B. Gerstein, PhD, Yale; Naoto Ueno, MD/PhD, MD Anderson; & Jeffrey Chuang, PhD, JAX) SWOG/CSHL Highlight SWOG/Integrated Translational Science Center 2014 Pilot Project Park J., Wysocki, R.W., Amoozgar, Z., Maiorino, L., Fein, M.R., Jorns, J., , Schott, A.F., Kinugasa‐Katayama, Y., Lee, Y., Won, N.H., Nakasone, E.S., Hearn, S.A., Küttner,V., Qiu, J., Almeida, A.S., Perurena, N., Kessenbrock, K., Goldberg M.S., and Egeblad.M. Cancer cells trigger neutrophils to induce metastasis‐supporting extracellular DNA traps. Sci. Transl. Med. (Accepted) Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps Mikala Egeblad and Anne Schott 5 m Neutrophils and DNA “clouds” surround metastatic 4T1 breast cancer cells in lungs 4T1 cancer cells Neutrophils DNA (DAPI) Lung imaging, 2 hrs after i.v. injection of cancer cells Park et al., Science Translational Medicine, In press Neutrophil Extracellular Traps (NETs) capture and kill pathogens in the extracellular space Peptidylarginine deiminase 4 (PAD4)-mediated histone modification Bacteria/LPS Bacterial trapping NADPH oxidase NADPH + 2O2 => NADP+ + H+ + 2O2- Cathepsin G Myeloperoxidase Elastase Chromosome decondensation Protease association Expelled DNA w. Cathepsin G Myeloperoxidase Elastase J Clin Invest. 2013 Jul 1. pii: 67484 Are NETs found in human breast cancer? ITSC pilot project w. Anne Schott, Julie Jorns et al. NETs are present in human breast cancer Primary human breast tumor Neutrophil NET forming neutrophil 20μm Myeloperoxidase Citrullinated histone H3 DNA (DAPI) Julie Jorns Anne Schott Youngseok Lee Nam H. Won Anne Schott Julie Schor Bobby Wysocki Laura Maiorino Presence of NETs in metastatic human breast tumors is associated with the triple negative breast cancer subtype Park et al., Sci Transl, accepted A transwell co-culture model to study cancer cell / neutrophil interactions Cancer cells Cancer cell invasion? 22h Matrigel (basement membrane) Serum free media Neutrophils Neutrophil activation? 50 m +DNase I Invasive capacity (% of serum-free) The DNA scaffold of NETs is required for neutrophil-induced cancer cell invasion p=0.03 p=0.02 200 150 100 50 0 DAPI Histone Neutrophil Elastase Park et al., Sci Transl, accepted Conditioned medium (CM) from neutrophils induced to form NETs promotes invasion Cancer cells Cancer cells CM Neutrophils Juwon Park Yumi Kunigasa How do cancer cells induce NETs? How do cancer cells induce NETs? G-CSF secreted by cancer cells Induces NET formation Inhibition of G-CSF p=0.03 NET formation (A.U.) NET formation (A.U.) p=0.03 Recombinant G-CSF 4T1 cancer cells Park et al., Sci Transl, accepted Can NETs be targeted in vivo? Recombinant DNase I is used to treat cystic fibrosis Plasma DNase I (ng/ml) DNase I-coated nanoparticles have higher activity in blood than free DNase I 75U DNase I (free or coated on nanoparticles) injected i.p. per mouse. Plasma DNase I concentration was determined at indicated time after injection in radial diffusion assay. Park et al., Sci Transl, accepted Nets per tissue area (NETs per mm2) DNase I-coated nanoparticles reduce NETs after cancer cell injection Park et al., Sci Transl, accepted DNase I-mediated digestion of NETs reduces breast cancer metastasis Ctrl. nanoparticles DNase I-coated nanoparticles 4 mm Metastatic burden 4 weeks after cancer cells inj. Nanoparticles inj. i.p. daily for 2 weeks after cancer cell inj. Park et al., Sci Transl, accepted Conclusions and Perspectives Neutrophil Extracellular Traps promote metastasis Neutropenia, induced by some types of chemotherapy, is treated with G-CSF - and NETs are induced by G-CSF… Is this a problem? Cancer patients with post-surgical infection have up to 3fold increased risk of metastatic recurrence – could NETs be targets to reduce this risk? How do NETs work? Are they scaffolds for concentrated enzymatic activities? Acknowledgements Egeblad Lab Juwon Park Robert Wysocki Laura Maiorino Miriam Fein Jean Albrengues Collaborators Michael Goldberg & Zohreh Amoozgar (DFCI) Julie Jorns & Anne Schott (U. Michigan) Youngseok Lee & Nam H. Won (Korea U.) Mark Looney & Max Krummel (UCSF) George Peeters (Solamere Technologies) Emilis Bruzas Victoria Kuettner Mario Shields Jacqueline Cappellani Contributing alumni: Yumi Kunigasa Elizabeth Nakasone Ana Almeida Jing Qiu Funding SWOG/JAX/CSHL ITSC DOD BRCP Era of Hope Scholar Integrated Translational Science Program: SWOG, JAX and CSHL We Acknowledge the GENEROUS support of