Instructions for viewersBrought to you by the Science/AAAS Custom Publishing Office

• To share webinar via social media:

• To see speaker biographies, click:  View Bio under speaker name

• To ask a question, click the Ask A Question button under the slide window

• To share webinar via e‐mail:

In vivo imaging today and tomorrow: How multimodality imaging is driving translational researchDecember 9, 2015

Webinar Series

Sponsored by

Brought to you by the Science/AAAS Custom Publishing Office Participating experts

In vivo imaging today and tomorrow: How multimodality imaging is driving translational researchDecember 9, 2015

Webinar Series

Sponsored by

Christopher H. Contag, Ph.D.Stanford UniversityStanford, CA

Anna Moore, Ph.D.Massachusetts General HospitalHarvard Medical SchoolBoston, MA

3

Christopher H. Contag, Ph.D.

Professor, Departments of Pediatrics, RadiologyBioengineering, and Microbiology & Immunology

Assoc. Chief, NeonatologyCo-Director, Molecular Imaging Program at Stanford (MIPS)

Stanford University School of Medicine

4

Catalyzing a paradigm shift in animal modelsImaging enables:• Access to new information because

the contextual influences of the host are intact

• Increased data per animal◦ Whole body scans◦ Temporal changes ◦ Ease of use permits fine temporal

resolution• Improved statistics--”Built-in”

internal controls• Image-guidance for sampling the

correct tissue at the right time• Tracking of labeled therapeutics,

targets or both• Image-guided “Omics”• Cell culture to in vivo links to refine

studies of mammalian biologyDynamic in vivo measures

of gene expression

5

Opening new windows into mammalian biology

7 d7 d 9 d9 d 16 d16 d

00 77 1414 Time (d)Time (d)HSCsMemory T cellsTumorcidal T cells

Whole body radiation

6

Stem cell therapies and regenerative medicine

Dorsal Lateral Ventral Lateral

4d1d 7d

Cao et al. Proc. Nat. Acad. Sci. 101(1):221-226Cao et al. Transplantation 80(1): 134-139

7

Hematopoiesis from a single stem cell

Cao et al. Proc. Nat. Acad. Sci. 101(1):221-226Cao et al. Transplantation 80(1): 134-139

8 NKT Cells Preinfected With Vaccinia (vvDD): Lymphoma

Imaging accelerates development of combination therapies3) Treatment and Relapse(+24 days)

1) PBS

2) NKT Cells

3) NKT+VV

0 10 20 30 40

PBS TreatedNKTNKT+VV Treated

Time (d)

1007

1008

1009

Tum

or B

urde

n (P

hoto

ns/s

ec)

1006

1005

1) Tumor Formation(10 days)

Myc off

2) Tumor Regression(+10 days)

Myc on andtreatment

Thorne et al. Science. 311:1780-1784Thorne et al. Mol Ther. 18(9): 1698-1705 Contag et al. Cancer Res. 70:9837-9845

9

Emerging areas of biological investigation

Using optogenetic approaches to modulate neuronalactivity. Activation of channel rhodopsin by bioluminescenceaffects behavior in mice Birkner et al, Proceedings SPIE,2014

Imaging lymphoma progression over 5 days in responders (left)versus non-responders (right) following CRISPR/Cas9-mediateddeletion of Mcl-1 in vivo . Aubrey et al, Cell Reports, 2015

Imaging of DiR-labeled extracellular vesicles revealaccumulation of EVs in the liver, spleen, GI and lungs. Wiklanderet al, J. Extracell Vesicles, 2015

Genome Editing and Synthetic BiologyOptogenetics

Characterization of Extracellular VesiclesValidation of Diagnostic Platforms

Validating specificity and functionality of novel probiotic(PROP-Z) diagnostic platform for detecting cancers viaurine samples. Danino et al, Science Trans, 2015

10

Targeting diseases that are “undetectable”

Imaging , blood test and optical imaging

3 years

6 years

9 years

tum

or v

olum

e do

ublin

g tim

e (T

VDT)

= 1

20 d

ays

Minimally detectable tumor size by detecting secretion of biomarkers in blood: PSA, CA125,…

MRI and CT

D = 1 cm

Fluorescence microscopy

Mammography(D = 2 mm)

20 cell doublings

10 cell doublings

White light endoscopy

Note: After 30 cell doublings first symptoms may begin to appear

30 cell doublings

Note: After 20 cell doublings tumor may begin to generate metastatic cells

1 billion cellstumor D = 1 cmtumor V = 1 cm3

tumor M = 1 gm

1 million cellstumor D = 1 mmtumor V = 1 mm3

tumor M = 1 mg

1,000 cellstumor D = 100 mtumor V = 0.001 mm3

tumor M = 1 g

11

Insertable and implantable high resolution devices

Tabletop Microscope

Miniaturization

Wang, TD et al. Optics Letters. 28(6): 414-6Liu JT et al. Optics Letters 32(3):256-8Liu JT, J Biomed Opt 15 (2):026029Piyawattanametha, W et al. J Biomed. Optics 17(2): 021102

12

Clinical imaging at high resolution

Piyawattanametha et al. J Biomed. Optics 17(2):021102

13

Surgical navigation at high resolution

14

New tools and probes for surgical navigation

Image guided Surgery Molecular Probes for guided surgery in clinical trials • Blaze Bioscience BLZ-100 - Phase I

to visualize cancer cells• EC0652- Phase I PSMA-targeted

molecular imaging agent• MDX1201-A488- Phase I Anti-PSMA

Fluorescent Antibody During Robotic Assisted Laparoscopic Prostatectomy

• EC-17- Phase I Folate-FITC agent Intraoperative Imaging for Parathyroidectomy and other conditions

• Bevacizumab-IRDye800CW-Antibody conjugate for detection of multiple indications

Solaris Open Air Fluorescence system (for pre-clinical use only)

Pre-surgery

Post-surgery

Resection of mastocytoma in 45kg dog utilizing Solaris Imaging System

15

Optical imaging in the clinic: anti-EGFR antibodyClinical trials with fluorescent image-guided surgeries are underway in the Netherlands and US

Eben Rosenthal, Stanford University

• Imaging over a range of scales—macro to micro

• In humans to histologic sections• Real-time imaging in ambient light

FLUORESCENCE SCANNER

16

Improved assessment of margins & histological validation M

ucos

al S

urfa

ce

Res

ecte

d Tu

mor Fluorescent (positive)

margin

Eben Rosenthal, Stanford University

17

The future

Expanding Optical Imaging in short wave IR with carbon nanotubes (wavelengths of 0.8-1.3 µm)

Micro-optical devices and microendoscopy

Liu et al., Anal Cell Pathol(Amst). 2011, 34(3):81–98.

Wearables and Smart Sensor technologiesCounting circulating tumor cells

Bonnie King, Mike Mandella and Christopher Contag, unpublished

18

AcknowledgementsContag Lab

CollaboratorsMini-microscopesGordon Kino, StanfordOlav Solgaard, StanfordPierre Khuri-Yakub, StanfordPathologyDavid Rimm, Yale UniversityClinicalRob Negrin, StanfordEben Rosenthal, StanfordShai Friedland, Palo Alto VAJean Tang, StanfordStem CellsAmy Wagers, HarvardIrv Weismann, StanfordProbe ChemistryPaul Wender, StanfordChristina Zavaletta, StanfordMatt Bogyo, StanfordLarry Marnett, VanderbiltDave Ostrov, Univ. of FloridaSam Gambhir, Stanford

Jonathan Hardy Bonnie KingMike Mandella Gunilla JacobsonMasamitsu Kanada Michael Bachmann Nathan Loewke Ryan SpitlerLaura Bronsart Zhen QuiStephan Rogalla Christian StokesMaruti Didwania Frank SchonigRecent Lab MembersSteve Thorne (Univ. of Pittsburgh)Jonathan Liu (SUNY—Stony Brook)Mike Helms (Cenix BioScience GmbH)Wibool Piyawattanametha (National Electronics

and Computer Technology Center, Thailand)Jen Prescher (UC Irvine)Tom Wang (Univ. Michigan)Henry Haeberle (Univ. New South Wales)Mark Sellmyer (U Penn)Winston Wey (Cornell University)Yu-An Cao (Transderm Inc) Hyejun Ra (Apple Computer)Susie Suh (Northwestern University)Sophie Kusy (Peer J Publishing)Markus Deutschmann (University Clinic of Zürich)Ellis Garai (Leeo Inc.)Steve Sensarn (Leeo Inc.)

Brought to you by the Science/AAAS Custom Publishing Office Participating experts

In vivo imaging today and tomorrow: How multimodality imaging is driving translational researchDecember 9, 2015

Webinar Series

Sponsored by

Christopher H. Contag, Ph.D.Stanford UniversityStanford, CA

Anna Moore, Ph.D.Massachusetts General HospitalHarvard Medical SchoolBoston, MA

20

Anna Moore, Ph.D.

Professor, Department of RadiologyDirector, Molecular Imaging Laboratory

Massachusetts General HospitalHarvard Medical School

21

Image-guided Precision Medicine as a therapeutic paradigm of the future

• Cost of sequencing a genome - $95,000 in early 2000s down to $5,000 in 2015

• White House initiative, January 2015• Customize care based on the genotype and phenotype

of the patient• Patient’s genetic code becomes part of medical

records and directs personalized therapy• Novel therapies are based on rational, individualized

and targeted approach – nanotheranostics• Combine therapeutic (siRNA, microRNA) and imaging

components

22

Imaging is a key player in developing molecular therapies

23

In vivo bioluminescence imaging of siRNA therapies

Takeshita F et al. PNAS 2005, 102:12177-12182

Mice injected with PC-3M-luc-C6 (prostate cancer) cells

24

1. siRNA to luciferasewas complexed withcyclodextrin polycations and modified with DOTA at 5’ sensestrand2. 64Cu served as positron tracer3. Tf-targeted nanoparticles

PET/CT and BLI for monitoring siRNAdelivery and gene silencing

Bartlett D et al, PNAS, 2007, 104:15549-54

Imaging of siRNA delivery using multimodal imaging

25

Image-guided nanodrugs for siRNA delivery –imaging informs therapy

siRNA

membrane-translocation moiety

Cy5.5

Medarova Z et al, Nat Med, 2007; 13:372-377Kumar et al, Cancer Res, 2010; 70:7553-7561Ghosh S et al, Int J Cancer, 2014;134:1758-1766

26

In vivo imaging of epigenetic targets – response to therapy in late stage cancers

Pre Post

Yigit M et al, Oncogene, 2013, 32:1530-1538

Delivery

Therapy

anti-miR-10b nanodrugMRI NIRF

BLI

MDA-MB-231-luc

Cy5.5

27

Imaging of combination therapy for breast cancer metastasis

Yoo et al, Cancer Res, 2015, 75:4407-4415

28

Driving drug development: compounds tested/validated pre-clinically on the IVIS

MLN9708 (Takeda): multiple myeloma

ABT-888 (Abbott): multiple diverse tumor models

Panzem (EntreMed Pharmaceuticals): orthotopic gliosarcoma

AEE788 (Novartis): intraperitoneal tumor model

IT-101/CRLX 101 (Insert Therapeutics, Cerulean Pharma Inc.): Ewings sarcoma

NPI-0052 (Nereus Pharmaceuticals): subcutaneous tumor model

Tafenoquine (GSK and MMV): Plasmodium Vivax Malaria

JX-594 Pexa-Vec (Sillajen): Multiple cancer

EZN-2208 (Enzon): Neuroblastoma

NK-012 (Nippon Kayaku): Multiple cancer types

BGJ398 (Novartis): Bladder Cancer

ASP3026 (Astellas): Lymphoma

Sutent (Pfizer): subcutaneous tumer xenograft

Dasatinib (Bristol-Myers Squibb): chronic myelogenous leukemia

Tasigna (Novartis): leukemia/metastasis model

Cubicin (Cubist Pharmaceuticals): bacterial peritonitis model

Aflibercept (Sanofi-Aventis): orthotopic renal cancer

Velcade (Millennium Pharmaceuticals): multiple myeloma

Prolia (Amgen): bone metastases

FDA-approved compounds

Combination Therapies: Clinical Trials

Therapeutic Candidates in Clinical Trials

Vorinostat + Radiation Therapy (Merck and Thomas Jefferson U): Brain tumors and metastases

Vorinostat and Niacinamide (Columbia University): Lymphoma

Vandetanib, Cisplatin, and Radiation Therapy (MD Anderson): Head and Neck Squamous Cell Carcinoma

29

Sample of BIOPHARMA companies using the IVIS for Preclinical R&D

AbbvieAmgenAcceleronAstraZenecaAlexionAstellasBristol-Myers SquibbBiogenBoehringer IngelheimBayerCovanceCharles RiverCubistEisai

Merck SeronoMomenta MerrimackNovartisOtsukaOncoMedPfizerRegeneronRocheSanofiSiena BiotechTakedaVertex3M

EntreMedFibroGenGenmabGlaxoSmith KlineHalozymeIPSENIntrexonJohnson&JohnsonLillyMerckMedlmmunePierre Fabre

30

Combined Optical and X-ray Tomosynthesis Breast Imaging

Fang et al, Radiology, 2011, 258:89-97

Reconstructed DBT and HbT images of an invasive ductal carcinoma in a 42-yo woman. Reconstructed DBT and HbT images of

an fibroadenoma in a 42-yo woman.

31

Acknowledgements

Zdravka MedarovaByunghee YooPeter WangAmol KavishwarChongzhao RanPamela PantazopoulosAlana Ross--------------------Former lab membersMehmet YigitSubrata GhoshNatalia EvgenovMohan Kumar

Molecular Imaging Lab,Martinos Center, MGH

Support: NIBIB, NCI,Breast Cancer Alliance

Dana-Farber Cancer InstituteKornelia Polyak

Beth Israel DeaconessMedical CenterVictoria Petkova

Center for Breast Cancer, MGHSteven Isakoff

Brought to you by the Science/AAAS Custom Publishing Office

To ask a question, click the Ask A Questionbutton under the slide window

Participating experts

In vivo imaging today and tomorrow: How multimodality imaging is driving translational researchDecember 9, 2015

Webinar Series

Sponsored by

Christopher Contag, Ph.D.Stanford UniversityStanford, CA

Anna Moore, Ph.D.Massachusetts General HospitalHarvard Medical SchoolBoston, MA

Look out for more webinars in the series at:

webinar.sciencemag.org

To provide feedback on this webinar, please e-mailyour comments to webinar@aaas.org

Brought to you by the Science/AAAS Custom Publishing Office

For related information on this webinar topic, go to:

www.perkinelmer.com/InVivoImaging

In vivo imaging today and tomorrow: How multimodality imaging is driving translational researchDecember 9, 2015

Webinar Series

Sponsored by