PowerPoint Presentation
National Cancer Institute (NCI)Specialized Programs of Research
Excellence (SPORE)Hans E. Grossniklaus MD
Professor of Ophthalmology and PathologyDirector, Ocular
Oncology and Pathology ServiceDirector, L.F. Montgomery
LaboratoryEmory University School of Medicine
Financial Disclosures
I have the following financial interests or relationships to
discloseNIH R01CA176001NIH P30EY06360Aura BiosciencesClearside
Biomedical
SPORESpecialized Program Of Research Excellence
A cornerstone of NCIs efforts to promote collaborative,
interdisciplinary translational cancer research.
SPORE grants involve both basic and clinical/applied scientists
working together and support projects that will result in new and
diverse approaches to the prevention, early detection, diagnosis,
and treatment of human cancers.
SPOREs are designed to enable the rapid and efficient movement
of basic scientific findings into clinical settings.
trp.cancer.gov
We are developing the first SPORE to focus on eye tumors,
including uveal melanoma & retinoblastoma, the most common
primary eye cancers affecting adults & kids.
The Winship Cancer Institute, Emory University
Emory Eye Tumor SPORE
Overall
Emory Eye CenterNationally Recognized Eye CenterEmory Winship
Cancer InstituteNCI Designated Cancer Institute
Key PersonnelProject 1Project 2Project 3Project 4Core ACore
BCore CDRPCEPGrossniklausXXXVan MeirXXWallerXLawsonXXGudkovXJ
YangXXMittalXMaoXHarbourXHubbardXBruceXXXBergstromXKowalskiXBratX
Person Project Matrix
Hans E. Grossniklaus, MD, MBAProfessor of Ophthalmology and
PathologyDirector, L.F. Montgomery Ophthalmic Pathology
LaboratoryFounding Director, Ocular Oncology and Pathology
Service2- R01 grantsErwin G. Van Meir, PhDProfessor of
Neurosurgery, Hematology & Medical OncologyFounding Director of
the Cancer Biology Graduate Program,Winship Cancer Institute3- R01
grants
Aim 1: To develop new treatments for metastatic uveal melanoma
to the liver based on the biology of local microenvironment events
in the liver.
Aim 2: To develop novel imaging modalities to detect early
metastatic uveal melanoma in the liver in order to guide and follow
treatment success.
Aim 3: To understand the unique molecular pathology of
retinoblastoma invasion, anaplasia/de-differentiation and seed
formation and develop new biologic therapies with minimal
toxicities.
Aim 4: To develop innovative outreach programs via digital
platforms for tele imaging of patients with ocular tumors, thus
enhancing ocular oncology education, conferencing, clinical trials
and patient advocacy.
Uveal Melanoma
Retinoblastoma
Choroid
Vitreous seedsHistologic high risk features
Histologic invasion
A
RetinocytomaMild AnaplasiaModerate AnaplasiaSevere Anaplasia
upregulatedupregulateddownegulated
Gene expression in severely vs non severely anaplastic
RBCytologic Rb Anaplasia and De-Differentiation
differentiatedun-differentiatedde-differentiation
25
P1 Entolimod for Treatment of Metastatic UM EW, AG, DLP3
Molecular Pathology Based Targets for RetinoblastomaHG, JWH, BHP2
ProCa Imaging of Metastatic UMJY, HM, PMPathology and Biospecimen
CoreHG, DB P50 Novel Methods for Diagnosis and Treatment of Ocular
TumorsAdministrative CoreEVM, HG
Design, Analysis, andData Admin Core (DADA)BB, JKP4
Teleimagingof Ocular TumorsBB, CBDevelopment Research Program JY,
BBCareer Enhancement Program EVM, EW
ProjectsCoresPrograms
Project 1Edmund Waller, MD, PhDDavid Lawson, MDAndrei Gudkov,
MD, PhDEntolimod for Treatment of Metastatic Uveal Melanoma
Edmund Waller, MD, PhDProfessor of Hematology and
OncologyDirector, Bone Marrow and Stem Cell Transplant Center1- R01
grant1- R41 grantDavid Lawson, MDProfessor of Hematology and
OncologyMedical Director, Emory University Hospital Oncology
UnitCo-investigator of R01 grantP1
Model for the action of Entolimod
Figure 8. Schematic description of a plausible mechanism of the
liver metastasis suppression effect of Entolimod. [Burelya &
Gudkov PNAS 2013].
Fig 9. (A) Model of ocular melanoma treated with PBS vs
Entolimod; (B) corresponding hepatic metastasis treated with PBS vs
Entolimod; these metastases are enumerated in (C) showing a
decrease in metastases due to NK cell boost in the liver (D); there
is a mild boost in intrinsic NK cells (E) and a substantial boost
in circulating NK cells (F)
31
Jenny J. Yang, Ph.D. (GSU) Pardeep Mittal, M.D. (Emory) Hui Mao,
Ph.D. (Emory)
Project 2: Early detection and Progression of Liver Metastatic
Uveal Melanoma by Precision MR Imaging NCI 12-9-2015
Jenny Yang, PhD Distinguished Professor of Biochemistry and
BiophysicsAssociate Director, Center for Diagnostics and
TherapeuticsGeorgia State University2- R01 grants
Hui Mao, PhDProfessor, Department of RadiologyHead, Laboratory
of Functional Molecular Imaging and Nanomedicine2- R01
grantsPardeep Mittal, MDAssociate Professor, Department of
RadiologyDirector, MRI Body ImagingP2
Pressing Unmet Medical Needs
Cancer Stages
Survival RateEovistStage 20.05-0.5 mmStage 4> 20 mmLow
SurvivalNo treatmentHigh SurvivalBetter treatment
??Early Detection by Imaging. All detected lesions are at a late
stage associated high death rate.
Needs non-invasive, sensitive and precision imaging for early
detection, following high risk patients, selecting targeted
therapy, imaging guide intervention and Precision medicine.
ProCAs: Protein MRI Contrast Agents
David S Xue et al., PNAS, 2015
T2/T1
MRI Dual Imaging Liver Metastases by ProCAXue et al., PNAS,
2015
IND Enabled StudiesAPIActive Pharmaceutic Ingredient Time Cost
($) YearsPK: ADME(single and repeat doses) Manufactory
formulationpreparationToxicology (GLP)ImmunogenicityPD(GLP): MRI
Rodent and MonkeyRespiratory function (r), Cardiovascular function
(in vitro hERG, d/m), CNS (r), Renal and Liver function
IND PreparationCMC(Chem. Manu. &
controlProductionFermentation, Purification PegylationComplex
formationIndication, Strategy
38
Hans E. Grossniklaus, MD, MBAProfessor of Ophthalmology and
PathologyDirector, L.F. Montgomery Ophthalmic Pathology
LaboratoryFounding Director, Ocular Oncology and Pathology Service2
R01 grantsP3G. Baker Hubbard, MDProfessor of OphthalmologyDirector,
Vitreoretinal ServiceCo-investigator of two COG grants
J. William Harbour, MDProfessor of OphthalmologyDirector, Ocular
Oncology ServiceVice-Chair, Translational Research University of
MiamiR01 grants
Histologic and Cytologic Grading in RB
RetinocytomaMild AnaplasiaModerate AnaplasiaSevere Anaplasia
Ophthalmol 1989;96:217-222AJO 2015; 159: 764-776
42
Retinal seeds relatively dormant, inhypoxic tissue and form
spheroids-cancer stem cell properties
VEGFTGF
Ki-67 IHC stainingin subretinal seedsand vitreous seeds
comparedwith main tumor
optic nerve invasion
optic nerve invasion
Ophthalmol 1989;96:217-222
Project 4Teleimaging of High Risk Ocular Nevi and Ocular
MelanomaDirector: Beau Bruce MD, PhD
Co-Director: Chris Bergstrom MD
Beau Bruce, MD, PhDAssistant Professor of Ophthalmology and
NeurologyExpertise in tele-imaging in ophthalmologyR01 and K23
grants
Chris Bergstrom, MD, ODAssistant Professor of
OphthalmologyExpertise in clinical care of uveal melanoma
patients
P4
EDI OCTTele-imaging of fundus phots
High-risk choroidal nevi~9% convert to melanoma in 5
yearsRequire frequent monitoring (q4-6 months)Usually monitored at
specialized ocular oncology centers (only about 50 ocular
oncologists in the US)Results in substantial burdens to patients
(long travel, lost work, etc.)
Aim 1 Telemedicine - GoalsEstablish regional telemedical network
with established referral partners
Telemedicine - GoalsEvaluate the network through a randomized
cross-over studyRTelemedicineUsual CareUsual
CareTelemedicinetime018 m36 m
Safety assessmentPlan 1 year pre-trial phase where patients will
have local testing that they bring to Emory. Testing will be
repeated at discretion of Emory ocular oncologist. Throughout usual
care arm performed at Emory will also do same packet of services
before the in person evaluation and will have a blinded review as
though it were telemedicineMonitor concerns from patients and hub
and spoke clinicians
Avoidable Costs Commuting OnlyTotal Average Commuting Time Spent
per Patient (hours, 5 year span)6.17Total Average Commuting Miles
Driven per Patient (miles, 5 year span)384.89Total Number of
Patients (5 year span)2021Total Avoidable Cost of Commuting Miles
Driven (5 year span) $439,492 Total Avoidable Loss of Time Worked
(5 year span) $267,846 Total Avoidable Cost (5 year span) $707,339
Total Avoidable Cost per Patient (5 year span) $349.99
Aim 2: Novel Imaging - GoalsImage all patients with nevi and
melanomas presenting to Emory not participating in Aim 1Relate
imaging findings to primary outcomesTransformation of nevi into
melanomaMortality for melanoma
Thickness by enhanced depth imaging (EDI) by optical coherence
tomography (OCT)
Fundus PhotographB-scan Ultrasound
Standard OCT
EDI OCT
55
Joseph Carroll, U Wisc Milwaukee
OCT AngiographyFundus Autofluorescence
Aim 3: Biology - Goals
melanoma genetics will mediate associations between tumor
imaging characteristics and prognosis/treatment response
Radioactive Fluorescent Seq" by Abizar at en.wikipedia. Licensed
under CC BY-SA 3.0 via Wikimedia Commons -
https://commons.wikimedia.org/wiki/File:Radioactive_Fluorescent_Seq.jpg#/media/File:Radioactive_Fluorescent_Seq.jpg
CURRENT PRACTICEPARADIGM SHIFTPROJECTS, DRP, CEPAIM 1Focus on
mechanisms of progression of primary uveal and applying them to
metastasisFocus on mechanisms of metastasis of uveal melanoma that
occur in the liver, the primary site of metastasisP1-Entolimod
targets mechanisms in liver including boosting host immune response
AIM 2Focus on detecting metastatic uveal melanoma in the liver when
the metastases are relatively largeFocus on detecting early, small
metastatic uveal melanoma in the liverP2-ProCa imaging of uveal
melanoma micrometastasis and small metastasis based on receptor
ligand interactions DRP-ProAgio targets both angiogenesis and
migration of stellate cells AIM 3Focus on general chemotherapeutic
agents, including melphalan, etoposide, carboplatin and vincristine
for the treatment of retinoblastomaFocus on molecular pathology of
retinoblastoma tumor progression and seed formation in order to
develop biologic therapies with limited collateral damageP3-Gene
expression profiling of highly anaplastic versus non highly
anaplastic retinoblastoma , retinoblastoma seeds, and development
of biologic treatmentCEP-suprachoroidal and intravitreous drug
delivery based on location and properties of subretinal and
vitreous seedsAIM 4Patients are referred to ocular oncology centers
for evaluation, management, treatment and follow-upFocus on digital
technology, imaging, and transmission of images via the internet
for evaluation, follow, and recommendations for patients with uveal
nevi; digital conferencing for patient support and advocacy groups,
meetings and conferencesP4-Tele-imaging of digital funds images for
evaluation of choroidal nevi for population studies, evaluation and
management; correlation with gene expression profiles of melanomas
that develop Administrative core-support of digital conferencing
including SEOP, patient support and advocacy groups
Full Service Ocular Oncology Program
Fig 3. Left: Top and Bottom, relationship between WCI, Eye
Center, Egleston, and EUH J Wing (open 2017). Right: Emory Proton
Beam Therapy center in midtown (open 2016). The WCI and Emory Eye
Center will be able to offer the full range of treatments for
patients with ocular malignancies.
Chris Bergstrom MDHans E. Grossniklaus MDG. Baker Hubbard MDJill
Wells MD
SEOPRb Kids DayJournalOcular Oncology Tumor BoardOcular Oncology
Journal Club
Multi PI SPORE (Grossniklaus, Van Meir)Emory Eye Center/Winship
Cancer InstituteAtlanta-based multi-institutional (Emory, Georgia
Tech, Georgia State, Morehouse)Infrastructure in place-ocular
oncology service, SEOP, tumor board, proton beam, eye pathology
lab, etc.
Summary
P1-Edmund Waller, MD, PhDP2-Jenny Yang, PhDP3-Hans E.
Grossniklaus, MDP4-Beau Bruce, MD, PhDCore A-Hans E. Grossniklaus,
MDCore B-Hans E. Grossniklaus, MDCore C-Beau Bruce, MD,
PhDDRP-Jenny Yang, PhDCEP-Erwin Van Meir, PhD
CORE A
Core A
Administrative Core
Hans E. Grossniklaus, MD, DirectorErwin G. Van Meir, PhD,
Co-Director
Research PlanIn this core, we will provide administrative
support for the projects, foster development and innovation of new
projects, and enable educational/support opportunities for ocular
oncology providers and patients. We will accomplish this through
three specific aims: Aim 1: To provide integration within the SPORE
and affiliated institutes in AtlantaAim 2: To provide opportunities
to develop new translational ocular oncology projects Aim 3: To
provide education, support and outreach to ocular oncology service
providers and patients
Figure 1. The administrative structure of our SPORE includes
regular interactions of the PIs with the NCI, administrative
support through the administrative core, and oversight by the
executive committee of the overall scientific program, CEP, DRP,
cores, and projects.
Lines of authority for decision-making and committeesDr.
Grossniklaus has overall authority for scientific decision-making
and overall day-to-day administration and management of the SPORE.
Dr. Van Meir serves as Deputy to the SPORE Director.
The Executive Committee is the policy-making body of the SPORE
and meets monthly.The translational Working group (Grossniklaus,
Bruce, Hubbard, Lawson, Kudchadkar, Mittal, Waller)will meet
bi-monthly.
SPORE monthly progress report seminar (all SPORE PIs and lab
personnel)
CORE B
Core B
Pathology and Biospecimen Core
Hans E. Grossniklaus, MD Director
Daniel Brat, MD, PhD Co-Director
Hans E. Grossniklaus, MD, MBAProfessor of Ophthalmology and
PathologyDirector, L.F. Montgomery Ophthalmic Pathology
LaboratoryFounding Director, Ocular Oncology and Pathology Service2
R01 grants
Daniel Brat, MD, PhDProfessor of Pathology and Laboratory
MedicineVice-Chair, Translational ProgramsDirector, Cancer Tissue
and Pathology Shared Resource, Winship Cancer InstituteDirector,
Neuropathology Division2 R01 grants
Specific Aim 1: Comprehensively acquire, process, store, catalog
and disburse tissues, cells and blood with relevant clinical
correlative data. Maintain a catalogue of ocular cancer cell lines
utilized for in vitro and xenotransplantation models. Sub-Aim 1a:
Comprehensive formalin fixed paraffin embedded (FFPE) and fresh
frozen tissue acquisition and maintenance of archived ocular cancer
specimens.Sub-Aim 1b: Grading and TNM classification of
retinoblastoma and uveal melanoma specimens. Sub-Aim 1c: Maintain a
catalogue of ocular retinoblastoma and uveal melanoma cell
linesSpecific Aim 2: Provide assistance in creating and evaluating
models of ocular cancers.Sub-Aim 2a: Assist in creating and
evaluating transgenic models of retinoblastoma and xenograft
metastatic uveal melanoma.Sub-Aim 2b: Assist in creating and
evaluating xenograft models of retinoblastoma and uveal melanoma.
Specific Aim 3: Promote intra-SPORE collaboration between SPORE
investigators, inter-SPORE collaboration between investigators at
other SPORE sites and collaboration between investigators at our
own and other institutions including other peer-reviewed projects
funded by NCI/NIH and other agencies using SPORE-generated tissues
and cells.
First 50 years: 15,000 casesLast 20 years: 55,000 casesL. F.
Montgomery Ophthalmic Pathology LaboratoryFully accreditedCLIA
certificateFree standing pathology laboratory
Type of Tumor1941 - 19992000 - 20092010 - 2014TOTALUveal
melanoma1,4583572102,025Conjunctival melanoma4812072240Conjunctival
primary acquired
melanosis52111101264Retinoblastoma20510150356Conjunctival squamous
cell carcinoma307153154Conjunctival
dysplasia145306336787Conjunctival lymphoma466923138Vitreoretinal
lymphoma22371877TOTAL2,0061,1728634,041
Ocular Oncology SpecimensL. F. Montgomery LaboratoryAlso-access
to approximately 1,000 COMS eyes with uveal melanomaand
corresponding database
cell linedescriptionsourceWERI Rb 1human retinoblastomaATTC
HTB-169Y79human retinoblastomaATCC HTB 1892.1human uveal
melanomaGreg Luyten Univ RotterdamOMM11human uveal melanomaGreg
Luyten Univ RotterdamMel 202human uveal melanomaBruce Ksander
Schepens InstMel 270human uveal melanomaBruce Ksander Schepens
InstMel 290 human uveal melanomaBruce Ksander Schepens InstOMM
2.2human uveal melanomaBruce Ksander Schepens InstOMM 2.3human
uveal melanomaBruce Ksander Schepens InstOMM 2.5human uveal
melanomaBruce Ksander Schepens InstOCM1human uveal melanomaJune
Kan-Mitchel Wayne StateOCM3human uveal melanomaJune Kan-Mitchel
Wayne StateB16LS9mouse melanomaDario Rusciano Friedrich Miescher
InstB16F10mouse melanomaJerry Niederkorn UT Southwestern
Cell Lines
L.F. Montgomery Laboratory-independent, CLIA certified, full
time ophthalmic pathology laboratoryDatabase of FFPE tissue of
2,000 uveal melanoma cases (plus 1,000 COMS cases) and 300
retinoblastoma cases30 frozen specimens in tissue bank-expanding
the tissue bank14 retinoblastoma and melanoma cell linesExpertise
in models of uveal melanoma and retinoblastoma
Core CDesign, Analysis, and Data Administration Core(DADA)
DirectorBeau B. Bruce, MD, PhDAssistant Professor of
Ophthalmology, Neurology, and EpidemiologyEmory University
Worked on fundus photographyin the emergency departmentand
telemedical aspects
Co-DirectorJeanne Kowalski, PhDDirector, Biostatistics and
Bioinformatics Shared ResourceAssociate Professor of Biostatistics
and Bioinformatics
Proven track record in the designand analysis of clinical,
laboratory and molecular investigations in oncology.
Co-DirectorMichael E. Zwick, PhDAssociate Professor of Human
Genetics and PediatricsAsst Dean (SOM) & Asst VP (WHSC)of
ResearchDir of Res Tech Program (ACTSI)Emory University
Use of cutting edge technologiesand informatics approaches
tohuman genomic variation
Career Enhancement Program (CEP)Erwin G. Van Meir, PhD,
DirectorEdmund K. Waller MD, PhD, Co-Director
CEP
Aims:
To recruit, mentor and train prospective junior faculty members
with a career interest in translational ocular oncology research.To
provide research support to promising junior faculty for a career
in ocular oncologyTo develop a pipeline of new projects within the
SPORE
CEP Committee:Dr. E.G. Van Meir, ChairDr. E.K. WallerDr. H.G.
GrossniklausDr. B. Bruce
Meets bi-annuallyAdvertises CEP pilot fund programSelects
awardeesOrganizes mentoring for awardeesReviews projects
progress
Candidate. Qing Zhang MDDr. Zhang is currently a postdoc in the
Ophthalmology Dept. at Emory University School of Medicine. She is
expected to have an offer to become an Assistant Professor at Emory
by the time of the SPORE start date.
Project Title: Microfluidic Device to Capture Circulating Ocular
Melanoma Cells
Objectives:Develop a non-invasive tool for the accurate
identification and measurement of circulating tumor cells (CTCs) in
melanoma patients. Hypothesis:Quantification of circulating tumor
cells (CTCs) in melanoma patients blood will predict metastasis,
survival and guide adjuvant therapy. Specific Aims:Capture
circulating melanoma cells from PBS or whole blood spiked with
tumor cells.Isolate circulating melanoma cells from peripheral
whole blood in a mouse model of uveal melanoma Isolate circulating
melanoma cells from peripheral whole blood in patients with uveal
melanoma, and investigate the correlation of the number of CMCs
with patients survival rate and treatment response
Preliminary data:Microfluidic system to capture circulating
melanoma cells from whole blood
National Cancer Institute
A First in the 10 years of SPORE history.Eye Tumor SPORE
Overall Strengths of our SPORE:Our CommunityStrength in
Personnel and Resources at Emory, GSU, & GTStrength in Greater
Ocular Oncology & Pathology CommunityEnables Horizontal
Outreach and Collaboration
Our ProjectsInnovative & ExcitingPotential applications for
other diseases Greater than just Uveal MelanomaTargets different
issues within care: diagnosis, imaging, prevention, treatment,
metastasis
You, Our PatientsThese are some of our researchers &
physicians, but the other main part of the active SPORE team
is..
The EyeSPORE Website: A Portal for Information &
Interaction
http://eyespore.emory.edu
Greater Outreach for Rare Eye Disease