specialized program of research excellence (spore) update: uniting to advance ocular melanoma...
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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
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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)
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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
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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
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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
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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