Presentation on theme: "Amy K. LeBlanc, DVM Diplomate ACVIM (Oncology)"— Presentation transcript:
1Amy K. LeBlanc, DVM Diplomate ACVIM (Oncology) Comparative Oncology: “One Health” in action American College of Laboratory Animal Medicine ACLAM Forum May 5, 2014Amy K. LeBlanc, DVM Diplomate ACVIM (Oncology)
2An overview What is comparative oncology? What resources are available to those employing a comparative approach for drug development, biomarker discovery, other endeavors?How are such studies designed and executed?How can comparative oncology be an example for other One Health initiatives?
3Amy K. LeBlanc DVM, Diplomate ACVIM (Oncology) Coming in July.....Amy K. LeBlanc DVM, Diplomate ACVIM (Oncology)Staff Scientist - Comparative Oncology Program
7A Comparative and Integrated Approach to Cancer Drug Development Based on these rationale, I have argued that a comparative and integrated approach to cancer drug development would allow the dog with cancer would compliment conventional preclinical and early clinical trials by asking important questions that could lead to the optimal design of first in human studies and may be equally if not more valuable in transitions between phase I and later phase studies in patients.Nature Reviews Cancer 2008
8Comparative OncologyTO PROVIDE OPPORTUNITIES TO INCLUDE NATURALLY OCCURRING CANCER MODELS IN THE STUDY OF CANCER BIOLOGY AND THERAPYBMC Genomics 2009Expression Profiles for Canine and Human Osteosarcomaare IndistinguishableOsteosarcomaNormal TissuesCompanion Animal Cancer ModelsLarge outbred animalsStrong genetic similarities to humansNaturally occurring cancersImmune competant and syngeneicRelevant tumor histology/geneticsRelevant response chemotherapyNo “Gold Standards”Compressed progression timesTumor heterogeneityRecurrence/ResistanceMetastasis biologyThe field of comparative oncology seeks to include naturally occurring cancers models in the study of cancer biology and therapy. My program has focused on the pet dog with cancer. There are many features of these large animals with cancer that contributes to their value as models of of cancer and in particular cancer drug development.In support of these similarities, when we compared canine and human osteosarcoma primary tumors using canine and human affymetrix oligonucleotide arrays, we were struck by the fact that cluster analysis of thoursands of orthologous genes from canine in black and human in yellow there was no segregation of samples based on species suggesting that the osteosarcoma expression phenotype was indistinguishable between dog an human. These data provide support to the hypothesis that dogs with cancer can add value to the study of cancer biology and and from our perspective cancer drug development.
91960 1980 1990 2000 2012 Regulatory Comparative Oncology Guidance 2009 Program and Comparative Oncology Trials Consortium-NCI founded 2003Tumor vaccines administered forcanine lymphoma 13,14Canine GenomeRelease 2005Cytokine and chemotherapeuticinhalation strategies first assessedin dogs with cancer 76-79Defined toxicity, activity, PKand tumoral PD with tyrosinekinase inhibition 44, 84Development of bone marrow transplantation regimes in dogs 11,12Evaluation of BCG immunotherapyin canine melanoma 9Measurable and minimal residual diseaseIntegratedDescriptive design: size focused19601980199020002012DNA vaccineapproved for use incanine melanoma 37,99-100L-MTP-PE evaluatedin MRD osteosarcoma guided COG studies 94Hyperthermia (thermoradiotherapy)techniques correlated with clinical efficacy in a canine model 69Canine ComparativeOncology and GenomicsConsortium founded 2006Limb sparing optimizedin canine osteosarcoma 71,72Paoloni and Khanna Nature Reviews Cancer 2008
10Projected “Value” of an Integrated Drug Development Path 1009040302010# of Cancer Drugs Reaching This Phase in Development# of Drugs in CONVENTIONAL DRUG PATH# of Drugs in INTEGRATED DRUG PATHPreclinical Phase I Phase II Phase III ApprovalGordon, I et al. PLoS Med 6(10): e doi: /journal.pmed
11Projected “Value” of an Integrated Drug Develpment Path $3b1009040302010# of Cancer Drugs Reaching This Phase in DevelopmentCumulative Cost of Cancer Clinical Trials$2b$1b# of Drugs in CONVENTIONAL DRUG PATH# of Drugs in INTEGRATED DRUG PATHCost of CONVENTIONAL DRUG PATHCost of INTEGRATED DRUG PATH$0bPreclinical Phase I Phase II Phase III ApprovalGordon, I et al. PLoS Med 6(10): e doi: /journal.pmed
12Comparative Oncology Program – Center for Cancer Research Comparative Oncology Trials Consortium (COTC)Reagent/Resourcesto conduct studies in Comparative OncologyGenomicsProteomicsAntibodiesBiospecimen RepositoryPD CoreCanine Comparative Oncology and Genomics ConsortiumAdvocacy for the Appropriate Integration of Comparative Oncology TrialsAcademiaPharmaNCIRegulatory BodiesProgress by the Comparative Oncology Trials Consortium (COTC)Initiated of Letters of Intent 19Initiated study protocols 11Studies completed 9Studies published 3Studies in progress/in press 7Studies of COTC are published under a “Collection” in PLoS OneTo provide these answers, I developed and now lead the COTC through my program at the NCI.
13Canine Comparative Oncology & Genomics Consortium (CCOGC) Pfizer-CCOGC Biospecimen Repository is now open for tissue releaseCurrently houses over 2,000 patient samplesosteosarcoma, lymphoma, melanoma, pulmonary tumors, mastcell tumor, soft tissue sarcomas and hemangiosarcoma.tumor and normal tissues (formalin fixed, snap frozen and OCT), frozen serum,plasma, urine and whole blood.
14Requests for samples/data from fixed sample resource PfizerCCOGC RepositoryFrederick MDMTACCOGCPathology ReviewCCOGCSample CollectionSitesCCOGCBioBankReviewMTA/MOUOwnership oftissue and IP is heldbut may be transferredby CCOGCAcademiaGovernmentPharmaBiotechRepository business modelRepository business model
15Tumor and Normal Tissues BloodFrozenRNAlaterFormalin fixed
16CCOGC Sample Distribution Progress Nearly 1000 canine patient samples have been distributed world-wide since October 2012.
17COTC Pharmacodynamic (PD) Core Purpose: To develop an efficient virtual lab that can be responsive to the service and scientific needs of the COTCCOTC studies biologically intensivePD “heavy”Previously done internally or contracted outTime consumingDid not engage the quality or expertise in the veterinary academic community
18COTC PD Core Provide assay services and scientific expertise Scientific guidance and trial reviewPreclinical studies prior to trial initiationTrial pharmacodynamic and biologic endpoint supportMultiple members from COTC member institutionsProspectively identified via solicitation of collaborationDevelopment of a “catalog” to streamline process
19COTC PD Core - areas of interest/expertise Cell Culture/ Proliferation/ Migration/InvasionCell linesClinical Pathology*PathologyPARR for clonalityIHC / ICCFlow cytometryGene ExpressionProteomicsWestern BlotPharmacologyBone MetabolismqRT-PCR* Majority of clinical pathology performed at GLP veterinary laboratory
21Clinical Data Collection GCP-compliantGLP clinical pathology
22COTC Study Development: Discuss questions not answered fully through conventional models or human trials.Determine if the dog can be used to answer questions.Validation of target/drug biology in the dogCCOGC Biospecimen RepositoryPD CoreIterative collaboration to define study overview/endpointsDevelop study protocol and data baseSelection of COTC sites to manage clinical studyBased on study completion goals and protocol intensityConduct studyAmend protocol with data inputComplete studyPatient EligibilitychecklistDay 0 AgentadministrationDay 7 AgentDay 21 AgentDay 14 AgentDay 28: patientreassessmentBiopsyTumor/NormalImagingPatient Enrollment checklist
23Lawrence J et al: Vet Radiol Ultrasound 50(6): 660, 2009 Advanced imaging with pathologic correlates is possible and increasing among COTC sitesLawrence J et al: Vet Radiol Ultrasound 50(6): 660, 2009
24Comparative Oncology Trials Consortium: Study Examples Antitumor activity and immunomodulatory effects“Evaluation of IL-12 and IL-2 Immunocytokines in Tumor Bearing Dogs”Tumor Specific Targeting – Tolerability“Evaluation of RGD Targeted Delivery of Phage Expressing TNF-a to Tumor Bearing Dogs”Modeling Personalized Medicine Delivery in DogsMolecuiarly informed therapyPick the Winner – Biological and Antitumor activity“Preclinical Comparison of Three TOPO-1 inhibitors in Dogs with Lymphoma”
34COTC007: Novel Topoisomerase I Inhibitors: Integrated Comparative Approach to Identify Lead Agent ToxicityPharmacokineticsPharmacodynamicsTherapeutic Index
35COTC007: Novel Topoisomerase I Inhibitors: Integrated Comparative Approach to Identify Lead Agent ToxicityPharmacokineticsPharmacodynamicsTherapeutic IndexMinimal Residual DiseaseCombinational TherapiesNovel BiomarkersOpportunities to Answer Questions to Inform Phase III Designs:No “Gold Standards” so ability to treat in naïve diseaseCompressed progression timesAssess activity of drugs that uniquely target metastatic progression
36Integrated Approach to Osteosarcoma Drug Development Translational studies of agents that target “vulnerable” metastatic cells.Localized PrimaryCanine OS TrialsMinimal ResidualDiseaseDistant GrossMetastasisMinimal residual disease studiesComparative Oncology Trials Consortium5 new agents in 5 yrsPrioritize agents for human MRD/adjuvant based studies of metastatic progression12 MonthsTherapeutic Approach:AminobisphosphonatesRapalog inhibition of mTOREzrin small molecule inhibitorsEarly Phase TrialsBecause of the complexity of the metastatic process we believe that in vivo studies are essential to understand this biology. To this end we have developed a multispecies comparative approach to study metastasis that includes the mouse, the pet dog (through the CCR-Comparative Oncology Program) and the human osteosarcoma patient.We believe that findings related to metastasis that are found consistent as we move across models and then across species are more likely to find relevance and translation to the the human condition.Later Phase TrialsMeasurableDiseaseMinimal ResidualDisease
37Perceived Risks and Concerns with the Integration of a Comparative Approach Study DurationTimelines are longer than those in rodent modelsStrategic inclusion of pet dogs should allow timely integration of data into human trialsPatient to Patient VariabilityTumor-bearing dogs represent a different clinical population compared to research dogsSNP frequency amongst dogs is similar to that of patients in early phase cancer studiesCancer Prevalence by HistologyMost common: sarcomas and lymphoid neoplasmsLess common: Breast, prostate, gastrointestinal, lung carcinomasStudies in the less common histologies require more time for completion and more clinical trial centersHistology is increasingly replaced with biology and not often a primary question for trial designTarget biology may be unique and must be defined (“credentialed”)Canine Comparative Oncology and Genomics ConsortiumPfizer - Canine Oncology and Genomics Consortium Biospecimen RepositoryComparative Oncology Program Tissue Array Resource
38Drug and Budget Requirements Greater drug supply needed Perceived Risks and Concerns with Integration of a Comparative ApproachDrug and Budget RequirementsGreater drug supply neededGMP not requiredStudy costs include: clinical management, serial biopsy of tumors, imaging and other correlative endpointsControl and reporting of dataGood Clinical Practice guidelinesAdverse Event reporting: Assign severity, duration, and attributionCompliance by pet owners and study investigators is very highRegulatory oversight/reportingPre-IND agents - guidance has been proposed and used(Khanna et al Clin Cancer Res 2009)Post-IND agents - guidance existsBiotech and aversion to “rocking” the development boat
40In conclusion… are you convinced? What is comparative oncology?What resources are available to those employing a comparative approach for drug development, biomarker discovery, other endeavors?How are such studies designed and executed?How can comparative oncology be an example for other One Health initiatives?
41The UT Molecular Imaging and Translational Research Program