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Amy K. LeBlanc, DVM Diplomate ACVIM (Oncology)
Comparative Oncology: “One Health” in action American College of Laboratory Animal Medicine ACLAM Forum May 5, 2014 Amy K. LeBlanc, DVM Diplomate ACVIM (Oncology)
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An 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?
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Amy K. LeBlanc DVM, Diplomate ACVIM (Oncology)
Coming in July..... Amy K. LeBlanc DVM, Diplomate ACVIM (Oncology) Staff Scientist - Comparative Oncology Program
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Image courtesy of Eric Carlson, DMD, MD, FACS
Oral cavity/mucosal malignant melanoma Biologically aggressive, responsive to immune-based therapies Canine: BRAF(-); c-kit (-); N-ras (-) Image courtesy of Eric Carlson, DMD, MD, FACS
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A 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
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Comparative Oncology TO PROVIDE OPPORTUNITIES TO INCLUDE NATURALLY OCCURRING CANCER MODELS IN THE STUDY OF CANCER BIOLOGY AND THERAPY BMC Genomics 2009 Expression Profiles for Canine and Human Osteosarcoma are Indistinguishable Osteosarcoma Normal Tissues Companion Animal Cancer Models Large outbred animals Strong genetic similarities to humans Naturally occurring cancers Immune competant and syngeneic Relevant tumor histology/genetics Relevant response chemotherapy No “Gold Standards” Compressed progression times Tumor heterogeneity Recurrence/Resistance Metastasis biology The 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.
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1960 1980 1990 2000 2012 Regulatory Comparative Oncology Guidance 2009
Program and Comparative Oncology Trials Consortium-NCI founded 2003 Tumor vaccines administered for canine lymphoma 13,14 Canine Genome Release 2005 Cytokine and chemotherapeutic inhalation strategies first assessed in dogs with cancer 76-79 Defined toxicity, activity, PK and tumoral PD with tyrosine kinase inhibition 44, 84 Development of bone marrow transplantation regimes in dogs 11,12 Evaluation of BCG immunotherapy in canine melanoma 9 Measurable and minimal residual disease Integrated Descriptive design: size focused 1960 1980 1990 2000 2012 DNA vaccine approved for use in canine melanoma 37,99-100 L-MTP-PE evaluated in MRD osteosarcoma guided COG studies 94 Hyperthermia (thermoradiotherapy) techniques correlated with clinical efficacy in a canine model 69 Canine Comparative Oncology and Genomics Consortium founded 2006 Limb sparing optimized in canine osteosarcoma 71,72 Paoloni and Khanna Nature Reviews Cancer 2008
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Projected “Value” of an Integrated Drug Development Path
100 90 40 30 20 10 # of Cancer Drugs Reaching This Phase in Development # of Drugs in CONVENTIONAL DRUG PATH # of Drugs in INTEGRATED DRUG PATH Preclinical Phase I Phase II Phase III Approval Gordon, I et al. PLoS Med 6(10): e doi: /journal.pmed
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Projected “Value” of an Integrated Drug Develpment Path
$3b 100 90 40 30 20 10 # of Cancer Drugs Reaching This Phase in Development Cumulative Cost of Cancer Clinical Trials $2b $1b # of Drugs in CONVENTIONAL DRUG PATH # of Drugs in INTEGRATED DRUG PATH Cost of CONVENTIONAL DRUG PATH Cost of INTEGRATED DRUG PATH $0b Preclinical Phase I Phase II Phase III Approval Gordon, I et al. PLoS Med 6(10): e doi: /journal.pmed
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Comparative Oncology Program – Center for Cancer Research
Comparative Oncology Trials Consortium (COTC) Reagent/Resources to conduct studies in Comparative Oncology Genomics Proteomics Antibodies Biospecimen Repository PD Core Canine Comparative Oncology and Genomics Consortium Advocacy for the Appropriate Integration of Comparative Oncology Trials Academia Pharma NCI Regulatory Bodies Progress by the Comparative Oncology Trials Consortium (COTC) Initiated of Letters of Intent 19 Initiated study protocols 11 Studies completed 9 Studies published 3 Studies in progress/in press 7 Studies of COTC are published under a “Collection” in PLoS One To provide these answers, I developed and now lead the COTC through my program at the NCI.
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Canine Comparative Oncology & Genomics Consortium (CCOGC)
Pfizer-CCOGC Biospecimen Repository is now open for tissue release Currently houses over 2,000 patient samples osteosarcoma, lymphoma, melanoma, pulmonary tumors, mast cell tumor, soft tissue sarcomas and hemangiosarcoma. tumor and normal tissues (formalin fixed, snap frozen and OCT), frozen serum, plasma, urine and whole blood.
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Requests for samples/data from fixed sample resource
Pfizer CCOGC Repository Frederick MD MTA CCOGC Pathology Review CCOGC Sample Collection Sites CCOGC BioBank Review MTA/MOU Ownership of tissue and IP is held but may be transferred by CCOGC Academia Government Pharma Biotech Repository business model Repository business model
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Tumor and Normal Tissues
Blood Frozen RNAlater Formalin fixed
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CCOGC Sample Distribution Progress
Nearly 1000 canine patient samples have been distributed world-wide since October 2012.
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COTC Pharmacodynamic (PD) Core
Purpose: To develop an efficient virtual lab that can be responsive to the service and scientific needs of the COTC COTC studies biologically intensive PD “heavy” Previously done internally or contracted out Time consuming Did not engage the quality or expertise in the veterinary academic community
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COTC PD Core Provide assay services and scientific expertise
Scientific guidance and trial review Preclinical studies prior to trial initiation Trial pharmacodynamic and biologic endpoint support Multiple members from COTC member institutions Prospectively identified via solicitation of collaboration Development of a “catalog” to streamline process
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COTC PD Core - areas of interest/expertise
Cell Culture/ Proliferation/ Migration/Invasion Cell lines Clinical Pathology* Pathology PARR for clonality IHC / ICC Flow cytometry Gene Expression Proteomics Western Blot Pharmacology Bone Metabolism qRT-PCR * Majority of clinical pathology performed at GLP veterinary laboratory
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Clinical Data Collection
GCP-compliant GLP clinical pathology
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COTC 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 dog CCOGC Biospecimen Repository PD Core Iterative collaboration to define study overview/endpoints Develop study protocol and data base Selection of COTC sites to manage clinical study Based on study completion goals and protocol intensity Conduct study Amend protocol with data input Complete study Patient Eligibility checklist Day 0 Agent administration Day 7 Agent Day 21 Agent Day 14 Agent Day 28: patient reassessment Biopsy Tumor/Normal Imaging Patient Enrollment checklist
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Lawrence J et al: Vet Radiol Ultrasound 50(6): 660, 2009
Advanced imaging with pathologic correlates is possible and increasing among COTC sites Lawrence J et al: Vet Radiol Ultrasound 50(6): 660, 2009
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Comparative 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 Dogs Molecuiarly informed therapy Pick the Winner – Biological and Antitumor activity “Preclinical Comparison of Three TOPO-1 inhibitors in Dogs with Lymphoma”
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Study Implementation and Contract Process
Protocol Development Study Implementation and Contract Process
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COTC007: Novel Topoisomerase I Inhibitors: Integrated Comparative Approach to Identify Lead Agent
Toxicity Pharmacokinetics Pharmacodynamics Therapeutic Index Low throughput selection of “lead”
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Lead Candidate Discrimination/Selection Study: COTC007b
Biological Endpoints Serum Pharmacokinetics Tumoral drug Levels Drug Target/Modulation Biological Activity Circulating Tumor Cell Numbers Target Modulation Biological Activity Normal tissue (Bone marrow)
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Grade 4 Neutropenia & Thrombocytopenia (DLT). Cohort 5 expanded.
17.5 mg/m2 Grade 4 Neutropenia & Thrombocytopenia (DLT). Cohort 5 expanded. Grade 5 event. Not attributable to IND. Expanded cohort 1 (3mg/m2). Grade 5 event. Not attributable to IND. Cohort 3 expanded. Currently in cohort 5. Grade 4 Neutropenia & Thrombocytopenia (DLT). Cohort closed. Grade 3 Allergic reaction. Cohort 4 (125mg/m2) expanded. Grade 2 Hypersensitivity reaction. Grade 4 Neutropenia, Thrombocytopenia, AST, ALT (DLT) Grade 4 Neutropenia (DLT). Cohort Closed. 100 mg/m2
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Biological Activity: H2AX Cytospin Images
Agent X-3 Cohort 3 (75mg/m2/day) Pre-dose D1 6h D6 D1 2h Tumor Aspirate Pre-dose D6 Bone Marrow JI/NCTVL
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Comparison of Tumoral Drug Exposure:
Compound and Cohort
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Agent Agent 2 Agent 3
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COTC007: Novel Topoisomerase I Inhibitors: Integrated Comparative Approach to Identify Lead Agent
Toxicity Pharmacokinetics Pharmacodynamics Therapeutic Index
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COTC007: Novel Topoisomerase I Inhibitors: Integrated Comparative Approach to Identify Lead Agent
Toxicity Pharmacokinetics Pharmacodynamics Therapeutic Index Minimal Residual Disease Combinational Therapies Novel Biomarkers Opportunities to Answer Questions to Inform Phase III Designs: No “Gold Standards” so ability to treat in naïve disease Compressed progression times Assess activity of drugs that uniquely target metastatic progression
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Integrated Approach to Osteosarcoma Drug Development Translational studies of agents that target “vulnerable” metastatic cells. Localized Primary Canine OS Trials Minimal Residual Disease Distant Gross Metastasis Minimal residual disease studies Comparative Oncology Trials Consortium 5 new agents in 5 yrs Prioritize agents for human MRD/adjuvant based studies of metastatic progression 12 Months Therapeutic Approach: Aminobisphosphonates Rapalog inhibition of mTOR Ezrin small molecule inhibitors Early Phase Trials Because 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 Trials Measurable Disease Minimal Residual Disease
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Perceived Risks and Concerns with the Integration of a Comparative Approach
Study Duration Timelines are longer than those in rodent models Strategic inclusion of pet dogs should allow timely integration of data into human trials Patient to Patient Variability Tumor-bearing dogs represent a different clinical population compared to research dogs SNP frequency amongst dogs is similar to that of patients in early phase cancer studies Cancer Prevalence by Histology Most common: sarcomas and lymphoid neoplasms Less common: Breast, prostate, gastrointestinal, lung carcinomas Studies in the less common histologies require more time for completion and more clinical trial centers Histology is increasingly replaced with biology and not often a primary question for trial design Target biology may be unique and must be defined (“credentialed”) Canine Comparative Oncology and Genomics Consortium Pfizer - Canine Oncology and Genomics Consortium Biospecimen Repository Comparative Oncology Program Tissue Array Resource
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Drug and Budget Requirements Greater drug supply needed
Perceived Risks and Concerns with Integration of a Comparative Approach Drug and Budget Requirements Greater drug supply needed GMP not required Study costs include: clinical management, serial biopsy of tumors, imaging and other correlative endpoints Control and reporting of data Good Clinical Practice guidelines Adverse Event reporting: Assign severity, duration, and attribution Compliance by pet owners and study investigators is very high Regulatory oversight/reporting Pre-IND agents - guidance has been proposed and used (Khanna et al Clin Cancer Res 2009) Post-IND agents - guidance exists Biotech and aversion to “rocking” the development boat
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In 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?
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The UT Molecular Imaging and Translational Research Program
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Acknowledgements Tumor and Metastasis Biology Section, Pediatric Oncology Branch, National Cancer Institute Ling Ren Arnulfo Mendoza Michael Lizardo James Morrow Allyson Koyen Tanasa Osborne Rhadika Gharpure Martin Mendoza Sung Hyeok Hong Manpreet Alhuwalia Jessica Cassavaugh Joseph Briggs Comparative Oncology Program CCR, National Cancer Institute Melissa Paoloni Christina Mazcko Ira Gordon Katherine Hansen Monika Jankowski Molecular Oncology Section, Pediatric Oncology Branch, National Cancer Institute Choh Yeung Lee Helman POB-OGS - NCI Jun Wei Javed Khan CGB CCR - NCI Paul Meltzer Liang Cao Sean Davis Pathology - NCI Stephen Hewitt Frederick - NCI Nancy Colburn Tim Veenstra Georgetown Aykut Uren C3D,- NCI Caryn Steakley Allison Wise Jeffrey Shilling Sawsan Sahin Deven Shah Rohit Paul COTC Amy LeBlanc Jeffrey Phillips Shelley Newman Doug Thamm Susan Plaza Christie Anderson Carolyn Henry Kimberly Selting David Vail Ilene Kurzman Karin Sorenmo Amy LaBlanc Timothy Fan William Kisseberth Barb Kitchell Heather Wilson CCOGC David Vail Matthew Breen Sue Lana Jaime Modiano Kerstin Linblad-Toh Elizabeth McNeil Phil Bergman Steve Withrow Mark Simpson Cheryl London Bill Kissebirth LCB - NCI Yien Cha Tsai Alan Weismann U. Chicago Hue Luu CSU Dan Gustafson Hansen
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