Comparative Oncology Program

1. Comparative Oncology Program

2. Normal Tissues Osteosarcoma Human Dog

3. TO PROVIDE OPPORTUNITIES TO INCLUDE NATURALLY OCCURRING CANCER MODELS IN THE STUDY OF CANCER BIOLOGY AND THERAPY Comparative Oncology • Cancer IN Companion Animals • 65 Million Companion Animals in the US • 4 million pet dogs diagnosed with cancer each year • Pet owners seek advanced care for their pets 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 Profiles to Conventional Chemotherapy Tumor Heterogeneity Metastasis Biology Recurrence/Resistance

4. The CCR - Comparative Oncology Program • Develop essential reagent kit for the study of comparative models in translational and biology-based research; • Develop multicenter collaborative network with extramural comparative oncology programs. Within this network design, implement and manage pre-clinical trials involving pet animals that will evaluate novel therapeutic strategies for cancer; • Increase the awareness of the appropriate use of naturally occurring cancer models within the cancer research community;

5. Resources and Reagents: opportunities for Layered Translation 5000 10000 15000 5000 10000 15000 5000 10000 15000 Human Serum 30 20 10 0 Canine Serum #1 30 20 10 0 Canine Serum #2 30 20 10 0 Canine Serum #3 30 20 10 0 5000 10000 15000

6. Comparative Oncology Trials Consortium (COTC)

7. Trial Review Process: Effort to ensure integration Collaboration Initiated -Pharma -NCI CCR-COP -Academia • Draft Trial Overview • 2-3 Page Summary • - Internal Review Trial Overview Board -CCR/CTEP/DTP Members - Focus on value of dog trial to development path Re-draft Re-draft Re-draft Solicit Ad Hoc Community Reviews -Individuals/Groups likely to be involved in clinical development COTC Consortium Members -Review Trial Overviews Approval Package Re-draft Decision Package for CCR Directors Solicit Ad Hoc Community to Review Full Protocol (JDC) -Individuals/Groups likely to be involved in clinical development and/or data management COTC Consortium Members -Review Full Protocol Commence Trial

8. Non-Human Primate Beagle Dog Phase I Human Clinical Trials Small Animal Preclinical Tumor-Bearing Dog Studies Tumor-Bearing Dog Studies Integration of a Comparative Approach Phase II Human Clinical Trials Phase III Human Clinical Trials New Cancer Drug Activity Toxicity Pharmacokinetics Pharmacodynamics Dose Regimen Schedule Biomarkers Responding Histologies Combination therapies

9. Large Pharma Merck • Status: CDA in place, meeting to discuss collaborations has been scheduled for early January 2006. Astrazeneca • Status: Meeting is planned for mid-November to discuss a trial in pet dogs. Small Pharma/Biotech Genzyme • Status: CRADA meeting and presentation completed. Locus Pharmaceuticals • Status: CDA has been completed and a Trial Overview is being drafted.

10. Academia/Biotech SemaCo • Status: CDA IN PLACE, in vitro evaluation underway (T Olgios in canine OSA cell lines) Colando Pharmaceuticals • Status: Currently validating their anti-RRM2 antibody in canine normal and tumor tissues by Western and Immunohistochemical analysis. Center for Cancer Research • Radiation Oncology (Jim Mitchel) Tempol • Evaluation of intravenous Tempol in pet dogs receiving fractionated radiation therapy in dogs with head and neck cancer • Status - Trial overview in second review • Surgery Branch (Steve Libutti) Phage Delivery of TNF- • Evaluation of RGD Targeted Delivery of Phage Expressing TNF- To Tumor Bearing Dogs • Status - Trial approved for initiation

11. The Good News…We have arrived. Now we must deliver News Nature Medicine11, 1018 (2005) Published online: 28 September 2005; | doi:10.1038/nm1005-1018a Cancer researchers usher in dog days of medicine George S Mack Columbia, South Carolina After thousands of years of friendship, man and dog will soon be working together to advance drug discovery. As part of a new comparative-oncology program at the US National Cancer Institute, researchers are set to begin drug trials in dogs that aim to bridge the gap between preclinical drug studies and effects of the same drug in people. Two multicenter trials, set to begin in early 2006, will evaluate new therapeutic approaches for cancer in dogs, says program chief Chand Khanna, a veterinary oncologist at the institute's Center for Cancer Research. "It turns out that many cancers, such as lymphoma, melanoma and osteosarcoma, are well represented in pet dogs," Khanna says. "The dogs will help us prioritize the agents that go into human clinical trials and help make those trials more efficient." Wall Street Journal July 7, 2005 Nature Medicine October 2005

12. Acknowledgments Tumor and Metastasis Biology Section, PEDIATRIC ONCOLOGY BRANCH CCR, National Cancer Institute Ling Ren Arnulfo Mendoza Jessica Cassavaugh Rachel Blackwood Sung-Hyeok Hong Lauren Shapiro Ben Bruce Rachel Newman Gaurav Khanna Comparative Oncology Program CCR, National Cancer Institute Melissa Paoloni Christina Mazcko Katherine Hansen

13. Acknowledgments • Oncogenomics Section, POB, NCI • Javed Khan Molecular Oncology Section Pediatric Oncology Branch CCR, National Cancer Institute Xiaolin Wan Choh Yeung Lee Helman • Cancer Genetics Branch, NHGRI • Kristin Baird • Paul Meltzer • State University of Ohio • Mark Berryman LCMB, CCR, National Cancer Institute Yanlin Yu Glenn Merlino • Cornell University • Anthony Bretscher • Tissue Array Research Project (TARP), CCR • Stephen Hewitt • Kimberly Parker • Columbia University • Charles Powell • Alain Borczuk • Biomedical Proteomics Program, CCR • LiRoung Yu • Ming Zhou • Tim Veenstra • University of Michigan • Evan Keller • Carcinogenesis/Prevention, CCR • Nancy Colburn • University of Umea • Goran Landberg