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Certis Oncology PDOX Models Improve Cancer Drug Testing
- 1. CERTIS ONCOLOGY SOLUTIONS Oncologist-Directed Solutions for Cancer Therapy & Drug Discovery Privileged & Confidential Do not distribute without permission Copyright © Certis Oncology Solutions, 2018 Pre-Clinical Research Offerings Jonathan Nakashima, PhD Director of Operations nakashima@certisoncology.com
- 2. Certis Oncology Solutions Operational focus on orthotopic xenograft mouse modeling • Employs the Surgical Orthotopic Implantation (SOI) micro- surgical technique to establish Patient-Derived Orthotopic Xenografts (PDOX) • Affiliated with physicians from UCLA and Memorial Sloan Kettering • Expanding our vivarium • Expanding our immortalized tumor bank to include patient drug response information • Received more than 300 patient tumors and counting • CLIA certified for high-complexity testing 2Copyright © Certis Oncology Solutions, 2018 New Pre-clinical CRO Facilities • San Diego-based facility on a Life Sciences campus • 7,000 sq. ft. facility • 2,000 sq. ft. of Lab space
- 3. 3Copyright © Certis Oncology Solutions, 2018 A Unique Model for Building Cohort Programs 3Copyright © Certis Oncology Solutions, 2018 1 2 3 Tumor samples are collected from the patient. Various drug therapies are tested simultaneously in multiple mice, providing valuable treatment data to the oncologist in order to individualize the patient’s therapy. Microscopic specimens are then surgically implanted in orthotopic locations where they grow and metastasize. All tumors are banked and cryogenically preserved for future therapy testing. Once passaged, tumors are cryopreserved and genetically analyzed.
- 4. 4 JCO Precision Oncology, 2017 Landmark PDOX Study (UCLA) Conclusions: • In the largest Soft Tissue Sarcoma PDOX study to date, we demonstrate a 62% establishment rate among untreated high- grade tumors with a median establishment time of 54 days. • Neoadjuvant therapy, particularly radiation, and pathologic response to treatment were associated with a reduced rate of PDOX establishment. Copyright © Certis Oncology Solutions, 2018
- 5. PDOX vs. PDX Placement of the tumor in the orthotropic location provides a more clinically relevant model of cancer. PDOX PDX Surgical Orthotopic Implantation Subcutaneous, non-surgical orthotopic Technology proven, innovation continues Commercializing patient treatment using technology unchanged in decades Reliably metastasizes Rarely metastasizes High tumor establishment success rate Lower success rate of tumor growth 3-4 months median interval to establishment and treatment recommendation; more accurate data 6-9 months to treatment recommendation 5Copyright © Certis Oncology Solutions, 2018 PDOX | PDX
- 6. 6Copyright © Certis Oncology Solutions, 2018 PDOX vs. PDX Orthotopic models grow faster than subcutaneous models and recur more often.
- 7. 7 Concordance Testing Copyright © Certis Oncology Solutions, 2018 Verified that the response of the mouse tumor closely matches that of the patient’s tumor • Our concordance study will be published as part of our submission for the CLIA license for High Complexity Testing • Disease progression and subsequent metastasis mimics the clinical progression in humans • Increases the accuracy of therapy and reduces the time to treat aggressive tumors • Closely simulates tumor response to each cancer treatment option • Certis PDOX’s time and accuracy provide a significant, sustainable competitive advantage over existing mouse models With Certis PDOX models, what happens in the mice happens in patients.
- 8. Core Needle Biopsy Study 8Copyright © Certis Oncology Solutions, 2018 Game changer because we will be collecting data in earlier stages of patient care • Study in progress • Does not disrupt therapy / standard procedure • Will allow us access to patient tumors well in advance of surgical biopsy and begin establishment from the time of diagnosis • Allows for longitudinal patient studies and access to more tumor material: 1. Biopsy 2. Surgical resection 3. Recurrence
- 9. 9 Certis PDOX Preclinical Research Services Drug discovery for genetic researchers, pharmaceutical companies, biotech and academic laboratories 1. Guidance in selecting models 2. Execution of drug screening and efficacy studies 3. Individual patient drug-efficacy information 4. Data analysis and reporting 5. Assistance writing and publishing papers 6. Assistance writing grant applications 7. Grant sub-contracting Copyright © Certis Oncology Solutions, 2018
- 10. Oncology Study Endpoints 10 • Overall survival • Tumor growth inhibition and regression • Evaluation of metastasis • Drug tolerance • Tissue harvest • Histological Analysis: IHC, IF, ISH, whole slide imaging, digital analysis Copyright © Certis Oncology Solutions, 2018
- 11. 11 Tumor Models and Drugs Evaluated Copyright © Certis Oncology Solutions, 2018 Novel Drugs Evaluated in PDOX • Cobmetinib • Dactolisib • Entinostat • Lapatinib • Linsitinib • Nab-paclitaxel • Palbociclib • Pazopanib • Trametinib • Trastuzumab • Vemurafenib • Yondelis PDOX Cancer Types Currently Available Cervical Colon Melanoma Pancreatic Liver metastasis • Pancreatic • Colon Sarcoma • Lipo • Leiomyo • GIST • Osteo • Synovial • Ewing’s • Spindle Cell • Myxofibro
- 12. Certis PDOX Preclinical Advantages Certis PDOX mouse models, which require highly skilled micro surgery, are proven to accurately reflect human disease. • We are expanding our cryo-preserved tumor bank for translational research applications. • Our models are proven to be more clinically relevant than PDX. Numerous outcomes have been published in peer- reviewed scientific journals. • Our relationships with oncologists position us to track patient outcomes over time and obtain drug-resistant tumors. 12Copyright © Certis Oncology Solutions, 2018
- 13. 13Copyright © Certis Oncology Solutions, 2018 Clinical Relevance PDOX008: Ewing’s Sarcoma with FUS-ERG fusion and CDKN2A deletion 46-year-old female diagnosed with rare Ewing's Sarcoma • Treated with two rounds of chemo (VCD) • En bloc resection and PDOX initiation • 12 cycles of chemo (VCD/IE) • 8 months after chemo, scans revealed diffuse bony mets, bone marrow studded with tumor, and severe cytopenias requiring frequent transfusions Primary Tumor Diffuse Metastasis 50 µm 50 µm PDOX retains histological features of the primary patient tumor. Primary Tumor PDOX Tumor
- 14. 14Copyright © Certis Oncology Solutions, 2018 Clinical Relevance PDOX008: Ewing’s Sarcoma with FUS-ERG fusion and CDKN2A deletion First PDOXexperiment showedsensitivitytoCDK4/6andIGF-1R inhibitors, whichwasusedtoobtainanINDfor single-patient compassionateuseof ganitumab(IGF-1Rinhibitor). Patient wasgiven8dosesof ganitumabwhichgreatlyincreasedquality of lifewithnoadditional transfusionsneeded. SecondPDOXexperiment showedtumor regressionafter irinotecan/temozolomidetreatment. After marrowrecovery, irinotecan/temozolomidewasinitiatedwith rapid, remarkableresponse, extendingthepatient’slifeby2years.
- 15. Clinical Relevance PDOX173: Recurrent high-grade leiomyosarcoma 15Copyright © Certis Oncology Solutions, 2018 63-year-old male diagnosed with HG leiomyosarcoma • Treated with 2 cycles of neo adjuvant Gem/Tax, followed by surgical resection, then 4 cycles Doxorubicin/Olaratumab • MRI left Lower extremity shows Multifocal Recurrence • Resection of L medial thigh lesion to establish PDOX • Started pazopanib but progressed 10/24/17: 10.2cm x 6.9cm TUMOR 10/24/17: 4.95cm
- 16. Clinical Relevance PDOX173: Recurrent high-grade leiomyosarcoma 16Copyright © Certis Oncology Solutions, 2018 PDOX experiment showed sensitivity to temozolomide/dacarbazine 4/10/18: 3.9cm x 3.6cm After 6 cycles of dacarbazine, the patient responded remarkably 4/10/18: 3.31cm 10/24/17: 10.2cm x 6.9cm TUMOR 10/24/17: 4.95cm
- 17. 17 Recent Scientific Publications Copyright © Certis Oncology Solutions, 2018 Igarashi et al. Intra-arterial administration of tumor-targeting Salmonella typhimurium A1-R regresses a cisplatin-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model. Cell Cycle, 2017, Vol. 16, No. 12, 1164–1170 https://doi.org/10.1080/15384101.2017.1317417. Igarashi et al. Patient-derived orthotopic xenograft (PDOX) mouse model of adult rhabdomyosarcoma invades and recurs after resection in contrast to the subcutaneous ectopic model. Cell Cycle, 2017, Vol. 16, No. 1, 91–94 http://dx.doi.org/10.1080/15384101.2016.1252885. Igarashi et al. High efficacy of pazopanib on an undifferentiated spindle-cell sarcoma resistant to first-line therapy is identified with a patient-derived orthotopic xenograft (PDOX) nude mouse model. J. Cell. Biochem. 118, 2739-3743, 2017. Kawaguchi et al. Tumor-targeting Salmonella typhimurium A1-R combined with temozolomide regresses malignant melanoma with a BRAF-V600E mutation in a patient-derived orthotopic xenograft (PDOX) model. Oncotarget, 2016, Vol. 7, (No. 52), pp: 85929-85936. Kawaguchi et al. Vemurafenib-resistant BRAF-V600E-mutated melanoma is regressed by MEK-targeting drug trametinib, but not cobimetinib in a patient-derived orthotopic xenograft (PDOX) mouse model. Oncotarget, Vol. 7, No. 44. Kawaguchi et a;. Tumor-Targeting Salmonella typhimurium A1-R Sensitizes Melanoma With a BRAF-V600E Mutation to Vemurafenib in a Patient-Derived Orthotopic Xenograft (PDOX) Nude Mouse Model. Journal of Cellular Biochemistry 118:2314–2319 (2017). Kawaguchi et al. Combination of gemcitabine and docetaxel regresses both gastric leiomyosarcoma proliferation and invasion in an imageable patient-derived orthotopic xenograft (iPDOX) model. Cell Cycle 16, 1063-1069, 2017. Kiyuna et al. Labeling the Stroma of a Patient-Derived Orthotopic Xenograft (PDOX) Mouse Model of Undifferentiated Pleomorphic Soft-Tissue Sarcoma With Red Fluorescent Protein for Rapid Non-Invasive Imaging for Drug Screening. Journal of Cellular Biochemistry 118:361–365 (2017).. Murakami et al. Effective molecular targeting ofCDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A- deletion doxorubicin-resistant Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) nude- mouse model. Oncotarget 7, 47556-47564, 2016. Murakami et al. Tumor-targeting Salmonella typhimurium A1-R regresses an osteosarcoma in a patient- derived xenograft model resistant to a molecular-targeting drug. Oncotarget, 2017, Vol. 8, (No. 5), pp: 8035- 8042. Murakami et al. Recombinant methioninase effectively targets a Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Oncotarget, 2017, Vol. 8, (No. 22), pp: 35630-35638. Igarashi et al. Patient-derived orthotopic xenograft (PDOX) mouse model of adult rhabdomyosarcoma invades and recurs after resection in contrast to the subcutaneous ectopic model. Cell Cycle 16, 91-94, 2017. Murakami et al. Tumor-targeting Salmonella typhimurium A1-R in combination with doxorubicin eradicate soft tissue sarcoma in a patient-derived orthotopic xenograft PDOX model. Oncotarget 7, 12783-12790, 2016. Kiyuna et al. High efficacy of tumor-targeting Salmonella typhimurium A1-R on a doxorubicin- and dactolisib- resistant follicular dendritic-cell sarcoma in a patient-derived orthotopic xenograft PDOX nude mouse model. Oncotarget 7, 33046-33054, 2016. Yamamoto et al. Efficacy of tumor-targeting Salmonella typhimurium A1-R on a melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse model. PLoS One 11, e0160882, 2016. Murakami et al. Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Oncotarget, Epub ahead of print. Kiyuna et al. Labeling the stroma of a patient-derived orthotopic xenograft (PDOX) mouse models of undifferentiated pleomorphic soft-tissue sarcoma with red fluorescent protein for rapid non-invasive drug screening. J. Cell. Biochem., Epub ahead of print. Kawaguchi et al. Vemurafenib-resistant BRAF-V600E mutated melanoma is regressed by MEK targeting drug trametinib, but not cobimetinib in a patient-derived orthotopic xenograft (PDOX) mouse model. Oncotarget 7, 71737-71743, 2016. Kawaguchi, et al. Tumor-targeting Salmonella typhimurium A1-R combined with Temozolomide regresses malignant melanoma with a BRAF-V600 mutation in a patient-derived orthotopic xenograft (PDOX) model. Oncotarget 7, 85929-85936, 2016.