Certis preclinical slideshare 7.28.18

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 Orthotopic Patient-Derived
Xenografts (PDXs)
• 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

4. 4
JCO Precision Oncology, 2017
Landmark Orthotopic PDX Study (UCLA)
Conclusions:
• In the largest Soft Tissue Sarcoma Orthotopic PDX 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
Orthotopic PDX establishment.
Copyright © Certis Oncology Solutions, 2018

5. Placement of the tumor in the orthotopic location provides
the most clinically relevant model because it reliably metastasizes.
5
Surgical Orthotopic Implantation (SOI) Subcutaneous, orthotopic injection
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
Orthotopic PDX | PDX
Orthotopic PDX vs. PDX
Copyright © Certis Oncology Solutions, 2018

6. 6Copyright © Certis Oncology Solutions, 2018
Orthotopic PDX 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 PDX’s time and accuracy provide a significant, sustainable
competitive advantage over existing mouse models
With Certis PDX 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 PDX 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 Certis PDX
• Cobmetinib
• Dactolisib
• Entinostat
• Lapatinib
• Linsitinib
• Nab-paclitaxel
• Palbociclib
• Pazopanib
• Trametinib
• Trastuzumab
• Vemurafenib
• Yondelis
Certis PDX 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 PDX Preclinical Advantages
Certis PDX 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 Orthotopic PDX 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 Orthotopic PDX 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
Certis PDX retains histological features of the primary patient tumor.
Primary Tumor
Orthotopic PDX Tumor

14. 14Copyright © Certis Oncology Solutions, 2018
Clinical Relevance
PDOX008: Ewing’s Sarcoma with FUS-ERG fusion and CDKN2A deletion
First Orthotopic PDX experiment showed sensitivity to CDK4/6 and IGF-
1R inhibitors, which was used to obtain an IND for single-patient
compassionate use of ganitumab (IGF-1R inhibitor).
Patient was given 8 doses of ganitumab which greatly increased quality
of life with no additional transfusions needed.
Second Orthotopic PDX experiment showed tumor regression after
irinotecan/temozolomide treatment.
After marrow recovery, irinotecan/temozolomide was initiated with
rapid, remarkable response, extending the patient’s life by 2 years.

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 Orthotopic PDX
• 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
Certis PDX 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.

18. Thank you!
nakashima@certisoncology.com
858.952.1820