Contenu connexe
Similaire à Certis Preclinical Slideshare (20)
Certis Preclinical Slideshare
- 2. Certis OncologySolutions
Operational focus on orthotopic xenograft mouse modeling
• Employs the Surgical Orthotopic Implantation (SOI)micro-
surgical technique to establish Patient-DerivedOrthotopic
Xenografts (PDOX)
• Affiliated with physicians from UCLAand Memorial Sloan
Kettering
• Expanding our vivarium
• Expanding our immortalized tumor bank to includepatient
drug response information
• Received more than 300 patient tumors and counting
• CLIA certified for high-complexitytesting
New Pre-clinicalCROFacilities
• SanDiego-based facilityon aLife
Sciencescampus
• 7,000 sq. ft.facility
• 2,000 sq. ft.ofLab space
Copyright © Certis OncologySolutions,2018 2
- 3. A Unique Model forBuildingCohort Programs
1 2
Tumor samples arecollected
from thepatient.
3
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 inorthotopic
locations where they grow and
metastasize.
All tumors arebanked
and cryogenically
preserved for future
therapy testing.
Once passaged,tumors
are cryopreserved and
genetically analyzed.
Copyright © Certis OncologySolutions,2018 3
- 4. Landmark PDOX Study(UCLA)
JCOPrecision Oncology, 2017
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 reducedrate of
PDOX establishment.
Copyright © Certis OncologySolutions,2018 4
- 5. PDOX vs.PDX
Copyright © Certis OncologySolutions,2018 5
Placement of the tumor in the orthotropic location provides a more clinically
relevant model ofcancer.
PDOX PDXPDOX | PDX
Surgical OrthotopicImplantation Subcutaneous, non-surgicalorthotopic
Technology proven, innovationcontinues Commercializing patient treatment
using technologyunchangedindecades
Reliablymetastasizes Rarelymetastasizes
Hightumor establishmentsuccessrate Lowersuccessrateof tumor growth
3-4monthsmedianintervalto
establishment andtreatment
recommendation; more accuratedata
6-9 months totreatment
recommendation
- 6. PDOX vs.PDX
Copyright © Certis OncologySolutions,2018 6
Orthotopic models grow faster than subcutaneous models and recur more often.
- 7. ConcordanceTesting
Verifiedthat 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 HighComplexity Testing
• Disease progression and subsequent metastasis mimicsthe
clinical progression inhumans
• Increases the accuracy of therapy and reduces the time to treat
aggressive tumors
• Closely simulates tumor response to each cancertreatment
option
• Certis PDOX’s time and accuracy provide a significant,
sustainable competitive advantage over existing mousemodels
Copyright © Certis OncologySolutions,2018 7
WithCertisPDOXmodels,what
happensinthemicehappensin
patients.
- 8. Core Needle BiopsyStudy
Game changer because we will be collecting data in
earlier stages of patient care
• Study in progress
• Does not disrupt therapy /standardprocedure
• 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
Copyright © Certis OncologySolutions,2018 8
- 9. Certis PDOX Preclinical ResearchServices
Drug discovery forgenetic researchers, pharmaceutical
companies, biotech and academic laboratories
1. Guidance in selecting models
2. Execution of drug screening and efficacystudies
3. Individual patient drug-efficacy information
4. Data analysis and reporting
5. Assistance writing and publishingpapers
6. Assistance writing grant applications
7. Grant sub-contracting
Copyright © Certis OncologySolutions,2018 9
- 10. Oncology StudyEndpoints
• Overall survival
• Tumor growth inhibition andregression
• Evaluation of metastasis
• Drug tolerance
• Tissue harvest
• Histological Analysis: IHC, IF,ISH, whole slideimaging,
digital analysis
Copyright © Certis OncologySolutions,2018 10
- 11. TumorModels and Drugs Evaluated
Novel DrugsEvaluated
in PDOX
• Cobmetinib
• Dactolisib
• Entinostat
• Lapatinib
• Linsitinib
• Nab-paclitaxel
• Palbociclib
• Pazopanib
• Trametinib
• Trastuzumab
• Vemurafenib
• Yondelis
PDOX CancerTypes
CurrentlyAvailable
Cervical
Colon
Melanoma
Pancreatic
Livermetastasis
•Pancreatic
•Colon
Sarcoma
•Lipo
•Leiomyo
•GIST
•Osteo
•Synovial
•Ewing’s
•SpindleCell
•Myxofibro
Copyright © Certis OncologySolutions,2018 11
- 12. Certis PDOX PreclinicalAdvantages
Certis PDOX mouse models, which require highly skilled micro
surgery, are proven to accuratelyreflecthuman 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.
Copyright © Certis OncologySolutions,2018 12
- 13. ClinicalRelevance
PDOX008: Ewing’sSarcoma withFUS-ERG fusionand CDKN2Adeletion
46-year-old female diagnosed with rareEwing's Sarcoma
• Treated with two rounds of chemo(VCD)
• En bloc resection and PDOXinitiation
• 12 cycles of chemo(VCD/IE)
• 8 months after chemo, scans revealed
diffuse bony mets, bone marrowstudded
with tumor, and severe cytopenias
requiring frequent transfusions
Primary Tumor Diffuse Metastasis
50 µm
Copyright © Certis OncologySolutions,2018 13
50 µm
PDOXretainshistologicalfeaturesoftheprimarypatienttumor.
PrimaryTumor
PDOXTumor
- 14. ClinicalRelevance
Copyright © Certis OncologySolutions,2018 14
PDOX008: Ewing’sSarcoma withFUS-ERG fusionand CDKN2Adeletion
FirstPDOXexperimentshowedsensitivitytoCDK4/6andIGF-1R
inhibitors,whichwasusedtoobtainanINDforsingle-patient
compassionateuseofganitumab(IGF-1Rinhibitor).
Patientwasgiven8dosesofganitumabwhichgreatlyincreasedquality
oflifewithnoadditionaltransfusionsneeded.
SecondPDOXexperimentshowedtumorregressionafter
irinotecan/temozolomidetreatment.
Aftermarrowrecovery,irinotecan/temozolomidewasinitiatedwith
rapid,remarkableresponse,extendingthepatient’slifeby2years.
- 15. ClinicalRelevance
PDOX173: Recurrenthigh-gradeleiomyosarcoma
63-year-old male diagnosed with HG leiomyosarcoma
• Treated with 2 cycles of neo adjuvant Gem/Tax,followedby
surgical resection, then 4 cyclesDoxorubicin/Olaratumab
• MRIleft Lower extremity shows Multifocal Recurrence
• Resection of Lmedial thigh lesion to establishPDOX
• Started pazopanib but progressed
10/24/17: 10.2cm x 6.9cm
TUM OR
10/24/17: 4.95cm
Copyright © Certis OncologySolutions,2018 15
- 17. Copyright © Certis OncologySolutions,2018 17
Recent ScientificPublications
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 aBRAF-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 gastricleiomyosarcoma
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 Modelof
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 apatient-
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 modelsof
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.
