Patient Derived Xenograft Models ---Clinical Applications Chong-xian Pan, MD, PhD, MS Professor of Medicine and Urology Co-Leader of Cancer Therapeutic Program University of California Davis School of Medicine UC Davis Comprehensive Cancer Center Sacramento, CA, USA Staff Physician VA Northern California Health Care System Mather, CA
DISCLOSURE: I have financial interest/arrangement or affiliation with Name of Organization Relationship Accelerated Medical Diagnostics Inc Co-founder and shareholder LP Therapeutics Inc Co-founder and shareholder Pandomedx Inc Co-founder and shareholder Four patents 1. Bladder cancer-specific ligand cQDGRMGFc for imaging detection, immunotherapy and targeted therapy of bladder cancer (filed. Inventors: Chong-xian Pan, Hongyong Zhang, Kit Lam and Olulanu Aina). US Patent application No. 61/245,492. 2. Leukemia stem cell-targeting ligand and methods of use. Ligands containing the LR(S/T) amino acid motif for targeted therapy and detection of acute myeloid leukemia. (filed. Inventors: Chong-xian Pan and Hongyong Zhang). Patent application No. 14/130,909. 3. Porphyrin-based cancer-targeting nanometer-scale micelles for photodynamic diagnosis and therapy (Inventors: Yuanpei Li, Kit S. Lam, Chong-xian Pan, Tzu-yin Lin). US Provisional patent Application No. 61/736,067. 4. Treatment of Drug Resistant Metastatic Prostate Cancer Using Niclosamide. (Inventors: Allen Gao, Chengfei Liu, Wei Luo and Chong-xian Pan). U.S. Patent Application No. 15/134,228
Introduction Tradition Cancer Medicine Precision Medicine State-of-the-art technologies: Diagnosis and staging -omics Computational biology to Empirical identify targets their corresponding One formula fits all Individualized therapy Tsimberidou et al: RR 12% with matched targeted therapy vs. 5% with unmatched therapy (Clin Cancer Res. 2014; 20:4827) Andre et al. RR 9% plus 21% stable disease with matched targeted therapy in breast cancer (Lancet Oncology, 2014; 15:267) Slides are the property of the author. Permission required for reuse.
Patient-derived models of cancer (PDMCs) for precision medicine Prior to relapse Relapse Primary treatment Secondary treatment Patient Engraft tumor into Secondary Tx informed by NSG mice outcomes in mice Remission Relapse Response? P1 Primary treatment Secondary treatment A growth (same as patient) P1 Primary treatment Secondary treatment B P0 growth (same as patient) NSG mice growth P1 Primary treatment Secondary treatment C growth (same as patient) P1 Primary treatment Secondary treatment D growth (same as patient) Target validation with Integrative IHC, IF, western, etc Deep sequencing Computational Biology Target selection Slides are the property of the author. Permission required for reuse.
PDXs for precision medicine Features and applications of PDXs Special features: • PDXs are directly derived from unselected uncultured clinical specimens • PDXs are patient-specific • PDXs and patient cancers have the same genetic background • Many identical PDXs can be generated for repeated studies • Frequent biopsies can be done to study resistance mechanisms Slides are the property of the author. Permission required for reuse.
36 bladder cancer PDXs Clinical Characteristics of the donor patients Stages Tumor ID Age (yrs) Stage Surgery Prior chemo BL0269F 58 pT4 N0 Mx Cystectomy No BL0293F 77 pT2a N2 Mx Cystectomy No BL0307F 78 pT3b N2 Mx Cystectomy No BL0382F 82 pT2 Nx Mx TURBT No BL0428F 70 pT2 Nx Mx TURBT No BL0429F 60 pT4a N3 M1 Cystectomy No Myoinvasive BL0479F 78 pT2b Nx Mx Cystectomy YES (carbo/gem/PTX) bladder BL0440F 71 pT4a N2 Mx Cystectomy YES (gem/cis) cancer BL0515F 78 pT3bN0Mx Cystectomy YES (Gem/Cis) BL0545F 70 pT2 N0 Mx Cystectomy No BL0601F 83 pT3 N0 Mx Cystectomy No BL0629F 74 pT3 N0 Mx Cystectomy No BL0645F 75 pT4a N2 Mx Cystectomy YES (MVAC)# BL0648 71 pT4a N2 Mx Cystectomy No. AdenoCa BL0262F 64 pTa High TURBT No BL0364F 76 pTa Low TURBT No Non-myo- BL0381F * 60 pTa High TURBT No invasive BL0398F * 60 pT1 No Mx Cystectomy No bladder BL0470F 55 pTa Nx Mx TURBT No cancer BL0591F 65 pTis N0 Mx Cystectomy No BL0606F 77 pT1Nx Mx TURBT No BL0622F 63 pTis cystectomy Slides are the property of the author. Permission required for reuse. BL0674F 54 pT1N0Mx cystectomy NO
PDXs for precision medicine Characterization of PDXs Genetic Alterations BL0293-Patient BL0293-Passage 6-S.C. BL0293-Passage 4-orthotopic 100� BL0429� Conserva on� 90� BL0440� 80� 70� 60� 50� Percentage� 40� 30� 20� BL0440-Patient BL0440-Passage 6-S.C. BL0440-Passage 4-orthotopic 10� 0� Variants� dbSNPs� Nonsynonymous+InDels� Nonsynonymous� Indels� w/o� All� Variants� Variant� Type� Conservation of genetic Fidelity of morphology aberrations (92-97%) Slides are the property of the author. Permission required for reuse.
Applications of PDMCs Screening for effective targeted therapy Screening for effective chemotherapy Re-purposing of FDA approved drugs PDX:BL0269 30 BL0293 Tumor Response BL0269 Tumor Response Vehicle BL0382 Tumor Response Vehicle 10 Lapatinib (30 mg/kgB.W.) BEZ235 (30 mg/kg) 2000 Elucidation of resistance mechanisms 2000 Mean tumor volume (mm 3 +/-SE) 1500 Mean tumor volume (mm 3 +/-SE) Sorafenib (20 mg/kgB.W.) Mean tumor volume (mm 3 +/-SE) +Lapatinib (30 mg/kgB.W.) Tumor Ratio Ponatinib (10 mg/kg B.W.) 30 Vehicle 1500 20 Vehicle Tumor Ratio 1500 40 Overcoming resistance BGJ398 (30 mg/kg, B.W.) 1000 Lapatinib (30 mg/kg, B.W.) Palbociclib 1000 tumor size ratio 1000 5 30 Tumor Ratio Group 1 - Vehicle Group 1 - Vehicle 20 10 500 500 Group 2 - Cisplatin Group 2 - Cisplatin 500 Group 3 - Gemcitabine Group 3 - Gemcitabine 20 Group 4 - Cisplatin & Gem Group 4 - Cisplatin & Gem 0 0 20 40 60 80 PDX: BL0293 10 0 20 Days 0 Vehicle 10 20 10 30 40 0 50 Group 1 - Vehicle -20 0 20 40 60 80 (Day 0 = treatment initiation) 1 6 12 15 5 10 15 20 FGFR3 inhibitor Days Group 2 - Cisplatin Days Drug treatment (Days) (Day 0 = treatment initiation) Drug treatment (Days) (Day 0 = treatment initiation) Group 3 - Gemcitabine Group 4 - Cisplatin & Gem 0 15 0 Re-transplant 0 10 20 30 40 50 1 6 11 14 19 23 and expansion days Drug treatment (Days) Tumor Ratio Robertson et al. Cell. 2017; 171:540 Lapatinib: ERBB2/3 inhibitor BL0440 Tumor Response BL0515 Tumor Response 10 Palbociclib: CDK4/6 inhibitor 2500 Mean tumor volume (mm 3 +/-SE) 2000 Mean tumor volume (mm 3 +/-SE) Group 1 - Vehicle 2000 Group 2 - Cisplatin ERBB2 5 FGFR3 1500 Group 3 - Gemcitabine 1500 Group 4 - Cisplatin & Gem 1000 1000 0 1 4 8 12 15 17 500 Drug treatment (Days) 500 Biopsy Biopsy 0 0 20 40 60 80 Days Group 1 - Vehicle -10 0 10 20 30 40 50 (Day 0 = treatment initiation) Days Group 2 - Cisplatin (Day 0 = treatment initiation) Group 3 - Gemcitabine Group 4 - Cisplatin & Gem Slides are the property of the author. Permission required for reuse.
Applications of PDMCs -Drug development Bladder cancer-specific PLZ4-nanoparticles (Kit Lam, MD, PhD) Nanoparticle In vitro delivery In vivo delivery: left: Lung; Right: bladder PTX 10 mg/Kg PBS PLZ4-NM-PTX 30mg/Kg PLZ4-NM-PTX 10mg/Kg Treatment OS WBC 10.0 (days) (K/ml) 7.5 3.96 ± 1.40 Tumor ratio PBS 11 5.0 1.16 ± 0.19 PTX 10mg/kg 27 2.5 2.03 ± 0.81* PLZ4-NP-PTX 10 24 mg/kg 0.0 0 5 10 15 20 25 30 35 40 45 50 1.08 ± 0.28 Days After First Treatment PLZ4-NP-PTX 30 >70 In vivo anti-tumor activity mg/kg IND No: 117868 Slides are the property of the author. Permission required for reuse.
Applications of PDMCs -Drug development - Smart “9 -in- 1” PLZ4 -nanoporphyrin Polyethylen e glycol 1. Photodynamic diagnosis 2. Photodynamic therapy 3. Photothermal therapy 4. Chelation of Gd(III) for MRI 5. Chelation of 64 Cu for PET 6. Chelation of 67 Cu for radiation therapy 7. Targeted delivery of chemo 8. Chelation of gallium for sonodynamic Tx 9. Near infrared imaging 10. combination of the above PLZ4-NP targets and deliver chelated metal to the cancer site Li et al. Nature Communication. 2014 Lin et al. Biomaterials. 2016 Slides are the property of the author. Permission required for reuse.
Applications of PDMCs PLZ4-nanoporphyrin -Drug development Photodynamic diagnosis Pre-IND: 132838 30-40X difference NIRF DAPI (nucleus) Merge Hema3 TM BL269 PDX PNP 5637-DiO labeled Phase * Uro 6000 ** * BL269 4000 ** ** 2000 Ur BL269 ** Ur o Normal Urothelial o bladder Normal 0 0 5 10 15 20 25 30 35 Human bladder cancer cell line 5637 Human patient-derived xenograft 40x 2-3X for 5-ALA Control DOX PNP+L B mode Tumor temperature 70 NPs Light on o C) Control Temperature ( 60 50 40 30 contrast 0 100 200 mode Time (s) Bladder Gross Photothermal therapy Photodynamic therapy Slides are the property of the author. Permission required for reuse.
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