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
Patient Derived Xenograft Models ---Clinical Applications
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
their corresponding
Introduction
Slides are the property of the author. Permission required for reuse.
State-of-the-art technologies: -omics
Computational biology to identify targets
Individualized therapy
Precision Medicine
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)
Tradition Cancer Medicine
Diagnosis and staging
Empirical
One formula fits all
Patient-derived models of cancer
(PDMCs) for precision medicine
Slides are the property of the author. Permission required for reuse.
Engraft tumor into
NSG mice
P0
growth
Primary treatment
(same as patient) Secondary treatment A
P1
growth
Secondary treatment B
Secondary treatment C
Patient
NSG mice
P1
growth
P1
growth
Primary treatment
(same as patient)
Primary treatment
(same as patient)
Secondary treatment D P1
growth
Primary treatment
(same as patient)
Response?
Secondary Tx informed by
outcomes in mice
Relapse
Relapse
Deep sequencing
Target selection
Remission
Target validation with
IHC, IF, western, etc
Prior to relapse
Secondary treatment Primary treatment
Integrative
Computational
Biology
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.
Clinical Characteristics of the donor patients
Stages Tumor ID Age (yrs) Stage Surgery Prior chemo
Myoinvasive
bladder
cancer
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
BL0479F 78 pT2b Nx Mx Cystectomy YES (carbo/gem/PTX)
BL0440F 71 pT4a N2 Mx Cystectomy YES (gem/cis)
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
Non-myo-
invasive
bladder
cancer
BL0262F 64 pTa High TURBT No
BL0364F 76 pTa Low TURBT No
BL0381F * 60 pTa High TURBT No
BL0398F * 60 pT1 No Mx Cystectomy No
BL0470F 55 pTa Nx Mx TURBT No
BL0591F 65 pTis N0 Mx Cystectomy No
BL0606F 77 pT1Nx Mx TURBT No
BL0622F 63 pTis cystectomy
BL0674F 54 pT1N0Mx cystectomy NO
36 bladder cancer PDXs
Slides are the property of the author. Permission required for reuse.
PDXs for precision medicine Characterization of PDXs
0
10
20
30
40
50
60
70
80
90
100
AllVariants
Variantsw/odbSNPs
Nonsynonymous+InDels
Nonsynonymous
Indels
PercentageConserva
on
VariantType
BL0429andBL0440:ComparisonofVariantsinPTandPDX-P0
BL0429
BL0440
Genetic Alterations
Fidelity of morphology Conservation of genetic
aberrations (92-97%)
BL0293-Passage 6-S.C. BL0293-Patient
BL0440-Patient BL0440-Passage 6-S.C. BL0440-Passage 4-orthotopic
BL0293-Passage 4-orthotopic
Slides are the property of the author. Permission required for reuse.
Applications of PDMCs
Slides are the property of the author. Permission required for reuse.
Screening for effective targeted therapy
Robertson et al. Cell. 2017; 171:540
1 6 12 150
5
10
Vehicle
Lapatinib (30 mg/kgB.W.)
Sorafenib (20 mg/kgB.W.)+Lapatinib (30 mg/kgB.W.)
Drug treatment (Days)
Ponatinib (10 mg/kg B.W.)
Tu
mo
r R
ati
o
5 10 15 20
10
20
30
Vehicle
Drug treatment (Days)
BEZ235 (30 mg/kg)
PDX:BL0269
Tu
mo
r R
atio
Screening for effective chemotherapy
BL0269 Tumor Response
0 10 20 30 40 500
500
1000
1500
2000
Group 1 - Vehicle
Group 2 - Cisplatin
Group 3 - Gemcitabine
Group 4 - Cisplatin & Gem
Days(Day 0 = treatment initiation)
Mean
tu
mo
r v
olu
me (
mm
3+
/-S
E)
BL0293 Tumor Response
0 20 40 60 800
500
1000
1500
2000
Group 1 - Vehicle
Group 2 - Cisplatin
Group 3 - Gemcitabine
Group 4 - Cisplatin & Gem
Days(Day 0 = treatment initiation)
Mean
tu
mo
r vo
lum
e (
mm
3+
/-S
E)
BL0382 Tumor Response
-20 0 20 40 60 80
500
1000
1500
Group 1 - Vehicle
Group 2 - Cisplatin
Group 3 - Gemcitabine
Group 4 - Cisplatin & Gem
Days(Day 0 = treatment initiation)
Mean
tu
mo
r vo
lum
e (
mm
3+
/-S
E)
BL0515 Tumor Response
-10 0 10 20 30 40 50
500
1000
1500
2000Group 1 - Vehicle
Group 2 - Cisplatin
Group 3 - Gemcitabine
Group 4 - Cisplatin & Gem
Days(Day 0 = treatment initiation)
Mean
tu
mo
r v
olu
me (
mm
3+
/-S
E)
BL0440 Tumor Response
0 20 40 60 800
500
1000
1500
2000
2500
Group 1 - Vehicle
Group 2 - Cisplatin
Group 3 - Gemcitabine
Group 4 - Cisplatin & Gem
Days(Day 0 = treatment initiation)
Mean
tu
mo
r vo
lum
e (
mm
3+
/-S
E)
Re-purposing of FDA approved drugs
0 10 20 30 40 500
10
20
30
40 Vehicle
Palbociclib
days
tum
or
siz
e r
ati
o
Palbociclib: CDK4/6 inhibitor
ERBB2 FGFR3
1 6 11 14 19 230
10
20
30 Vehicle
BGJ398 (30 mg/kg, B.W.)
Drug treatment (Days)
Lapatinib (30 mg/kg, B.W.)
Tu
mo
r R
ati
o
Lapatinib: ERBB2/3 inhibitor
Elucidation of resistance mechanisms Overcoming resistance
1 4 8 12 15 170
5
10
15
20Vehicle
FGFR3 inhibitor
Drug treatment (Days)
PDX: BL0293
Tu
mo
r R
ati
o
Biopsy
Re-transplant
and expansion
Biopsy
Applications of PDMCs -Drug development
Slides are the property of the author. Permission required for reuse.
Bladder cancer-specific PLZ4-nanoparticles (Kit Lam, MD, PhD)
Treatment OS (days)
WBC
(K/ml)
PBS 11 3.96±1.40
PTX 10mg/kg 27 1.16±0.19
PLZ4-NP-PTX 10
mg/kg 24 2.03±0.81*
PLZ4-NP-PTX 30
mg/kg >70 1.08±0.28
0 5 10 15 20 25 30 35 40 45 500.0
2.5
5.0
7.5
10.0
PBS PTX 10 mg/Kg
PLZ4-NM-PTX 10mg/Kg PLZ4-NM-PTX 30mg/Kg
Days After First Treatment
Tu
mo
r ra
tio
In vivo anti-tumor activity
In vivo delivery: left: Lung; Right: bladder In vitro delivery Nanoparticle
IND No: 117868
1. Photodynamic diagnosis 2. Photodynamic therapy
3. Photothermal therapy 4. Chelation of Gd(III) for MRI
5. Chelation of 64Cu for PET 6. Chelation of 67Cu for radiation therapy
7. Targeted delivery of chemo 8. Chelation of gallium for sonodynamic Tx
9. Near infrared imaging 10. combination of the above
Li et al. Nature Communication. 2014
Lin et al. Biomaterials. 2016
-Smart “9-in-1” PLZ4-nanoporphyrin
Slides are the property of the author. Permission required for reuse.
Polyethylene glycol
PLZ4-NP targets and deliver chelated metal to the cancer site
Applications of PDMCs -Drug development
PLZ4-nanoporphyrin
PNP 5637-DiO labeled Phase NIRF DAPI (nucleus) Merge Hema3TM
BL
269 P
DX
N
orm
al
bla
dd
er
Ur
o
Uro
BL269
Ur
o
40x
0 5 10 15 20 25 30 35
0
2000
4000
6000
Normal Urothelial
BL269
*
***
** ****
Human bladder cancer cell line 5637 Human patient-derived xenograft
Slides are the property of the author. Permission required for reuse.
Control DOX PNP+L
B m
ode
contr
ast
mode
Bla
dder
Gro
ss
Photodynamic therapy
Photodynamic diagnosis 30-40X difference
2-3X for 5-ALA
Tumor temperature
0 100 20030
40
50
60
70 NPsControl
Light on
Time (s)
Te
mp
era
ture
(oC
)
Photothermal therapy
Applications of PDMCs -Drug development
Pre-IND: 132838
PLZ4-nanotheranostics -PLZ4-nanoporphrin
• PLZ4-nanoporphyrin kills cancer cells and release tumor antigens;
• Photodynamic therapy (PDT) produces reactive oxygen species (ROS) which can modify macromolecules, and make them more immunogenic.
• Heat from photothermal therapy (PTT) denatures macromolecules and makes them more immunogenic.
• PDT is more effective than radiation in potentiate immunotherapy.
• PDT has been used in bladder cancer. But the photosensitizer has low efficiency, low potent, nonspecific (Cancer : normal ratio: 2-3 times), and high toxicity.
PLZ4-nanoporphrin to potentiate immunotherapy
PLZ4-nanotheranostics -PLZ4-nanoporphrin to potentiate immunotherapy
Creation of bilateral syngrafts: Cells: MB49 Mice: C57BL/6
Intravenous injection of PNP
Photodynamic therapy of the left tumor
Monitoring growth of the right tumor
PLZ4-nanotheranostics -Photothermal and targeted chemotherapy
Ig G PNP + light RMP1-14 RMP 1-
14+PNP+light
10X
40X
0 4 8 120
4
8
12
PNP+L
PBS
PNP+L+PD1
PD1
IgG
days
Tu
mo
r G
row
th R
atio
Growth of the distant tumor (not treated with light)
Photodynamic therapy converts “cold” tumor to “hot” tumor
150 1000
Cancer-specific drug delivery
PLZ4-nanotheranostics -PLZ4-nanoporphrin to potentiate immunotherapy
PLZ4-nanoporphrin to potentiate immunotherapy -SV40T/Ras double transgenic mice
20-30 days Palpable mass MRI to confirm
Treatment: PD1: 200 µg/mouse, i.p., weekly PNP: i.v., weekly, plus light (0.2 w, 3 min) Tumor measurement: MRI/T2
Treatment: 1. Control 2. Anti-PD1 Ab 3. PNP + light 4. Anti-PD1 Ab +
PNP + light
1. Clinical followup
2. MRI 3. Molecular
correlative studies
Mice were obtained from Xue-Ru Wu at New York University.
PLZ4-nanotheranostics -PLZ4-nanoporphrin to potentiate immunotherapy
Groups Ear Tag# Date of Death Overall survival Current Status
Control
#539 #150
#1191 #2032 #1737
01/09/2018 01/10/2018 02/03/2018 02/24/2018 03/22/2018
31 days 28 days 36 days 23 days 37 days
Dead Dead Dead Dead Dead
Anti-PD1 antibody
#536 #542
01/16/2018 01/16/2018
38 days 38 days
Dead Dead
PDT and PTT
#560 #581 #582
#1791 #1783
01/07/2018 02/08/2018 03/16/2018 03/21/2018 04/12/2018
31 days 34 days 55 days 45 days 67 days
Dead Dead Dead Dead Dead
Anti-PD1 antibody + PDT + PTT
#1994 #535 #538
Alive Alive
03/08/2018
52 days 150 days 90 days
Study ongoing Study ongoing
Dead
Mice were obtained from Xue-Ru Wu at New York Univ.
PLZ4-nanotheranostics -PLZ4-nanoporphrin to potentiate immunotherapy
MRI to evaluate tumor growth
Control
Anti-PD1
PNP PDT
Anti-PD1 +
PNP PDT
Applications of PDMCs -Biomarker development
Slides are the property of the author. Permission required for reuse.
DNA adducts as a biomarker for chemoresistance to alkylating agents: • Platinum agents (cisplatin, carboplatin and oxaliplatin) kill
cancer cells through induction of DNA damage (adducts)
• Cells with high Pt-DNA adducts will be killed by chemotherapy, and are chemosensitive.
• We developed a microdosing approach to measuring DNA adducts after a non-toxic microdose of 14C-drug
Microdosing -Accelerator Mass Spectrometry (AMS)
Slides are the property of the author. Permission required for reuse.
• Carbon-14 dating to determine the age of fossils
• Measure 14C at 10-21 mole in mg-size specimens
• 14C-labeled drug: one drug molecule per cell in 105 cells
• Because of the ultrasensitivity, cells and patients are treated
with one non-toxic microdose of 14C-labeled drug to allow
the detection of DNA damage and chemoresistance
*
*
1) DNA
2) Cancer cells
Pt
H3N NH3
Diadducts
HOOC
HOOC
* +
[*14C]carboplatin
Accelerator Mass Spectrometry (AMS)
Study of chemoresistance -Microdosing technology
Slides are the property of the author. Permission required for reuse.
Low DNA adduct levels correlate with chemoresistance -Bladder cancer patient-derived xenografts (PDX)
Carboplatin microdosingNSG model comparison
BL0269 BL0293 BL0440 BL0645
*********
rela
tive c
arb
op
lati
n
ad
du
ct
level
BL0269 Tumor Response
0 10 20 30 40 500
500
1000
1500
2000
Group 1 - Vehicle
Group 2 - Cisplatin
Group 3 - Gemcitabine
Group 4 - Cisplatin & Gem
Days(Day 0 = treatment initiation)
Mean
tu
mo
r vo
lum
e (
mm
3+
/-S
E)
BL0440 Tumor Response
0 20 40 60 800
500
1000
1500
2000
2500
Group 1 - Vehicle
Group 2 - Cisplatin
Group 3 - Gemcitabine
Group 4 - Cisplatin & Gem
Days(Day 0 = treatment initiation)
Mean
tu
mo
r vo
lum
e (
mm
3+
/-S
E)
BL0293 Tumor Response
0 20 40 60 800
500
1000
1500
2000
Group 1 - Vehicle
Group 2 - Cisplatin
Group 3 - Gemcitabine
Group 4 - Cisplatin & Gem
Days(Day 0 = treatment initiation)
Mean
tu
mo
r vo
lum
e (
mm
3+
/-S
E)
Sensitive
Study of chemoresistance -Microdosing Clinical Trial
Bladder cancer and NSCLC
Phase 0 study: One microdose (1/100th) of 14C-carboplatin:
1. PK study (drug metabolism);
2. DNA adducts of PBMC.
3. Repair of DNA adducts in cultured PBMC.
4. DNA adducts in bladder cancer specimens from TURBT
Off-study therapeutic chemo with platinum chemotherapy
1. Evaluate response, and correlate with DNA damage and repair, PK, cell uptake and efflux,.
2. Molecular correlation (such as ERCC and XRCC)
A Phase 0 microdosing trial
Clinicaltrials.gov: NCT01261299; NCT02077998. PIs: Pan
Study of chemoresistance -Microdosing Clinical Trial
Slides are the property of the author. Permission required for reuse.
PK-all patients
500 1000 1500 2000-20000
0
20000
40000
60000
80000
100000#1 micro
#1 Tx
#2 Micro
#3 Micro
#4 Micro
#5 Micro
#6 Micro
#7 Micro
#8 Micro
#8 Tx
#9 MicroDNA Damage in PBMC over 24 hours-all patients
500 1000 1500 2000
-1
0
1
2
3
4#1 Micro
#2 Micro
#3 Micro
#4 Micro
#5 Micro
#6 Micro
#7 Micro
#8 Micro
1. 24 hr is the best time for biopsy/sampling 2. Microdosing predicts PK of therapeutic dosing 3. High DNA adduct levels correlate to response Why two pts with low DNA adducts responded? Is this because of the chemo partner drug?
Carboplatin plasma concentration
Therapeutic [g/mL]
Mic
rod
ose [
g/m
L]
0 10 20 30 40
0.0
0.1
0.2
0.3
0.4patient 1patient 8
patient 10
p < 0.0001
R2 0.8076
24h PBMC
Bladder Lung0.0
0.5
1.0
1.5
Responder
Non-Responder
Carb
op
lati
n
Mo
no
ad
du
cts
/10
8 n
t
Study of chemoresistance -Gemcitabine microdosing study
Slides are the property of the author. Permission required for reuse.
• Nucleoside analog
• Incorporation into DNA and block DNA replication
• Inhibits ribonucleotide reductase
• Combine with platinum for bladder cancer
• The level of gemcitabine in DNA correlates with cellular sensitivity to gemcitabine
• Using 3H- or 14C-labeled gemcitabine, the AMS-based microdosing approach may be able to measure the incorporation of gemcitabine into DNA and identify chemoresistance.
Study of chemoresistance -Microdosing -Gemcitabine
Slides are the property of the author. Permission required for reuse.
BL0269 Survival
0 20 40 60 800
25
50
75
100
125 Control
Carboplatin
Gemcitabine
Gem/Carbo
Days(Day 0 = treatment initiation)
% S
urv
iva
l
BL0293 Survival
0 20 40 60 800
25
50
75
100
125 Control
Carboplatin
Gemcitabine
Gem/Carbo
Days(Day 1 = treatment initiation)
% S
urv
iva
l
BL0440 Survival
0 20 40 60 800
25
50
75
100
125Control
Carboplatin
Gemcitabine
Gem/Carbo
Days(Day 1 = treatment initiation)
% S
urv
ival
BL0645 Survival proportions
0 20 40 60 800
25
50
75
100
125Control
Carboplatin
Gemcitabine
Gem/Carbo
Days(Day 1 = treatment initiation)
Tu
mo
r S
pecif
ic S
urv
ival
BL0269 BL0293 BL0440 BL06450
5
10
15
20
25
24h Gemcitabine microdosing
***
*
**
Gem
cit
ab
ine
Ad
du
cts
/10
8 n
t
BL0293 [14C]GemcitabineMicrodosing
4h 24h0
5
10
15 BL0293
BL0293R
p < 0.0001
p = 0.018
Gem
cit
ab
ine
Ad
du
cts
/10
8 n
t
BL0293 Gemcitabine Response
0 20 40 60 800
1
2
3
4
5 BL0293
BL0293R
PFS [days]:BL0293:BL0293R:
183
Days(Day 1 = treatment initiation)
Tu
mo
r vo
lum
e ra
tio
sensitive
sensitive
Resistant
Resistant
Low gemcitabine incorporation in DNA correlated with resistance
PDXs for Personalized therapy Summary
Slides are the property of the author. Permission required for reuse.
1. We have established over 30 Bladder cancer PDX
models;
2. PDXs retain the morphology and genetic aberrations of
parental patient cancers;
3. Deep sequencing identified multiple druggable targets;
4. PDX platform can potentially be used for: screening
for effective targeted therapy, chemotherapy, drug re-
purposing, replacing the role of serial biopsies to study
secondary drug resistance, facilitating drug
development, and developing biomarkers;
Acknowledgements
Lab: Chong-xian Pan. MD, PhD
Paul Henderson, PhD (Co-PI)
Ai-hong Ma, MD, PhD
Hongyong Zhang, DVM, PhD
Tzu-Yin (Cindy) Lin, DVM, PhD
Maike Zimmermann, PhD
Tifffany Scharadin, PhD
Weiming Yu, MD
Wei Shi MD
Shuxong Zeng, MD
Former lab members: Qilai Long, MD
Shuai Jiang, MD, PhD
Fuli Wang, MD
Sisi Wang, MD, PhD
Tao Li, PhD
Yanchun Wang, PhD
Miaoling He, BA
Financial Support: Dr. de Vere White’s philanthropic funding, R01, DoD, VA Merit grants and others.
Acknowledgements
PLZ4 project Kit S. Lam, MD, PhD: Yuanpei Li, PhD and their labs
UC Davis-others Ralph de Vere White, MD Christopher Evans, MD Primo Lara MD Marc Dall’Era MD Stanley Yap, MD Richard Valicenti MD Regina Gandour-Edward, MD Clifford Tepper, PhD EyePOD PDX
Edward Pugh, PhD Kit S Lam, MD, PHD
PDX Project Jackson Laboratory: Edison Liu MD Susie Airhart Carol Bult, PhD James Keck, PhD
Microchamber Project Alex Revzin Pantea Gheibi
PDXs for Personalized therapy Microchamber to complement PDXs
Slides are the property of the author. Permission required for reuse.
Drawbacks of PDX:
• Long time to develop P0 PDXs (4-6 mo);
• engraftment rate: 40%
• Expensive
Microchamber organoid cultures to complement PDXs
PDXs for Personalized therapy Microchamber to complement PDXs
Slides are the property of the author. Permission required for reuse.
Glass
slide
Cell Input/ Media reservoirs (500 µl)
Cell culture micro-
culture (1 µl)
Microchamber culture to complement PDXs (Originally developed for culture of hepatocytes)
Microchambers (µC, Alex Revzin) :
• Biocompatible • Optically transparent • Excellent oxygen transport • Accumulation of endogenous factors • Enhancement of autocrine and
paracrine signals • Long-term function maintenance of
difficult-to-culture cells (ex. Primary hepatocytes and mESC (mouse Embryonic Stem Cells))
> 2
mm
Matrigel Suspension Microchamber
75
µ
m
PDMS
PDXs for Personalized therapy Microchamber to complement PDXs
Slides are the property of the author. Permission required for reuse.
BL0
90
8 o
rgan
oid
s in
m
icro
cham
ber
s Day 3 Day 9 Day 7 Day 5 Day 1
DAPI
Actin
Merged Merged
Anti-pan cytokeratin
DAPI
BL0908 organoids on day 9
Patient specimen
PDX
BL0
26
9
BL0
44
0
D3 D5 D7 D9
Ki67
DAPI
Merged
DAPI
Merged Merged
DAPI
pan Cytokeratin
F-actin
PDXs for Personalized therapy Microchamber to complement PDXs
Slides are the property of the author. Permission required for reuse.
a.
0
1
2
3
4
5
6
7
8
9
D10 D12 D14 D16 D18 D20 D22 D24 D26 D28 D30
Rel
ativ
e gr
ow
th r
atio
Culture Duration (days)
BL0269 growth in microchamber
Ce
nte
r
Ou
ter
rim
DAPI F-actin Ki67 Middle Section
DA
PI
pan
-Cyt
oke
rati
n
BL0269 (D30)
b.
Cell growth is mainly at the edge of cell mass.
PDXs for Personalized therapy Microchamber to complement PDXs
Slides are the property of the author. Permission required for reuse.
Init
ial
D2
D
4
GDC-0941 Gemcitabine Cisplatin
BL0269 (Standard) in Microchambers
b. a.
Efficacy studies -BL0269 with a PI3K mutation
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Initial D2 D4
Exposure Duration (day)
Rel
ativ
e gr
ow
th r
atio
BL0269 (Standard) Drug Response Control
Cisplatin
Gemcitabine
Cisplatin + Gemcitabine
GDC 0941
Triple Combination *
*
*
*
*
PDXs for Personalized therapy Microchamber to complement PDXs
Slides are the property of the author. Permission required for reuse.
0
0.2
0.4
0.6
0.8
1
1.2
1.4
D10 D12 D14 D16 D16 D18 D20 D22 D22 D24 D26 D28 D28 D30
GDC−0941 Recovery GDC−0941 Recovery GDC−0941 Recovery GDC−0941
1st Exposure 2nd Exposure 3rd Exposure 4thExposure
Rel
ativ
e gr
ow
th r
atio
* * * *
d.
e.
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
0 1 2 3 4 5 6 7 8 9 10 11 12
Rel
ativ
e gr
ow
th r
atio
Culture Duration (day)
S1
D22 D24 D26 D28 D30 D10
f.
D12 D14 D16 D18 D20
D0 D10
Standard Media
+GDC-0941
D12 D16
+GDC-0941
D18 D22
+GDC-0941
D24
Standard Media
+GDC-0941
D28 D30
Standard Media Standard Media
Tumor heterogeneity
PLZ4-nanotheranostics -Summary
1. PLZ4 specifically binds to human and dog bladder cancer cells
2. Nanomicelles coated with PLZ4 can specifically deliver the
drug load to bladder cancer in vitro and in vivo.
3. Micelle formulation of PTX significantly decreases the toxicity
and prolongs the overall survival in mice carrying PDXs.
4. PLZ4 nanoporphyrin can be potentially used for PDD, PDT,
PET, MRI, photothermal therapy, radiation, targeted
chemotherapy and combination of the above.
5. Combination of PNP and immunotherapy