patient derived xenograft models ---clinical applications...lapatinib (30 mg/kgb.w.) sorafenib (20...

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

http://uscnorriscancer.usc.edu/about/nci_designation/

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=4lgPRDC4fv6iWM&tbnid=k7dA-1N2ETeQDM:&ved=0CAUQjRw&url=http://www.eventbrite.com/org/2322839851&ei=pBZcUtiPO-WOiAKr4YDgCw&bvm=bv.53899372,d.cGE&psig=AFQjCNE97n1jCXImZCmSfqzBD9snF1xVYQ&ust=1381853215240887

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


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


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)




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


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


Applications of PDMCs


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


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)


0 20 40 60 800

500

1000

1500

2000

Group 1 - Vehicle

Group 2 - Cisplatin




Mean

tu

mo

r vo

lum

e (

mm

3+

/-S

E)


-20 0 20 40 60 80

500

1000

1500

Group 1 - Vehicle

Group 2 - Cisplatin




Mean

tu

mo

r vo

lum

e (

mm

3+

/-S

E)


-10 0 10 20 30 40 50

500

1000

1500

2000Group 1 - Vehicle

Group 2 - Cisplatin




Mean

tu

mo

r v

olu

me (

mm

3+

/-S

E)


0 20 40 60 800

500

1000

1500

2000

2500

Group 1 - Vehicle

Group 2 - Cisplatin




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.)


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


PDX: BL0293

Tu

mo

r R

ati

o

Biopsy

Re-transplant

and expansion

Biopsy

Applications of PDMCs -Drug development


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


Polyethylene glycol

PLZ4-NP targets and deliver chelated metal to the cancer site


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


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


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-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.


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.


MRI to evaluate tumor growth

Control

Anti-PD1

PNP PDT

Anti-PD1 +

PNP PDT

Applications of PDMCs -Biomarker development


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)


• 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


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


0 10 20 30 40 500

500

1000

1500

2000

Group 1 - Vehicle

Group 2 - Cisplatin




Mean

tu

mo

r vo

lum

e (

mm

3+

/-S

E)


0 20 40 60 800

500

1000

1500

2000

2500

Group 1 - Vehicle

Group 2 - Cisplatin




Mean

tu

mo

r vo

lum

e (

mm

3+

/-S

E)


0 20 40 60 800

500

1000

1500

2000

Group 1 - Vehicle

Group 2 - Cisplatin




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


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


• 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


BL0269 Survival

0 20 40 60 800

25

50

75

100

125 Control

Carboplatin

Gemcitabine

Gem/Carbo


% S

urv

iva

l

BL0293 Survival

0 20 40 60 800

25

50

75

100

125 Control

Carboplatin

Gemcitabine

Gem/Carbo


% S

urv

iva

l

BL0440 Survival

0 20 40 60 800

25

50

75

100

125Control

Carboplatin

Gemcitabine

Gem/Carbo


% S

urv

ival

BL0645 Survival proportions

0 20 40 60 800

25

50

75

100

125Control

Carboplatin

Gemcitabine

Gem/Carbo


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


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


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

Thank you very much!!!

Questions?

PDXs for Personalized therapy Microchamber to complement PDXs


Drawbacks of PDX:

• Long time to develop P0 PDXs (4-6 mo);

• engraftment rate: 40%

• Expensive

Microchamber organoid cultures to complement PDXs



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



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



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.



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 *

*

*

*

*



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

patient derived xenograft models ---clinical applications...lapatinib (30 mg/kgb.w.) sorafenib (20...

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