PDX AS AN ESTABLISHED IN-VIVO MODEL FOR PANCREATIC CANCER Golan - - PowerPoint PPT Presentation

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PDX AS AN ESTABLISHED IN-VIVO MODEL FOR PANCREATIC CANCER Golan Lab, Sheba Medical Center Daniel Yehuda, Arrow project student June, 2018 Targeted Treatment- pharmacology Experiment the Appropriate new drugs and treatment for the Well

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PDX AS AN ESTABLISHED IN-VIVO MODEL FOR PANCREATIC CANCER

Daniel Yehuda, Arrow project student Golan Lab, Sheba Medical Center

June, 2018

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Targeted Treatment- pharmacology Appropriate treatment for the individual patient New Targets Disease biology Experiment the new drugs and therapy

Well Established Representing Model

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The model

PDX IN-VIVO MODEL FOR PANCREATIC CANCER

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What was the alternative?

“When evaluating our approach to target discovery, we should consider if our current, powerful genomic technologies are being used on model systems that have poor clinical predictive power(…) (…) The selective pressure of cell culture allows the least differentiated cells to thrive, resulting in distinct and irreversible losses of important biological properties ”

Patient-Derived Tumor Xenografts: Transforming Clinical Samples into Mouse Models Despina Siolas and Gregory J. Hannon 10.1158/0008-5472.CAN-13-1069 Published September 2013

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My Project Aims

To further assist in the establishment and

characterization of the PDX model as a preclinical model “mimicking” pancreatic cancer.

To develop a pancreatic cancer clinical data base

that will enable a translational study in the future

To investigate the correlation between the clinical

disease course and the PDX model characteristics.

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PDX model and its Clinical Correlations hypothesis

The PDX model is a preclinical model that “mimics”

pancreatic cancer (Morphologically and gnomically).

We gather data regarding 4 aspects:

– In-Vivo model – Clinical data – Histological characteristics – Genomic characteristics

Hypothesis: the model characteristics correlate with

the biological features and the clinical course of the disease.

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Core needle biopsy (Liver metastases) PDX

400 800 1200 1600 30 60 90 120 150 180 Tumor volume (mm3) Days post cell injection

73.2 86.2 87.2 90.1 99.2 105.3 116.3 144.1

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Histologically classified 47 first generation

PDX.

We created a clinical data base.

Methods

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Clinical data base

Diagnosis- date, stage
Treatment- dates, reaction to treatment, surgery, type
f treatment
Past medical history and co morbidity
Well being- He
hight, weight, sleeping habits
Habits- alcohol use, drug use, physical activity
Family history
BRCA status
Overall survival
Metastatic disease survival

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PDX model and its Clinical Correlations Methods- Clinical Aspect

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Introduction- PDAC

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PDX model and its Clinical Correlations Methods- Histological Aspect

Ascites/pleural PDX – F1 generation H&E HLA Masson’s trichome

Pt. 87

Patients clinical samples Cell block Liver biopsy

Pt. 86

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PDX model and its Clinical Correlations Methods- summary

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47 patients > Xeno 1 PDX’s.
Minimal tumor volume of 1000 mm*3.

Methods

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The population

clinical course In Vivo Growth In Vivo Growth

49 PDX’s of 47 Pts.

39 PDX’s reached minimal volume 37 PDX’s of 37 pts. 30 Pts. Died 7 Pt. alive with disease (AWD)

2 Mice – different kinetics.

10 PDX’s excluded

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The population

Clinical Aspects

3 4 30

Stage At Diagnosis n=37

IIB III IV 10 6 2 19

BRCA Status n=37

BRCA BRCAness NOT TESTED WT Stage at diagnosis Median OS (Months) median time of metastatic disease (Months) IIB 28 13 III 13.50 IV 6.5

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The population

In- Vivo Aspects

14 17 1 4 1

Tissue Origin n=37

As Liver Mesenterium Pancreas PE

2 12 10 7 1 1 5 10 15 20 25 Naïve Resistant

Clinical Time of Tissue Acqusition

Pancreas Liver As

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Limitations

PDX’s that underwent sacrifice before

reaching the minimal size.

Different cell number in the first injected

tumor tissue/cells.

Different tissue origin.

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Objectives

To investigate the correlation between the clinical

disease course and the PDX model characteristics (histologic & In vivo growth)

– Time to sacrifice vs. Overall survival – Does Necrosis (%) correlate with Time to sacrifice? – Does glands forming cells (%) correlate with Time to sacrifice? – Does Stage at Diagnosis correlate with the spread level in PDX (invasive/remote)?

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Results

20 40 60 80 100 120 < 10 11-25 26-50 50 > 50

Average Time to sacrifice % of necrosis

Averge Time to Sacrifice vs. % of Necrosis

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Results

20 40 60 80 100 120 140

< 25 50 > 50 > 75

Average Time to Sacrifice

f Glands forming cells %

Average Time to Sacrifice vs. % of Glands forming cells

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Results

5 10 15 20 25 30 35 40 0.00 20.00 40.00 60.00 80.00 100.00 120.00 140.00 160.00 180.00 200.00

Metastatic disease survival (months) Time To Sacrifice (days)

Metastatic disease survival vs. Time to Sacrifice Ascites Origin

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Results

5 10 15 20 25 30

0.00 50.00 100.00 150.00 200.00 250.00 300.00

Metastatic disease survival (months)

Time To Sacrifice (days)

Metastatic disease survival vs. Time to Sacrifice

Liver Origin

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Results

5 10 15 20 25 30 35

IIB III IV

num. of PDX’s

Stage at diagnosis

Stage at Diagnosis vs. spread In-vivo

no spred locally invasive involved Lymph nodes

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In the future

We need to expand our cohort .
Automatization of our histologic

characterization is the next point to investigate.

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Thank you!

Dr. Talia Golan

Dikla Atias Sharon Halperin Maria Raitses-Gurevich Yulia Glick-Gorman Sally Zisman

Dr. Michael Schvimer, Pathologist

Liat Ashkenazi

Arrow Project

Prof. Anat Achiron
Mrs. Yaffit Rot