Patient-Derived Tumor Xenograft Models

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1 Patient-Derived Tumor Xenograft Models An emerging way to personalized medicine in translational cancer research Webinar Taconic Leuven, 10/03/2016 Department of Oncology, UZ Leuven KU Leuven Els Hermans, DVM

2 Establishment Quality control & characterization Applications Drawbacks

3 Problem in Cancer R&D Pre-Clinical Phase Clinical Phase Economical and ethical impact Arrowsmith J and Miller P, Nat Rev Drug Discov 2013

4 How can we improve the efficiency of drug development in oncology? Use preclinical models which more closely recapitulate the heterogeneity of human cancers Perform studies for genotype /response correlation on a population scale, to achieve scientific solidity. Couzin-Frankel J, Science 2014

5 An emerging platform in translational cancer research

6 Patient-Derived Tumor Xenograft To improve accuracy and accelerate R&D in oncology Based on National Cancer Plan Grant End 2012 Platform in UZ Leuven KU Leuven in collaboration with other hosiptals and research institutes

7 Introduction Quality control & characterization Applications Drawbacks

8 One mouse, one patient paradigm: new avatars of personalised cancer therapy Malaney P.; Cancer Lett, 2013

9 PDX PATIENT ESTABLISHMENT OF PDXS Transplantation of tumor biopsy in immunocompromised mice over different passages Tumor take rate: 60% Tumor biopsies FNB STORAGE OF PDXS PDX Tissue: FFPE, snap frozen, cryopreserved Frozen & Viable Biobank PDX ANNOTATION Clinical data Preclinical data Histopathology Genomics and/or transcriptomics Pharmacologic analysis QUALITY CONTROL Histology SNP-Based Fingerprinting APPLICATION OF PDXS Pre-clinical drug screening Biomarker analysis Identify sensitivity/resistance mechanisms

10 Develop a new systematic approach to evaluate response to targeted therapy Delineate new avenues for intervention in managing a variety of cancers

11 Input Future: Centre Hospitalier Universitaire de Liège, Universitair ziekenhuis Brussel, Universiteit Gent, Universiteit Antwerpen? Prostate cancer Ovarian cancer Endometrial cancer & Uterine sarcoma Pancreatic cancer Melanoma Breast cancer Colorectal cancer Lymphoma Head & neck cancer Meningioma

12 Number of Tumors (tumor types=11) Implanted (244) Engrafted (123)

13

14 Individual Ventilated Cages (IVC)

15 Introduction Establishment Applications Drawbacks

16 Quality control & characterization Characterization Patient (F0) Validation of PDX Model Tumor tissue in different conditions & therapy response Engraftment Phase (F1) Expansion Phase (F2) Validation Phase (F3)

17 Endometrial Carcinoma Mesonefric Serous Endometrioid F0 - Humane F1 - PDTX F3 - PDTX Depreeuw J. et al, Gynaecologic Oncology 2015

18 Specific markers: tumor type PDX PDAC003 Pancreatic Ductal Adenocarcinoma PDX EMC016 Endometrioid endometrial carcinoma, grade 2 Cytokeratin CK7 20x F0 - Humane F3 - PDTX Human progesterone receptor 20x F0 - Humane F3 - PDTX PDX OVC005 Serous ovarian carcinoma, grade 3 PDX BRC008 Breast Invasive Ductal Adenocarcinoma Human WT-1 20x HER2 20x F0 - Humane F3 - PDTX F0 - Humane F3 - PDTX

19 A B C Specific markers: Micro-environment F0 - Humane F1 - PDTX F1 - PDTX F3 - PDTX F3 - PDTX MT huvim mucd31 Pancreas cancer

20 Genetic profile: Shallow Sequencing Similarity between human tumor & xenograft: % Endometrial cancer Depreeuw J. et al, Gynaecologic Oncology 2015

21 Genetic profile: Whole Exome Sequencing (): Cancer Consensus Genes Endometrial cancer Depreeuw J. et al, Gynaecologic Oncology 2015

22 Clonal dynamics over multiple passages in time Clonal dynamics are reproduced in replicate transplants Eirew P, Nature 2014

23 Transcription profile: RNA Sequencing PRO gene list (764) (Verfaillie et al. 2015) INV gene list (591) (Verfaillie et al. 2015) Melanoma Unpublished data by Rambow F, Lab. Of Molecular Cancer Biology

24 Transcription profile: RNA Sequencing Isella et al, Nature genetics, 2015

25 Unpublished data by Annibali D, Translat. Research GNC Pharmacologic validation Tumor ID OVC-020 Stage Treatment Note FIGO IIIb TC 3w (6 cycles) Last 29/11/2013 On AMG386/placebo Till Dec 2014 Relapse(!) Primary tumor Surgery 16/07/2013 Tumor ID Stage Treatment Note OVC-002 FIGO Ic Several TC 3w (6 cycles) From 2004 till Nov 2012 partial remission Olaparib (2013) -- Progr Recurrence Surgery 6/11/ PDTX OVC PDTX OVC-002 Tumor Volume (mm3) Veh Carbo Tumor Volume (mm3) Carbo Veh 0 t0 d4 d7 d10 d14 d17 d21 0 t0 d4 d7 d10 d14 d17 d21

26 Introduction Establishment Quality control & characterization Drawbacks

27 PRE-CLINICAL DRUG SCREENING AND BIOMARKER ANALYSIS CO-CLINICAL TRIAL APPROACH PERSONALIZED MEDICINE STRATEGY ESTABLISHMENT OF PDXS DEVELOP HUMANIZED XENOGRAFT MICE

28 PRE-CLINICAL DRUG SCREENING AND BIOMARKER ANALYSIS CO-CLINICAL TRIAL APPROACH PERSONALIZED MEDICINE STRATEGY ESTABLISHMENT OF PDXS DEVELOP HUMANIZED XENOGRAFT MICE

29 Proposed preclinical screening and biomarker study in PDX models. Hidalgo M et al. Cancer Discovery 2014;4: by American Association for Cancer Research

30 Proposed preclinical screening and biomarker study in PDX models. Hidalgo M et al. Cancer Discovery 2014;4: by American Association for Cancer Research

31 Proposed preclinical screening and biomarker study in PDX models. Hidalgo M et al. Cancer Discovery 2014;4: by American Association for Cancer Research

32 Population-based preclinical drug screening and biomarker analysis Nature, 2015 Link treatment response of PDX & patient to mutational data Identify mechanisms of sensitivity - primary and secondary resistance to targeted therapy Define combination therapy in PDX to overcome resistance The Novartis approach: A proof of concept Nature, ,075 PDX models One animal per model per treatment (1x1x1) approach Population response for 62 treatments across 6 indications

33 Unpublished data by Cuppens T., Translat. Research GNC Searching for therapeutic targets in uterine sarcoma Comprehensive NGS project IHC for known targets In vivo treatment experiments using patient-derived models

34 Unpublished data by Cuppens T., Translat. Research GNC MOUSE CLINICAL TRIAL A dual PI3K/mTOR inhibitor A chemotherapy Combined treatment (PI3K/mTORi and chemo) Placebo Chemo Yondelis BEZ235 PI3K/mTORi Chemo Yondelis+BEZ235 PI3K/mTORi Tumor volume (mm³) EMC036 EMC EMC050 EMC Time (days) * Tumor volume (mm³) Time (days) * Tumor volume (mm³) * Time (days) Tumor volume (mm³) Time (days) * CONCLUSION Combination of chemo and PI3K/mTOR: no synergistic effects Do primary tumors respond better to PI3K/mTORi and chemo than recurrent tumors?

35 PRE-CLINICAL DRUG SCREENING AND BIOMARKER ANALYSIS CO-CLINICAL TRIAL APPROACH PERSONALIZED MEDICINE STRATEGY ESTABLISHMENT OF PDXS DEVELOP HUMANIZED XENOGRAFT MICE

36 Co-clinical trial approach with PDX models. Hidalgo M, Amant F. et al. Cancer Discovery 2014

37 Co-clinical trial approach with PDX models. Hidalgo M, Amant F. et al. Cancer Discovery 2014

38 Co-clinical trial approach with PDX models. Hidalgo M, Amant F. et al. Cancer Discovery 2014

39 Co-clinical trial approach with PDX models. Hidalgo M, Amant F. et al. Cancer Discovery 2014

40 Cell cultures Organoids Commercial Cell lines Primary Cell Culture PDCs PDXs Or RESISTANT SENSITIVE OBJECTIVES Investigation of resistance mechanism of action Development of new strategies to overcome resistance Design of novel and effective personalized targeted therapies

41 PRE-CLINICAL DRUG SCREENING AND BIOMARKER ANALYSIS CO-CLINICAL TRIAL APPROACH PERSONALIZED MEDICINE STRATEGY ESTABLISHMENT OF PDXS DEVELOP HUMANIZED XENOGRAFT MICE

42 Personalized medicine strategy. Hidalgo M, Amant F. et al. Cancer Discovery 2014

43 Personalized medicine strategy. Hidalgo M, Amant F. et al. Cancer Discovery 2014

44 Personalized medicine strategy. Hidalgo M, Amant F. et al. Cancer Discovery 2014

45 Personalized medicine strategy. Hidalgo M, Amant F. et al. Cancer Discovery 2014

46 Personalized medicine strategy. Hidalgo M, Amant F. et al. Cancer Discovery 2014

47 Personalized medicine strategy. Hidalgo M, Amant F. et al. Cancer Discovery 2014

48 PRE-CLINICAL DRUG SCREENING AND BIOMARKER ANALYSIS CO-CLINICAL TRIAL APPROACH PERSONALIZED MEDICINE STRATEGY ESTABLISHMENT OF PDXS DEVELOP HUMANIZED XENOGRAFT MICE

49 GOAL: Reconstitution of human immune system and cotransplantation of a PDX to allow preclinical testing of drugs targeting immune-checkpoints and humane T cell function Polymorphic SIRP-α Complement C5 Deficient Impaired Dendritic cell Function Impaired Macrophage Function NOD.Cg-Prkdc scid Il2rg tm1sug /JicTac B and T cell Deficient NK cell Deficient Impaired cytokine signaling

50 Introduction Establishment Quality control & characterization Applications

51 Drawbacks Lack of immune system of host Substitution of human stroma by murine tissue Engraftment failure: % Human stroma: brown (Endometrioid Endometrial Carcinoma) Cost & resources Human stroma: brown Replaced by murine stroma: grey

52

53 Innovative strategy in R&D Oncology Experimental data Pre-Clinical Phase PDX Clinical data Clinical Phase TCGA/CGP: Descriptive data Cost saving & increase patient OS/DFS

54 Trace Frédéric Amant Debby Thomas Ellen Gommé Marie-Astrid Van Hoorick Lab. Translational Gynaecologic Oncology: Daniela Annibali Tine Cuppens - Jeroen Depreeuw Stijn Moens Tom Van Nyen - Jelle Stans Carmen Andreu Oller Diether Lambrechts - Enrico Radaelli - Thomas Tousseyn Daan Dierickx Julie Morscio - Schalk van der Merwe Baki Topal Tania Roskams Hugo Vankelecom - Jean-Pascal Machiels Roxana Albu Ilse Gutierrez Fiona Burnotti Mathieu Luyckx Martine Berlière Francois Duhoux Paul Clement Vincent Vander Poorten Esther Hauben Marguerite Stas Pascal Wolter Jean-Christophe Marine Eleonora Leucci Karen Wilkens Aljosja Rogiers Florian Rambow - Joost van den Oord Lorenzo Tosco Christine Helsen Steven Joniau Evelien Lerut Frank Claessens Johan Swinnen - Marie-Rose Christiaens Patrick Neven Hans Wildiers Karin Leunen Ann Smeets Ignace Vergote Giuseppe Floris Philippe Moerman Sabine Tejpar Eric Van Cutsem Anna Sablina Jonathan Crowther -

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