Personalized Medicine in Cancer. (Ph.D.)

Transcription

1 Personalized Medicine in Cancer Mohammad Ali Saremi Mohammad Ali Saremi (Ph.D.)

2 Personalized Medicine

3 Effectiveness of drugs:

4 Danger of drugs: 6.7% of patients in hospitals experience serious 6.7% of patients in hospitals experience serious drug reactions

5 Old Paradigm:

6 New Paradigm:

7 Future Paradigm:

8 P.M.

9 Pharmacogenomics Does one size really fit all?

10 Pharmacogenetics Study of genetic variation that gives rise to different responses to drugs It is estimated that genetics can account for 20 to 95 percent of variability in drug disposition and effects. Nongenetic factors include: age, organ function, concomitant therapy, drug interactions, and the nature of the disease.

11 Pharmacogenomics Under the PM Umbrella Better medication choices 100,000 Americans die annually and 2,000,000+ are hospitalized due to adverse reactions to medications Predict individual reactions to dugs Safer dosing options More exact dosing, optimum result/side effect balance Improvements in drug development Exclude genetic variations from certain clinical trials, speeding up drug design time

12 1. OncoDNA in a few words 2. What is OncoDEEP? 3. Case studies using OncoDEEP 4. What is OncoSHARE? 5. Aurora Program

13 Mission / Vision A better characterization of the patient and his disease for a better treatment establishment and follow-up OncoDNA is a Cancer Theranostics Company bringing a unique combination of the most relevant technologies (mostly Next Generation Sequencing (NGS) and protein biomarker analyses (IHC)) to support physician/oncologist with treatment regimen establishment Our goal is to predict and follow the response to anticancer drugs Our goal is to predict and follow the response to anticancer drugs with a comprehensive and integreted (genomic anatomopathologic) approach.

14 OncoDNA in a few words Creation: November 2012 Shareholders Institute of Pathology and Genetics (Gosselies & Brussels, Belgium) 280 people analyses / year 3 rd European laboratory for cancer analyses (anatomical pathology) Sambrinvest Regional Private Equity and Venture Capital Firm Business Angels Scientific Council Prof Martine Piccart - President of the European Society for Medical Oncology (ESMO) Prof Jaak Janssens - President at Interventional Oncology Society Dr Christos Sotiriou i - Head at Breast Cancer Translational l Laboratory J-C Heuson Prof Jean-Pascal Machiels - Centre du Cancer (UCL)

15 OncoDNA : key facts OncoDEEP DX (v2: 60 genes) and Clinical (409 genes) are ISO15189 accredited since 2013 (CE IVD marked and CLIA certification in process) Development of Package Plus based and updated with latest publications More than 1000 samples processed from 25 countries worldwide and of more than 40 cancer types Selected by Breast Interfor for the AURORA project (around 4000 samples from 1300 patients to be sequenced with OncoDEEP Clinical + BRCA1/2 + Small Breast Cancer Specific Package Plus) Proprietary algorithm for CNV detections recently published in Bioinformatics OncoDEEP DX v2 released end of Summer along with Fusion Gene Panel OncoTRACE (RUO): circulating tumoral DNA monitoring

16 From research to diagnostic : first diagnostic application Cancer : Multigenic Disease Huge expertise at IPG (3 rd European laboratory for cancer analyses) Cancer known to be a genomic disease Refers to at least 100 forms of disease The field for the development of perzonalized treatments Di ith hi h i id d Disease with very high incidence and mortality

17 What is OncoDEEP? Choice of the treatment after complete p molecular characterization of patient s tumor sample.

18 Cancer treatment history parallel to cancer knowledge development Early times of targeted therapies Target a specific identified cause of the cancer Growth signal inhibitors Angiogenesis inhibitors Apoptosis inducing drugs Example Chronic Myelogenous Leukemia (CML) BCR ABL Fusion Gene Imatinib (Gleevec)

19 Todays view on cancer molecular network and on drugs which could interact with these pathways for cancer treatment Cancer treatment history parallel to cancer knowledge development Oncologists Need a New Molecular Analysis Tool to mtor inhibitors PI3 kinase inhibitors Akt inhibitors Better IGF1R EGFR Characterize EGFR JAK KIT inhibitors inhibitors inhibitors inhibitors inhibitors PDGFR ERK ERBB2 STAT3 inhibitors Patient s inhibitors inhibitors Tumor inhibitors!! FGFR MEK ERBB3 Prostate Cancer: up and down inhibitors inhibitors inhibitors regulated molecularpathways ERBB4 network in diseased inhibitors conditions

20 What is OncoDEEP? NGS analysis + Package Plus IHC analyses + Additional analyses Dabrafenib BRAF V600E mutation positive Cetuximab EGFR protein expression positive Temozolomide MGMT promoter methylation

21 What is OncoDEEP? NGS analysis + Package Plus To search drug actionable mutations in the genome of tumoral cells

22 What is OncoDEEP? NGS analysis + Package Plus To search drug actionable mutations in the genome of tumoral cells Comprehensive and non supervised search for variants Using Next Generation Sequencing: Powerful and Sensitive method to search variants At very high coverage to help avoiding false positive and false negative Ion Torrent allows a very fast turn around time to allow fast treatment decision

23 What is OncoDEEP? ABL1 ABL2 ACVR2A ADAMTS20 AFF1 AFF3 AKAP9 AKT1 AKT1 AKT2 AKT2 AKT3 AKT3 ALK ALK AMER1 APC AR ARID1A ARID2 ARNT ARNT ASXL1 ASXL1 ATF1 ATF1 ATM ATM ATR ATR ATRX AURKA AURKB AURKC AXL AXL BAI3 BAI3 BAP1 BAP1 BCL10 BCL10 BCL11A BCL11A BCL11B BCL2 BCL2L1 BCL2L2 BCL3 BCL6 BCL9 BCL9 BCR BCR BIRC2 BIRC2 BIRC3 BIRC3 BIRC5 BLM BLNK BMPR1A BRAF BRD3 BRIP1 BRIP1 BTK BTK BUB1B BUB1B CARD11 CARD11 CASC5 CBL CCND1 CCND2 CCNE1 CD79A CD79B CDC73 CDC73 CDH1 CDH1 CDH11 CDH11 CDH2 CDH20 CDH5 CDK12 CDK4 CDK6 CDK8 CDK8 CDKN2A CDKN2B CDKN2B CDKN2C CDKN2C CEBPA CHEK1 CHEK2 CIC CKS1B CMPK1 COL1A1 CRBN CRBN CREB1 CREB1 CREBBP CREBBP CRKL CRTC1 CSF1R CSMD3 CTNNA1 CTNNB1 CYLD CYLD CYP2C19 CYP2D6 CYP2D6 DAXX DAXX DCC DCC DDB2 DDIT3 DDR2 DEK DICER1 DNMT3A DPYD DPYD DST DST EGFR EGFR EML4 EP300 EP400 EPHA3 EPHA7 EPHB1 EPHB4 EPHB6 EPHB6 ERBB2 ERBB2 ERBB3 ERBB3 ERBB4 ERCC1 ERCC2 ERCC3 ERCC4 ERCC5 ERG ERG ESR1 ESR1 ETS1 ETS1 ETV1 ETV1 ETV4 EXT1 EXT2 EZH2 FANCA FANCC FANCD2 FANCF FANCF FANCG FANCG FAS FAS FBXW7 FGFR1 FGFR2 FGFR3 FGFR4 FH FH FLCN FLCN FLI1 FLI1 FLT1 FLT1 FLT3 FLT3 FLT4 FLT4 FN1 FOXL2 OncoDEEP FOXO1 DX FOXO3 FOXP1 OncoDEEP FOXP4 Clinical FZR1 FZR1 G6PD G6PD GATA1 GATA1 GATA2 GATA3 GDNF GNA11 GNAQ GNAS GPR124 GRM8 GRM8 GUCY1A2 GUCY1A2 HCAR1 HCAR1 HIF1A HLF HNF1A HOOK3 HRAS HSP90AA1 HSP90AB1 ICK ICK IDH1 IDH1 IDH2 IDH2 IGF1R IGF2 IGF2R IKBKB IKBKE IKZF1 IL2 IL2 IL21R IL21R IL6ST IL6ST IL7R IL7R ING4 ING4 IRF4 IRS2 ITGA10 ITGA9 ITGB2 ITGB3 ITGB3 JAK1 JAK1 JAK2 JAK2 JAK3 JAK3 JUN JUN KAT6A KAT6B 65 genes KDM5C KDM6A 50 KDR 409 KEAP1 genes KIT KIT KLF6 KLF6 KRAS KRAS LAMP1 LCK LIFR LPHN3 LPP LRP1B LTF LTF LTK LTK MAF MAF MAFB MAFB MAGEA1 MAGI1 MALT1 MAML2 MAP2K1 MAP2K2 pathway based MAP2K4 MAP3K7 MAP3K7 MAPK1 MAPK1 MAPK8 MAPK8 MARK1 MARK4 MBD1 MCL1 MDM2 MDM4 MEN1 MEN1 MET MET MITF MITF MLH1 MLH1 MLL MLL MLL2 MLL3 Actionnable MLLT10 MMP2 MN1 MN1 gene MPL selection MPL MRE11A MSH2 MSH2 MSH6 MSH6 MTOR MTR MTRR MUC1 MUTYH MYB MYB MYC MYC MYCL1 MYCL1 MYCN MYCN MYD88 MYD88 MYH11 MYH9 NBN NCOA1 NCOA2 NCOA4 NF1 NF1 NF2 NF2 NFE2L2 NFE2L2 NFKB1 NFKB1 NFKB2 NIN NKX2-1 NLRP1 NOTCH1 NOTCH2 NOTCH4 NPM1 NPM1 NRAS NRAS NSD1 NSD1 NTRK1 NTRK3 NUMA1 NUP214 NUP98 PAK3 PALB2 PARP1 PARP1 PAX3 PAX3 PAX5 PAX5 PAX7 PAX8 PBRM1 PBX1 PDE4DIP PDGFB PDGFRA PDGFRB PDGFRB PER1 PER1 PGAP3 PGAP3 PHOX2B PIK3C2B PIK3CA PIK3CB PIK3CD PIK3CG PIK3R1 PIK3R2 PIK3R2 PIM1 PIM1 PKHD1 PKHD1 PLAG1 PLCG1 PLEKHG5 PML PMS1 PMS2 POT1 POT1 POU5F1 POU5F1 PPARG PPARG PPP2R1A PPP2R1A PRDM1 PRKAR1A PRKDC PSIP1 PTCH1 PTEN PTGS2 PTPN11 PTPN11 PTPRD PTPRD PTPRT PTPRT RAD50 RAF1 RALGDS RARA RB1 RECQL4 REL REL RET RET RHOH RHOH RNASEL RNASEL RNF2 RNF213 ROS1 RPS6KA2 RRM1 RUNX1 RUNX1T1 SAMD9 SAMD9 SBDS SBDS SDHA SDHA SDHB SDHC SDHD SEPT9 SETD2 SF3B1 SGK1 SGK1 SH2D1A SH2D1A SMAD2 SMAD2 SMAD4 SMAD4 SMARCA4 SMARCB1 SMO SMUG1 SOCS1 SOX11 SOX2 SOX2 SRC SRC SSX1 SSX1 STK11 STK11 STK36 SUFU SYK SYNE1 TAF1 TAF1L TAL1 TAL1 TBX22 TBX22 TCF12 TCF12 TCF3 TCF3 TCF7L1 TCF7L2 TCL1A TET1 TET2 TFE3 TGFBR2 TGM7 TGM7 THBS1 THBS1 TIMP3 TIMP3 TLR4 TLR4 TLX1 TNFAIP3 TNFRSF14 TNK2 TOP1 TP53 TP53 TPR TPR TRIM24 TRIM24 TRIM33 TRIM33 TRIP11 TRRAP TSC1 TSC2 TSHR UBR5 UGT1A1 USP9X USP9X VHL VHL WAS WAS WHSC1 WRN WT1 XPA XPC XPO1 XRCC2 ZNF384 ZNF384 ZNF521 ZNF521 Genes in OncoDEEP DX Genes in OncoDEEP Clinical

24 OncoDeep Data Analysis Process Less False Positive Less False Negative

25 What is OncoDEEP? Reporting VARIANT TYPES REPORTED Inherited Variants Inherited Variants Not reported as Germinal Variant but as variant Medically with potential actionable hereditary incidental impact findings to be checked in non tumoral sample (e.g. blood) Actionable variants With Biological, Clinical and Therapeutical impact Polymorphism Benign polymorphism without biological and clinical impact Variants of Uncertain Significance (VUS) Not just polymorphism but with potential ti biological and clinical impact

26 OncoDEEP Reporting: Variant analysis α List Biomarkers related to Drug Label are paid a specific attention with manual check of aligned reads raw data

27 What is OncoDEEP? NGS analysis + Package Plus IHC analyses + Additional analyses To look at final cellular effectors quantity and/or activity

28 What is OncoDEEP? NGS analysis + Package Plus IHC analyses + Additional analyses To look at final cellular effectors quantity and/or activity A panel of 5 to 8 IHCs IHC specific of the analyzed cancer type Addressing chemotherapy, targeted therapy and pathway biomarkers Looking at presence (IHC) and activation of proteins (Phospho IHC)

29 What is OncoDEEP? NGS analysis + Package Plus IHC analyses + Additional analyses To look at final cellular effectors quantity and/or activity A panel of 5 to 8 IHCs IHC specific of the analyzed cancer type Addressing chemotherapy, targeted therapy and pathway biomarkers Looking at presence (IHC) and activation of proteins (Phospho IHC)

30 What is OncoDEEP? NGS analysis + Package Plus IHC analyses + Additional analyses Targeted Cancer Specific c Chemotherapy AEG 1 ERCC1 RRM1 TUBB3 PTEN C MET Phospho 4EBP1 Phospho S6 Phospho AKT Phospho ERK1/2 e.g. Breast cancer: Ki 67 ER PR TLE3 TS Top2A Her2 From the shelf PDL1 Topo1 EGFR β CATENIN

31 What is OncoDEEP? NGS analysis + Package Plus IHC analyses + Additional analyses Because some cancer biomarkers are very specific!!

32 What is OncoDEEP? NGS analysis + Package Plus IHC analyses + Additional analyses Because some cancer biomarkers are very specific!! Breast Cancer: FISH Analysis for Her2 Neu Amplification Hereditary NonPolyposis CR Cancer: Multiplex PCR for Microsatellite Instability NSC Lung Cancer: ALK EML4 Translocation Trastuzumab (Herceptin ) No Benefit of adjuvant 5 FU based chemotherapy Crizotinib (Xalkori)

33 Genomic test in routine FISH and IHC HER2 positive Relapse under Herceptin treatment Lapatinib Gender : Female Organ : Breast Tumor type : Advanced breast carcinoma Specimen : FFPE SLIDE Patient was getting worse very fast OncoDEEP Clinical Confirmation of HER2 Amplification Detection of the L755S variant in HER2, which is known to be Lapatinibresistant Patient oriented towards a clinical trial associated with new HER2 inhibitor whose mechanism is not based on Lapatinib mechanism

34 OncoDEEP DX No variant identified But discovery of a CDKN2A deletion dlti Gender : Female Organ : Breast Cancer Tumor type : ER/PR positive HER2 negative Treatment : Neo adjuvant therapy Clinic : Residual disease observed after surgery CDK4/6 : Therapy target? Clinicaltrial.gov NCT PENELOPE B CELL PROLIFERATION According to our information, patient has been enrolled on the basis of OncoDEEP results

35 What is OncoSHARE? OncoSHARE is a Web interface which allows: A comprehensive listing of all variant findings. Imagine a paper p listing of around 250 variants found in a OncoDEEP Clinical listed with all biological, clinical and therpeutical information listed in a pdf document. A detailed and interactive presentation of drug recommendations and clinical trials availability along with all related publication directly accessible through hyperlinks An easy sharing of the report by oncologists, with colleague(s), with Molecular Board or with Expert of the field [, with Patient]

36 OncoDEEP - OncoSHARE: How it works? 1 Analysis Ordering & Sample Shipment 2 5 Reports exchanges between oncologists and when allowed, with patients 4 Reporting Tec hnical Pro ocess 3 Data analysis and integration

37 OncoDEEP - OncoSHARE: How it works? 1 Analysis Ordering & Sample Shipment These Kits a barcoded and can ship FFPE tumor block and slides in cartridge. Kits also contain shipping bag and prefilled waybill for safe and FREE shipment O l i l it i d d i On sample arrival, it is encoded in our OncoLIMS for technical processes

38 OncoDEEP - OncoSHARE: How it works? 1 Analysis Ordering & Sample Shipment R d d i Recommanded prices starting from Belgium

39 OncoDEEP OncoSHARE: How it works? Sample Reception (FFPE) 2 Technical Process Do not reach Quality Criteria=> Stop Anapath Review and QC Reach Quality Criteria 3 4 days TAT DNA Extraction + OncoDEEP Sequencing 1 2 days TAT + Package testing (Immuno, Fish ) Bioinformatics + Gene analysis 1 2 days TAT 7 to 10 days delivery time Final comprehensive Report including analyses and final conclusions Confirmation by classical testing if required (FISH, ) Reporting (DX Clinical)

40 The image part with relationship ID rid6 was not found in the file. OncoDEEP - OncoSHARE: How it works? Data analysis 3 and integration EMA Knowledge DataBase OncoDNA Web reporting

41 OncoDEEP - OncoSHARE: How it works? Pathology report 4 Reporting List of variants discovered with NGS and their impact List of drugs recommended for the specific conditions of the patient Process summary Package Plus results List of clinical trials available for patients specific conditions List of publications related to report findings

42 OncoDEEP - OncoSHARE: How it works? 4 Reporting

43 OncoDEEP - OncoSHARE: How it works? 4 Reporting

44 OncoDEEP - OncoSHARE: How it works? 4 Reporting

45 OncoDEEP - OncoSHARE: How it works? 4 Reporting

46 OncoDEEP OncoSHARE: How it works? Drug recommendation In Indication Out of Indication In Development

47 OncoDEEP - OncoSHARE: How it works? Drug recommendation 4 Reporting General drug description Drug description in the sepcific cancer type context Clinical development stage

48 OncoDEEP - OncoSHARE: How it works? Drug recommendation 4 Reporting

49 OncoDEEP - OncoSHARE: How it works? 4 Reporting

50 OncoDEEP PHARMA : One product Four Options

51 OncoDeep : Challenges Integration of results from NGS, IHCs and anathomopathology testing is needed to have a multidimensional overview of the tumor Precious and limited material FFPE Block Turn around time is a priority Processes are multiple and require several expertices Sample is heterogenous, not only tumor cells DNA is degraded We have developped a one stop solution

52 OncoDEEP and AURORA The Breast International Group (BIG): A non profit organisation for breast cancer research 49 collaborative groups from around the world About 30 clinical trials are run or are under development Works closely with the US National Cancer Institute (NCI) and the North American Breast Cancer Group (NABCG) European based, Headquartered in Brussels Major financer is The Breast Cancer Research Foundation (USA)

53 Martine J. Piccart, MD, PhD, Speaking about OncoDNA and AURORA WHY Metastatic Breast Cancer (MBC)? The disease remains incurable... Despite 3 decades of research efforts The median survival of these women remains poor: about 30 months Unprecedented opportunity to make more rapid progress, using OncoDEEP Clinical Plus

54 Newly diagnosed dag osedor 1st Line MBC Patients N=1,300 Screening Failure n=300 Actionable Mutation(s) (n 300) Non Actionable Mutations (n 700) Downstream Targeted Clinical Trials as first or second line Standard of Care Clinical Outliers (Exceptional Responders and Rapid Progressors) to be subjected to WES Timeline. Continue until disease progression Entry in DCT Cycle 1 Cycle 2 Cycle 3 Cycle X Disease Progression Metastatic Lesion Biopsy TGS (real time) and RNAseq (on batches) Primary Tumour Archival TGS (real time) and RNAseq (on batches) Blood TGS (real time) Plasma/Serum Clinical Outcome Information Collection every 6 months up to 10 years Collection every 6 months up to 10 years

55 Program Protocol OBJECTIVES To improve the understanding of MBC by performing high coverage TGS and RNA sequencing on matched primary and metastatic samples to explore tumor heterogeneity, clonal evolution and transcriptional changes associated with mutational and CNV patterns. To discover biomarkers of response and/or resistance to systemic therapy using genomic and transcriptomic data of exceptional responders and rapid progressors. To build new therapeutic hypotheses based on findings generated by TGS. To evaluate the prognostic relevance of genomic alterations detected in tumour metastatic biopsies and archived primary tissue. To correlate molecular alterations in patients with the efficacy endpoints (response rate, progression free survival (PFS) and OS). To identify patients with candidate driver alterations in their tumours that can be matched to biomarker driven clinical trials.

56 Martine J. Piccart, MD, PhD, Speaking about OncoDNA and AURORA WHY having chosen OncoDNA? OncoDNA has participated, without knowing about it, to a pilot trial of 30 MBC samples tested using OncoDEEP Clinical. Data generated were compared, blind, to data generated by the Sanger platform, 1 other academic lab and one other vendor (not disclosed). d) 1) Data quality and robustness on those very small metastasis biopsies and 2) delivery time were the major two differenciating factors. «OncoDNA has been chosen because it offers a real professional and quality service»

57 Martine J. Piccart, MD, PhD, Speaking about OncoDNA and AURORA What does OncoDNA do in AURORA? Next Generation Sequencing analysis of our Clinical panel (409) along with NGS analysis of BRCA1 2 ImmunoHistoChemistry analysis of ER, PR, HER2 and Ki 67. Slide digitalization and image archiving. FISH analysis of HER2 in case of IHC HER2 3+ Temporary biobanking b of FFPE samples, frozen biopsies i and blood sample. Potential future work (depending offinancing availability) WES Potential future work (depending of financing availability): WES (Whole exome sequencing), WTS (Whole transcriptome sequencing);

58 Quality Assurance IS for IPG (Medical laboratories Particular requirements for quality and competence: specifying the quality management system requirements particular to medical laboratories) ISO17025 for Bio.be (The main ISO/CASCO standard used by testing and calibration laboratories) GCLP Compliant Audited by from pharma partners CLIA/CAP Certification in process Official biobank for Belgian National Cancer Plan (IPG) Official Belgian Genetics Centre (IPG) IVD marking according to Directive 98/79/EC

59 Partners

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