istvan petak, md, phd founder, scientific director tm
TRANSCRIPT
ISTVAN PETAK, MD, PHDFOUNDER, SCIENTIFIC DIRECTOR
TM
7,6 MILLION13,1 MILLION
1:4GLOBOCAN 2008, WHO
Growth factor
Growth Factor ReceptorTyrosin kinases
Nucleus
Mutant Gene
A
Faulty signal transduction protein
Cancer Cell Targeted drugDivision
Which are the drugable gene mutations?
USA
Dr. ISTVAN PETAK
Dr. RICHARD SCHWAB
SWISS
1995 => 2002Story of kps (2003)
Biomedical RESEARCHERS trained in the usa and swiss
Schwab Richárd, Peták István, Pintér Ferenc….Kopper László, Kéri György, Pap Ákos
J Clin Oncol. 2005 Oct 20;23(30):7736-8.
Story of kps (2004)First molecular diagnostics based targeted tHerapy of a LUNG CANCER
PATIENT
MOLECULAR DIAGNOSTIC LABORATORY
LCM (ZEISS-PALM)
100%MULTIPLEX
XS-dXtm
OPTIMIZEDDIRECT PCR
PATENTED TECHNOLOGY TO ANALYZE SMALL SAMPLES
28 db 56 db
EGFR EXON 21 L858R
Successful diagnostics in 84 cells
(italian patient)
Response to therapy
INTERNATIONAL EXPANSION WITH THE SUPPORT OF VENTURE CAPITAL INVESTMENT IN 2012
1% of all genes90% somatic mutations20% germline mutations 10% show both somatic and germline mutations
500,000 mutations in 460 cAncer genes
Symbol Name GeneID Chr Chr Band
Cancer Somatic Mut
Cancer Germline Mut Tumour Types (Somatic Mutations) Tumour Types (Germline Mutations) Cancer Syndrome
Tissue Type
Cancer Molecular Genetics Mutation Type Translocation Partner
AKT1 v-akt murine thymoma viral oncogene homolog 1 207 14 14q32.32 yes breast, colorectal, ovarian, NSCLC E Dom MisAKT2 v-akt murine thymoma viral oncogene homolog 2 208 19 19q13.1-q13.2 yes ovarian, pancreatic E Dom AALDH2 aldehyde dehydrogenase 2 family (mitochondrial) 217 12 12q24.2 yes leiomyoma M Dom T HMGA2ALK anaplastic lymphoma kinase (Ki-1) 238 2 2p23 yes yes ALCL, NSCLC, Neuroblastoma, Breast, Colon ccneuroblastoma Familial neuroblastomaL, E, M Dom T, Mis, A NPM1, TPM3, TFG, TPM4, ATIC, CLTC, MSN, ALO17, CARS, EML4APC adenomatous polyposis of the colon gene 324 5 5q21 yes yes colorectal, pancreatic, desmoid, hepatoblastoma, glioma, other CNScolorectal, pancreatic, desmoid, hepatoblastoma, glioma, other CNSAdenomatous polyposis coli; Turcot syndromeE, M, O Rec D, Mis, N, F, SATRX alpha thalassemia/mental retardation syndrome X-linked 546 X Xq21.1 yes Pancreatic neuroendocrine tumors E Rec Mis, F, NBRAF v-raf murine sarcoma viral oncogene homolog B1 673 7 7q34 yes melanoma, colorectal, papillary thyroid, borderline ov, Non small-cell lung cancer (NSCLC), cholangiocarcinoma, pilocytic astrocytomaE Dom Mis, T, O AKAP9, KIAA1549BRCA1 familial breast/ovarian cancer gene 1 672 17 17q21 yes yes ovarian breast, ovarian Hereditary breast/ovarian cancerE Rec D, Mis, N, F, SBRCA2 familial breast/ovarian cancer gene 2 675 13 13q12 yes yes breast, ovarian, pancreatic breast, ovarian, pancreatic, leukemia (FANCB, FANCD1)Hereditary breast/ovarian cancerL, E Rec D, Mis, N, F, SCDKN2A -p16(INK4a) cyclin-dependent kinase inhibitor 2A (p16(INK4a)) gene 1029 9 9p21 yes yes melanoma, multiple other tumour typesmelanoma, pancreatic Familial malignant melanomaL, E, M, O Rec D, Mis, N, F, SCDKN2A- p14ARF cyclin-dependent kinase inhibitor 2A-- p14ARF protein 1029 9 9p21 yes yes melanoma, multiple other tumour typesmelanoma, pancreatic Familial malignant melanomaL, E, M, O Rec D, SCTNNB1 catenin (cadherin-associated protein), beta 1 1499 3 3p22-p21.3 yes colorectal, cvarian, hepatoblastoma, others, pleomorphic salivary adenoma E, M, O Dom H, Mis, T PLAG1DAXX death-domain associated protein 1616 6 6p21.3 yes Pancreatic neuroendocrine tumors E Rec Mis, F, NEP300 300 kd E1A-Binding protein gene 2033 22 22q13 yes colorectal, breast, pancreatic, AML, ALL, DLBCL L, E Rec T, N, F, Mis, O MLL, RUNXBP2ERBB2 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)2064 17 17q21.1 yes breast, ovarian, other tumour types, NSCLC, gastric E Dom A, Mis, OERCC2 excision repair cross-complementing rodent repair deficiency, complementation group 2 (xeroderma pigmentosum D)2068 19 19q13.2-q13.3 yes skin basal cell, skin squamous cell, melanomaXeroderma pigmentosum (D)E Rec Mis, N, F, SERCC3 excision repair cross-complementing rodent repair deficiency, complementation group 3 (xeroderma pigmentosum group B complementing)2071 2 2q21 yes skin basal cell, skin squamous cell, melanomaXeroderma pigmentosum (B)E Rec Mis, SERCC4 excision repair cross-complementing rodent repair deficiency, complementation group 42072 16 16p13.3-p13.13 yes skin basal cell, skin squamous cell, melanomaXeroderma pigmentosum (F)E Rec Mis, N, FERCC5 excision repair cross-complementing rodent repair deficiency, complementation group 5 (xeroderma pigmentosum, complementation group G (Cockayne syndrome))2073 13 13q33 yes skin basal cell, skin squamous cell, melanomaXeroderma pigmentosum (G)E Rec Mis, N, FFBXW7 F-box and WD-40 domain protein 7 (archipelago homolog, Drosophila)55294 4 4q31.3 yes colorectal, endometrial, T-ALL E, L Rec Mis, N, D, FFGFR2 fibroblast growth factor receptor 2 2263 10 10q26 yes gastric. NSCLC, endometrial E Dom MisIL6ST interleukin 6 signal transducer (gp130, oncostatin M receptor)3572 5 5q11 yes hepatocellular ca E Dom OKRAS v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homolog 3845 12 12p12.1 yes pancreatic, colorectal, lung, thyroid, AML, others L, E, M, O Dom MisMADH4 Homolog of Drosophila Mothers Against Decapentaplegic 4 gene4089 18 18q21.1 yes yes colorectal, pancreatic, small intestine gastrointestinal polyps Juvenile polyposis E Rec D, Mis, N, FMAP2K4 mitogen-activated protein kinase kinase 4 6416 17 17p11.2 yes pancreatic, breast, colorectal E Rec D, Mis, NMDM2 Mdm2 p53 binding protein homolog 4193 12 12q15 yes sarcoma, glioma, colorectal, other M, O, E, L Dom AMLH1 E.coli MutL homolog gene 4292 3 3p21.3 yes yes colorectal, endometrial, ovarian, CNScolorectal, endometrial, ovarian, CNS Hereditary non-polyposis colorectal cancer, Turcot syndromeE, O Rec D, Mis, N, F, SMSH2 mutS homolog 2 (E. coli) 4436 2 2p22-p21 yes yes colorectal, endometrial, ovarian colorectal, endometrial, ovarian Hereditary non-polyposis colorectal cancerE Rec D, Mis, N, F, SMSH6 mutS homolog 6 (E. coli) 2956 2 2p16 yes yes colorectal colorectal, endometrial, ovarian Hereditary non-polyposis colorectal cancerE Rec Mis, N, F, SMSI2 musashi homolog 2 (Drosophila) 124540 17 17q23.2 yes CML L Dom T HOXA9
460 cancer genes
SANGER DATABASE
2010. Október 6. 11. dia
Abbott Astra-Z GSK Lilly Merck Novartis Pfizer Roche Wyeth
EGFR x xVEGF/R x xIGF/R x x xcMET x x x xMulti x x x x x xPI3K/mTOR x x x x xRAF x x xMEK x xSRC x xCDK4/6 xCHK1 x xAurorakináz x x xEg5,kinezin xTubulin x xPARP x x xBCL2 xIAP xSurvivin xHSP90 x xDeacetiláz xEndotelin x x-szekretáz x xMDM2 xDKK1 x5-reduktáz xVDA x
TARGETED THERAPIES IN PIPELINES
5000< CLINICAL TRIALS FOR BREAST CANCER (WWW.CLINICALTRIALS.GOV)
MORE AND MORE BIOMARKER DRIVEN LOOKING FOR SMALL FRACTION OF PATIENTS
MOLECULAR TARGETS 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 …50
CLIN
ICAL
PAR
AMET
ERS
1
2
3
4
5
6
7
8
9
1
0 …
.
A
B
CPIONEERING NEXT GENERATION SEQUENCING IN ONCOLOGY
„HeurAA” Heuristic Amplicon Analyzer
PATENTED TECHNOLOGY TO find mutations IN MANY SEQUENCES
Number of genesnu
mbe
r
2009 2010 2011 2012
58 genesABL1, AKT1, ALK, APC, ATM, BRAF, CDH1, CDKN2A, CSF1R, CTNNB1, EGFR, ERBB2, ERBB4, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, GNAS, HNF1A, HRAS, IDH1, JAK2, JAK3, KDR, KIT, KRAS, MET, MLH1, MPL, NOTCH1, NPM1, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, RET, SMAD4, SMARCB1, SMO, SRC, STK11, TP53, VHL.+ egyedi gének+FISH: EGFR, HER-2, FGFR, ALK, MET
TARGETED RESEQUENCING PANELS
Illumina HiSeq™ 2000 platform for 2574 exons representing 176 genes captured using Agilent SureSelect™
50% acionable mutations
MGH's Diagnostic Molecular Pathology lab
SNaPshot assay, hotspot mutations in 14 oncogenes
50 to 60 patients per week
NEXT: NGS 50 different targets
Genomweb September 19, 2012+in combination with fluorescence in situ hybridization
MOLECULAR GENETICS BASED PERSONALIZED SIGNAL TRANSDUCTION THERAPIES
GENE TEST
CANCER CELLS
58< TARGET
280<TARGETED DRUGS
ONCOMPASS TM IS A “BLUE OCEAN” SERVICE IN A RAPIDLY GROWING MARKET
OUR COSTUMERS:
PATIENTS: THEY WANT ACCESS TO MORE EFFECTIVE AND LESS TOXIC TARGETED THERAPY
PHARMA: THEY WANT TO FIND PATIENTS WITH RARE GENETIC PROFILE MATCHING THEIR DRUG
PHARMA/CRO: THEY WANT TO RECRUIT PATIENTS WITH RARE GENETIC PROFILE TO ACCELERATE
DOCTORS/HOSPITALS: THEY WANT MORE PATIENTS, CLINICAL TRIALS ARE PROFITABLE AND COMPETITIVE
PAYERS/INSURANCE: THEY WANT MORE COST EFFECTIVE TREATMENT, THEY WANT MORE PATIENTS IN CLINICAL TRIALS
ONCOMPASS TM IS A “BLUE OCEAN” SERVICE IN A RAPIDLY GROWING MARKET IN THE NEXT 20 YEARS
ENGINES OF GROWTH:
PATIENTS: THE NUMBER WILL 2X IN THE NEXT 20 YEARS (INCREASE WILL BE FASTER IN ASIA)
DRUGS: THE NUMBER OF TARGETED DRUGS WILL 10X
GENES: NUMBER OF GENES ANALYZED ON ONE CHIP WILL 10X
THANK YOU FOR YOUR KIND ATTENTION!