Translational examination in colorectal tumor .

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Translational research in colorectal cancer. Tim Maughan Professor of Cancer Studies Consultant Clinical Oncologist. Developing a clinical research network. The Wales Cancer Trials Network 1998-2006. 1998 5.3 Staff 415 Patients 2.8% in Trials. Wales Cancer Trials Network. 2003
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Translational research in colorectal tumor Tim Maughan Professor of Cancer Studies Consultant Clinical Oncologist

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Developing a clinical research arrange The Wales Cancer Trials Network 1998-2006

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1998 5.3 Staff 415 Patients 2.8% in Trials Wales Cancer Trials Network

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2003 22.45 Staff 1242 Patients 8% in Trials Wales Cancer Trials Network A system of research staff to bolster persistent passage into clinical research thinks about And convey superb information accumulation

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An expert association Support clinical trial outline Collaborate to get look into subsidizing Trial raced to GCP/EU mandate necessities Data administration Pharmacovigilance/checking Data examination Publication

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Key accomplishments A legally binding mentorship assention between WCTN & MRC CTU Dec 2004 ZICE trial – financed by Roche and CTAAC approved Jan 2005 Fragmatic trial – endorsed and subsidized by CTAAC, bolster from Pfizer Feb 2005 NCRI accreditation Feb 2005 New offices Oct 2005 Associate Director appointed Oct 2005 Core subsidizing from CR-UK Dec 2005 First patient in ZICE Jan 2006 SCOPE trial financed by CTAAC Feb 2006

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National Cancer Research Institute (NCRI) Board Sub-Group on Clinical and Translational research Wales Cancer Bank National Cancer tissue asset NCRN Operational Steering Group Clinical Trials Units Committee Wales Cancer Trials Unit NCRN Coordinating focus National Cancer Research Networks (41) NCRI Clinical Study Groups (22) Wales Cancer Trials Network Wales agents Trial Approval Process CTAAC TRICC An entire framework approach

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What are the advantages of the NCRI? Trials are finished all the more rapidly Metastatic colorectal disease More eager trials are composed Inoperable lung tumor Improved connections with industry Oesophageal growth Improved translational research program Metastatic colorectal malignancy Increased expansiveness of issues tended to Prevention, early finding

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CR10 Improved open door for translational research MRC COIN trial in metastatic colorectal growth Chief Investigator Tim Maughan Merck KGaA

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807 COIN Second Line Chemo Therapy Irinotecan Based As NICE direction ARM A CONTINUOUS CHEMOTHERAPY Oxaliplatin + fluoropyrimidine chemotherapy proceeded until movement, total harmfulness or patient decision ARM B CONTINUOUS CHEMO + CETUXIMAB OxFp chemotherapy + week after week cetuximab proceeded until movement, aggregate lethality or patient decision ARM C INTERMITTENT CHEMOTHERAPY Oxaliplatin + fluoropyrimidine chemotherapy Treat for 12 weeks then stop and screen. Restart on movement for a further 12 weeks

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Why irregular chemotherapy? MRC CR06 general survival Median 2yr Stop 10.8 m 19% Continue11.4 m 13% HR 0.90 (95% CI 0.71-1.13) p=0.37 Stop Continue Maughan et al, Lancet, 2003; 361 : 457-64. MRC CR06 Comparison of discontinuous and ceaseless palliative chemotherapy for cutting edge colorectal: a multicentre randomized trial.

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EGF, TGF an Amphiregulin b - celluli, nHB-EGF Epiregulin NRG2 NRG3 Heregulins b - cellulin ligand Heregulins extracellular space Cysteine-rich areas 100 44 82 33 36 59 24 48 79 28 Tyrosine kinase space C-end ErbB-1 Her1 EGFR ErbB-2 Her2 neu ErbB-3 Her3 ErbB-4 Her4 How would we be able to enhance general survival in metastatic CRC? Epidermal Growth Factor Receptor EGFR, as a Treatment Target Expression 60-80% Colorectal tumor

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Cetuximab IgG1 monoclonal counter acting agent Exclusive for EGFR and its heterodimers Prevents ligand official to EGFR Higher partiality for EGFR contrasted with normal ligands Blocks receptor dimerization, tyrosine kinase phosphorylation, flag transduction Stimulates receptor disguise Fc area may instigate neutralizer subordinate cell-interceded cytotoxicity (ADCC) (invulnerable reaction)

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R RAS RAF K PI3-K SOS pY MEK GRB2 STAT pY PTEN AKT MAPK Cyclin D1 P myc cyclin D1 DNA Jun Fos expansion/development Myc metastasis chemotherapy/radiotherapy resistance survival/hostile to apoptosis angiogenesis EGFR flag transduction R Gene interpretation Cell cycle movement

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R RAS RAF K PI3-K SOS pY MEK GRB2 STAT pY PTEN AKT MAPK Cyclin D1 P myc cyclin D1 DNA Jun Fos multiplication/development Myc metastasis chemotherapy/radiotherapy resistance survival/against apoptosis angiogenesis EGFR flag transduction Gene translation Cell cycle movement

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NH 2 R Pt II NH 2 G A G DNA PK G Reduced DNA repair EGFR flag transduction Synergy?

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Cetuximab in first-line mCRC 1) Folprecht, et al. WCGIC (2005) [Abstract and notice No. P-053] 2) Rougier, et al. J Clin Oncol 2004;22(Suppl. 14s):248s [Abstract and publication No. 3513] 3) Rosenberg et al. ASCO 2002, (Abstract #536) 4 Diaz Rubio et al. ASCO 2005 #3535 5Seufferlein, et al. J Clin Oncol 2005;23(Suppl. 16s):281s [Abstract No. 3644] ; Lordick, et al. ASCO GI (2005) [Abstract No. 247]

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COIN trial endpoints Primary Endpoint: Overall survival Secondary endpoints: without progression survival time of malady control Response, lethality personal satisfaction cost adequacy. Translational endpoints Predictors of reaction and danger

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Tumor square accumulation Consent (Not discretionary) Consent shape + record on Rando/pre-treatment frame Copy assent shape + pathology ask for shape Local staff ask for piece from Pathology dept Document handle on Pathology CRF page Receive piece and pathology report from Pathology dept Label test and pathology Report with COIN trial no Anonymise way report Place in fixed envelope in jiffy sack Send to Wales Cancer Bank COIN trial test

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(Moroni et al, Lancet Oncology  2005;  6 :279-286 Paraffin implanted tumor gathering Consent required for EGFR IHC Blocks gathered at Wales Cancer Bank TMAs arranged, DNA removed IHC for EGFR, FISH for quality duplicate no IGF-1R extend

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Other translational studies Optional assent for \'further inside malignancy inquire about\' 96% concurred in MRC FOCUS trial Other examinations on paraffin Blood test for DNA extraction Subset of 300 new tumor accumulation Subset for examination of connection of rash to reaction rate

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2. Blood test accumulation Consent (discretionary) Document prepare on Pathology CRF page Take 20ml blood EDTA tube Label with date and COIN trial no Send to Dr J Cheadle COIN trial test lab Inst Medical hereditary qualities Cardiff Place in fixed postage prepaid Safe box

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COIN – trial 2,400 CRC patients digestion system/receptor pathways DNA repair profiles J.Cheadle J.Sampson A.Dallosso + H.Mcleod examinations G.Griffiths –MRC V.Moskvina – BBU I.Nikolov - BBU Blood Sample Overview

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Oxali 5FU

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" Patient\'s DNA repair profiles may alter reaction to, and symptoms from, chemotherapy " How would we expect to gauge \'repair profiles\' ? measure each cSNP that may modify protein work with a minor allele recurrence (MAF) >5%, in each repair quality in the human genome … .… 131 qualities for qualities lacking cSNPs, we will recognize and test other utilitarian polymorphisms in their promoters

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NER Main instrument of repair of platinum adduct harm

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XRCC2 (XPD) Lys751Gln

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Do we have adequate power ? single variation examinations >90% energy to distinguish a 20% diff. accordingly or symptom rates for cSNPs with minor allele frequencies (MAFs) ≥5% 80% energy to distinguish a 10% diff. accordingly or s.e. rates for cSNPs with MAFs ≥14% SNP mixes… repair profiles… max SNPs which can be broke down all the while to identify a 30% diff. accordingly or s.e. rates, while saving force of >80%, is eight

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3. Pharmacogenomics Sample of extricated DNA from Cardiff Sent to University of Washington, St Louis Prof Howard Mcleod USA master in pharmacogenomics of colorectal disease specialists Funded by NIH awards

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Macleod et al, Proc ASCO, 2004

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Fresh tissue to RNAlater for rna extraction from 200 pts Almac have created colorectal particular microarray (Johnson) 43% new transcripts not in Afymetrix chip Gene marks for reaction Colorectal cDNA microarray 4. Crisp tissue gathering

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No response Grade 1 Grade 2 Presence and force of acneiform rash predicts expanded survival 16 How? Hereditary fluctuation of EGFR pathway in skin and tumor? Resistant response? 14 12 10 Survival (months) 8 6 4 2 0 CRC Pancreatic SCCHN Grade 3 Propriones acnei = mycobacterium parvum Acne is a postponed extreme touchiness response Does this trigger an against tumor reaction? (Layton, Tabi, Clayton) 1. Saltz et al. Proc Am Soc Clin Oncol 2001;19: Abstract #7. 2. Saltz et al. J Clin Oncol 2004;22:1201-1208. 3. Cunningham D N Engl J Med 2004;351:337-345. 4. Van Cutsem et al. EORTC/NCI Geneva 2004. 5. Abbruzzese et al. Proc Am Soc Clin Oncol 2001; Abstract #518; 5. Kies et al. Proc Am Soc Clin Oncol 2002;20: Abstract #925.

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Genome wide DNA repair fluctuation EGFR IHC Pharmacogenomics of all specialists Colorectal cDNA microarray World class incorporated germline and tumor investigation intending to distinguish determinants of reaction

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Collaborating in disease look into UK wide scholarly joint effort 73 dynamic growth focuses crosswise over UK Collaboration of funders: CR-UK, MRC, Merck, NHS R&D, NIH Cardiff the center point of the translational research Wales Cancer Bank Genetics, Pharmacy, College of Medicine

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