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Translational research in colorectal cancer

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 cancer

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  1. Translational research in colorectal cancer Tim Maughan Professor of Cancer Studies Consultant Clinical Oncologist

  2. Developing a clinical research network The Wales Cancer Trials Network 1998-2006

  3. 1998 5.3 Staff 415 Patients 2.8% in Trials Wales Cancer Trials Network

  4. 2003 22.45 Staff 1242 Patients 8% in Trials Wales Cancer Trials Network A network of research staff to support patient entry into clinical research studies And deliver high quality data collection

  5. A professional organisation • Support clinical trial design • Collaborate to obtain research funding • Trial run to GCP / EU directive requirements • Data management • Pharmacovigilance / monitoring • Data analysis • Publication

  6. Key achievements • A contractual mentorship agreement between WCTN & MRC CTU Dec 2004 • ZICE trial – funded by Roche and CTAAC approved Jan 2005 • Fragmatic trial – approved and funded by CTAAC, support from Pfizer Feb 2005 • NCRI accreditation Feb 2005 • New offices Oct 2005 • Associate Director appointed Oct 2005 • Core funding from CR-UK Dec 2005 • First patient in ZICE Jan 2006 • SCOPE trial funded by CTAAC Feb 2006

  7. National Cancer Research Institute (NCRI) Board Sub-Group on Clinical and Translational research Wales Cancer Bank National Cancer tissue resource NCRN Operational Steering Group Clinical Trials Units Committee Wales Cancer Trials Unit NCRN Coordinating centre National Cancer Research Networks (41) NCRI Clinical Study Groups (22) Wales Cancer Trials Network Wales investigators Trial Approval Process CTAAC TRICC A whole system approach

  8. What are the benefits of the NCRI? • Trials are completed more quickly Metastatic colorectal cancer • More ambitious trials are designed Inoperable lung cancer • Improved links with industry Oesophageal cancer • Improved translational research programme Metastatic colorectal cancer • Increased breadth of issues addressed Prevention, early diagnosis

  9. CR10 Improved opportunity for translational research MRC COIN trial in metastatic colorectal cancer Chief Investigator Tim Maughan Merck KGaA

  10. 807 807 807 COIN Second Line Chemo Therapy Irinotecan Based As NICE guidance ARM A CONTINUOUS CHEMOTHERAPY Oxaliplatin + fluoropyrimidine chemotherapy continued until progression, cumulative toxicity or patient choice ARM B CONTINUOUS CHEMO + CETUXIMAB OxFp chemotherapy + weekly cetuximab continued until progression, cumulative toxicity or patient choice ARM C INTERMITTENT CHEMOTHERAPY Oxaliplatin + fluoropyrimidine chemotherapy Treat for 12 weeks then stop and monitor. Restart on progression for a further 12 weeks

  11. Why intermittent chemotherapy?MRC CR06overall 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 intermittent and continuous palliative chemotherapy for advanced colorectal: a multicentre randomised trial.

  12. EGF, TGFa Amphiregulin b-celluli, nHB-EGF Epiregulin NRG2 NRG3 Heregulins b-cellulin ligand Heregulins extracellular domain Cysteine-rich domains 100 100 100 44 82 33 36 59 24 48 79 28 Tyrosine kinase domain C-terminus ErbB-1Her1 EGFR ErbB-2 Her2 neu ErbB-3 Her3 ErbB-4 Her4 How can we improve overall survival in metastatic CRC?Epidermal Growth Factor Receptor EGFR, as a Treatment Target Expression 60-80% Colorectal cancer

  13. Cetuximab • IgG1 monoclonal antibody • Exclusive for EGFR and its heterodimers • Prevents ligand binding to EGFR • Higher affinity for EGFR compared to natural ligands • Blocks receptor dimerization, tyrosine kinase phosphorylation, signal transduction • Stimulates receptor internalization • Fc region may induce antibody-dependent cell-mediated cytotoxicity (ADCC) (immune response)

  14. R RAS RAF K K PI3-K SOS pY pY MEK GRB2 STAT pY PTEN AKT MAPK Cyclin D1 P P myc cyclin D1 DNA Jun Fos proliferation/ maturation Myc metastasis chemotherapy/ radiotherapy resistance survival/anti-apoptosis angiogenesis EGFR signal transduction R Gene transcription Cell cycle progression

  15. R R RAS RAF K K PI3-K SOS pY pY MEK GRB2 STAT pY PTEN AKT MAPK Cyclin D1 P P myc cyclin D1 DNA Jun Fos proliferation/ maturation Myc metastasis chemotherapy/ radiotherapy resistance survival/anti-apoptosis angiogenesis EGFR signal transduction Gene transcription Cell cycle progression

  16. NH2 R R PtII NH2 G A G G DNA PK G G Reduced DNA repair EGFR signal transduction Synergy?

  17. Cetuximab in first-line mCRC 1) Folprecht, et al. WCGIC (2005) [Abstract and poster No. P-053] 2) Rougier, et al. J Clin Oncol 2004;22(Suppl. 14s):248s [Abstract and poster 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]

  18. COIN trial endpoints • Primary Endpoint: Overall survival • Secondary endpoints: • Progression-free survival • time of disease control • Response, toxicity • quality of life • cost effectiveness. • Translational endpoints • Predictors of response and toxicity

  19. Tumour block collection Consent (Not optional) Consent form + record on Rando / pre-treatment form Copy consent form + pathology request form Local staff request block from Pathology dept Document process on Pathology CRF page Receive block and pathology report from Pathology dept Label sample and pathology Report with COIN trial no Anonymise path report Place in sealed envelope in jiffy bag Send to Wales Cancer Bank COIN trial sample

  20. (Moroni et al, Lancet Oncology 2005; 6:279-286 Paraffin embedded tumour collection • Consent required for EGFR IHC • Blocks collected at Wales Cancer Bank • TMAs prepared, DNA extracted • IHC for EGFR, • FISH for gene copy no • IGF-1R project

  21. Other translational studies • Optional consent for ‘further bowel cancer research’ • 96% agreed in MRC FOCUS trial • Other investigations on paraffin • Blood sample for DNA extraction • Subset of 300 fresh tumour collection • Subset for investigation of link of rash to response rate

  22. 2. Blood sample collection Consent (optional) Document process on Pathology CRF page Take 20ml blood EDTA tube Label with date and COIN trial no Send to Dr J Cheadle COIN trial sample lab Inst Medical genetics Cardiff Place in sealed postage prepaid Safe box

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

  24. Oxali Oxali 5FU 5FU

  25. ‘Patient’s DNA repair profiles may modify response to, and side effects from, chemotherapy’ • How do we intend to measure ‘repair profiles’ ? • assay every cSNP that may alter protein function with a minor allele frequency (MAF) >5%, in every repair gene in the human genome ….…131 genes • for genes lacking cSNPs, we will identify and assay other functional polymorphisms in their promoters

  26. NERMain mechanism of repair of platinum adduct damage

  27. XRCC2 (XPD) Lys751Gln

  28. Do we have sufficient power ? • single variant analyses • >90% power to detect a 20% diff. in response or side effect rates for cSNPs with minor allele frequencies (MAFs) ≥5% • 80% power to detect a 10% diff. in response or s.e. rates for cSNPs with MAFs ≥14% • SNP combinations…repair profiles… • max SNPs which can be analysed simultaneously to detect a 30% diff. in response or s.e. rates, whilst preserving power of >80%, is eight

  29. 3. Pharmacogenomics • Sample of extracted DNA from Cardiff • Sent to University of Washington, St Louis • Prof Howard Mcleod • USA expert in pharmacogenomics of colorectal cancer agents • Funded by NIH grants

  30. Macleod et al, Proc ASCO, 2004

  31. Fresh tissue to RNAlater for rna extraction from 200 pts Almac have developed colorectal specific microarray (Johnson) 43% new transcripts not in Afymetrix chip Gene signatures for response Colorectal cDNA microarray 4. Fresh tissue collection

  32. No reaction Grade 1 Grade 2 Presence and intensity of acneiform rash predicts increased survival 16 • How? • Genetic variance of EGFR pathway in skin and tumour? • Immune reaction? 14 12 10 Survival (months) 8 6 4 2 0 CRC CRC CRC CRC Pancreatic SCCHN Grade 3 Propriones acnei = mycobacterium parvum Acne is a delayed hypersensitivity reaction Does this trigger an anti tumour response? (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.

  33. Genome wide DNA repair variance EGFR IHC Pharmacogenomics of all agents Colorectal cDNA microarray World class integrated germline and tumour analysis aiming to identify determinants of response

  34. Collaborating in cancer research • UK wide academic collaboration • 73 active cancer centres across UK • Collaboration of funders: CR-UK, MRC, Merck, NHS R&D, NIH • Cardiff the hub of the translational research • Wales Cancer Bank • Genetics, Pharmacy, College of Medicine

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