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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 cancer

Translational research in colorectal cancer

Tim Maughan

Professor of Cancer Studies

Consultant Clinical Oncologist

developing a clinical research network

Developing a clinical research network

The Wales Cancer Trials Network

1998-2006

slide3

1998

5.3 Staff

415 Patients

2.8% in Trials

Wales Cancer Trials Network

slide4

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

slide5
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
key achievements
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
slide7

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

what are the benefits of the ncri
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

improved opportunity for translational research

CR10

Improved opportunity for translational research

MRC COIN trial in metastatic

colorectal cancer

Chief Investigator Tim Maughan

Merck KGaA

slide10

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

slide11

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.

slide12

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

cetuximab
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)
egfr signal transduction

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

egfr signal transduction15

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

egfr signal transduction16

NH2

R

R

PtII

NH2

G

A

G

G

DNA PK

G

G

Reduced

DNA repair

EGFR signal transduction

Synergy?

cetuximab in first line mcrc
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]

coin trial endpoints
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
tumour block collection
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

paraffin embedded tumour collection

(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
other translational studies
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
2 blood sample collection
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

blood sample overview

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
slide24

Oxali

Oxali

5FU

5FU

patient s dna repair profiles may modify response to and side effects from chemotherapy
‘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
do we have sufficient power
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
3 pharmacogenomics
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
4 fresh tissue collection
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
slide33

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.

slide34

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

collaborating in cancer research
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