Collaborating in Cancer Research

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Collaborating in Cancer Research

• Jim Cassidy
• CRUK Prof of Oncology
• Beatson , Glasgow

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Translation
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Why should we do it?

• Altruism
• Intellectual stimulation
• Fame seeking
• Employment and promotion prospects
• Financial gain

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Laboratory based scientists

• Clever
• Speak in riddles
• Lack practical knowledge of disease
• No insight into limitations of clinical practice
• Driven by craving for knowledge papers and
  grants

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Clinicians

• Clever
• Talk in riddles
• Busy and stressed
• Dis-interested sometimes
• Dont understand limits of science
• Driven by short term need to make people better

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Why we should do it together?

• Medium to long term gains for lots of patients
• Knowledge is power
• Cancer is the common enemy
• All the other bits are optional extras

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How ?

• Connect groups
• Physically
• Mentally
• Philosophically
• Practically
• BY EXAMPLE

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5 million population
Cancer Clinical Trials Unit Scotland
Statistics Bioinformatics Translational
science ASU
Main partners CRUK CTU Glasgow and ISD Edinburgh
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Translational clinical trials of epigenetic
therapies Robert Brown (r.brown_at_beatson.gla.ac.uk)
Centre for Oncology Applied Pharmacology,
CRUK Beatson Laboratories Glasgow University
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Epigenetics

• A hereditable change in gene expression not
  involving a change in DNA sequence
• DNA methylation
• (addition of methyl groups to CpG dinucletides
  in DNA at CpG islands)
• Histone modification and chromatin remodelling
• (e.g. acetylation/methylation of lysine in
  histones)

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DNA Methylation and Cancer
Normal tissue
Gene ON
Tumorigenesis
DNMT and HDAC inhibitor
Tumour
Gene OFF
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CpG-island Methylation in Cancer
Tumour progenitor cell
Carcinoma in-situ
Metastatic cancer
Resistant relapse
Epithelial
Carcinogenesis
Chemotherapy
Progression
Fibroblast
Somatic and cell-type specific methylation
Tumour specific methylation
Intra- and inter- tumour heterogeneity
Chemotherapy selected methylation
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Acquired drug resistance
Normal epithelia
Metastatic cancer
Resistant relapse
Tumorigenesis
Chemotherapy
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Acquired drug resistance
Normal epithelia
Metastatic cancer
Resistant relapse
Tumorigenesis
Chemotherapy
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Does CpG island methylation associate with
clinical outcome in Stage III/IV ovarian tumours
at presentation?

• Grouping genes based on known function identified
  methylation of any one of MGMT, GSTpi and BRCA1
  as associated with good response (plt0.05 n70,
  Teodoridis et al 2005)
• Supervised bioinformatic approach (Tree
  Harvesting) identifies novel methylation
  biomarkers as associated with good response
  (plt0.05 n70)

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Does CpG island methylation associate with
clinical outcome at relapse?

• Frequency of methylation of hMLH1 increased at
  relapse compared to at presentation (Strathdee et
  al 1999)
• 25 of ovarian cancer patients acquire
  methylation of hMLH1 in plasma DNA at relapse
  following carboplatin/taxol chemotherapy (Gifford
  et al 2004)
• Acquired methylation of MLH1 at relapse in plasma
  DNA independently is associated with poor survival

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Acquired hMLH1 methylation predicts patient
survival following tumour progression (SCOTROC1,
p0.007, HR1.96, n131)
Gifford et al 2004
Did not change
Became methylated
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Pharmacological inhibitors of DNA methylation
(Lyko Brown 2005)
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Decitabine (2-deoxy-5-azacytidine) sensitises
tumour xenografts with methylated MLH1 in vivo to
carboplatin.
A2780/cp70 MLH1 -ve
SW48 MLH1 -ve
Relative tumour volume
Relative tumour volume
Time (Days)
Time (Days)
Plumb et al 2000
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It is feasible to use decitabine in patients to
sensitise tumours to carboplatin?

• CR-UK sponsored Phase I trial of decitabine and
  carboplatin (and decitabine and epirubicin)
• Determine the maximum tolerated dose of
  decitabine in combination with carboplatin
• Pharmacodynamic secondary and tertiary objectives
• Toxicities were mainly haematological (G3/4
  neutropenia, grade1/2 thrombocytopenia)
• AUC6 carboplatin (day 1), 90 mg/m2 decitabine
  given as 6hrs infusion (day 8) q4 weekly
  recommended dose for Phase II

(Glasgow Royal Marsden)
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(Kim Appleton)
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Randomised Phase II trial of DNMT inhibitor
(decitabine) and carboplatin in ovarian cancer
Epithelial ovarian cancer that has responded to
initial chemotherapy but recurs 6-12 months
following treatment
Methylation of hMLH1 CpG island (and other
genes?) in plasma DNA
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Conclusions

• The demethylating agent decitabine sensitises
  drug resistant models to carboplatin and other
  cytotoxic drugs (Plumb et al 2000)
• The combination of decitabine and carboplatin is
  feasible in patients at doses that induce
  pharmacodynamic responses
• Ovarian cancer models and tumours show
  acquisition of hMLH1 methylation following
  chemotherapy (Strathdee et al 1999)
• A simple blood test identifies methylation of
  hMLH1 in tumour DNA from plasma and may allow
  identification of patients who will particularly
  benefit from demethylating agents (Gifford et al
  2004)
• Are there other genes whose methylation
  identifies patients who may benefit from
  demethylating agents?

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What next?

• Prof Nicol Keith
• Telomerase program
• Clinical contacts with many BOC people

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Gene Therapy Ad-hTR-NTR, a telomerase-specific
suicide gene therapy
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So what?

• Feasibility underway
• GLP assays as part of end-points
• POC allow us to go looking for drugs which act
  on same target
• Interaction with gene delivery program of JC
  /Schatzlien

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What about after that?

• BICR translational research
• Beatson Therapeutics
• Expand into other disease areas
• Clinical trials philosophy

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New Beatson Oncology Centre - Gartnavel
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CR-UK PHASE 1 STUDIES
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SELECTED PHASE 1 STUDIES
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Sample Collection for programs
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CR-UK Trials Office recruitment update
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Current 12 month overall totals

• NCRN (includes CR-UK) 494
• Non-NCRN non-commercial 345
• Commercial 212
• Screening 110
• GRAND TOTAL 1161
• Additional number that we co-ordinate 331