The story of the ATM gene in CLL:
Bench and Bedside
Tatjana Stankovic
School of Cancer Sciences, University of Birmingham
B cell chronic lymphocytic leukaemia

•Occurs in elderly individuals over age of 60
•Incidence 3680 new cases every year i...
Rise in lymphocyte count

B-cell chronic lymphocytic leukaemia (B-CLL)
has a variable clinical course
Progressive leukaemi...
VDJ recombination, Irradiation, chemotherapy, Oxidative
Metabolism cause DNA Double strand breaks (DSBs)
Zn2+

Rad50
Mre11...
Complete inactivation of ATM is frequent in
Chronic Lymphocytic Leukaemia:
Up to 40% of patients have ATM mutations in the...
ATM mutations in CLL alter DNA damage response
1. DNA damage response defect
B-CLL47 B-CLL7 B-CLL35 B-CLL9

IR

ATMdepende...
ATM mutations affect patients’ survival
Unselected cohort (18/155) 12%

p<0.0001

TP53 mutant (n=6)
ATM mutant (n=15)
ATM/...
ATM null leukaemias require alternative, personalized
treatment
Survival
ATM defect
DNA
Damage

tion
combina
s Re
mologou
Ho

PARP inhibition (Olaparib)
Single strand break repair

Conve...
Mimicking a clinical trial in patients

Victoria Weston

Tumour size mm 3

2000

Ceri Oldreive

No treatment (n=20)
Olapar...
Guy Pratt

Nicola Fenwick

Phase I/II clinical trial to assess the efficacy
and safety of Olaparib, a PARP-Inhibitor, in
r...
PICCLE Trial
Patients with
refractory
CLL and 11q del

Olaparib 200 mg bd->400mg bd

16

Weeks 1

ATM analysis

Clinical a...
Trial Objectives
Primary Objective:
– Phase I:To identify the maximum tolerated dose (MTD) of
olaparib
– Phase II: To asse...
From ATM gene to leukaemia patients: return to bedside
ATM mutations
in the most frequent
blood cancer

Clinical trial
wit...
Survival
ATM defect
DNA
Damage
Acknowledgements
Victoria Weston
Ceri Oldreive
Angelo Agathanggelou
Anna Skowronska
Gulshanara Ahmed
Eliot Marston
Katie M...
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Tanja Stankovic: Translating Your Research

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Tanja Stankovic: Translating Your Research

  1. 1. The story of the ATM gene in CLL: Bench and Bedside Tatjana Stankovic School of Cancer Sciences, University of Birmingham
  2. 2. B cell chronic lymphocytic leukaemia •Occurs in elderly individuals over age of 60 •Incidence 3680 new cases every year in UK •Prevalence 6.5 in 100 000 individuals •Currently incurable by chemotherapy
  3. 3. Rise in lymphocyte count B-cell chronic lymphocytic leukaemia (B-CLL) has a variable clinical course Progressive leukaemia Indolent disease Time from diagnosis Progressive disease associated with: Unmutated VH genes High Zap70, CD38 expression Del 17p, 11q (loss of single TP53 or ATM allele) Genomic complexity Short telomeres
  4. 4. VDJ recombination, Irradiation, chemotherapy, Oxidative Metabolism cause DNA Double strand breaks (DSBs) Zn2+ Rad50 Mre11 Nbs1 Mre11 Zn2+ Mre11 Nbs1 A B Mre11 B A Rad50 Head Arm ATM Accumulation of DNA damage p53 Responsive genes APOPTOSIS Chk2 CELL CYCLE DNA REPAIR Occurrence and progression of lymphoid tumours
  5. 5. Complete inactivation of ATM is frequent in Chronic Lymphocytic Leukaemia: Up to 40% of patients have ATM mutations in their tumour cells CLL5 CLL4 CLL3 CLL1 CLL5 CLL4 CLL3 CLL2 CLL1 CLL2 ATM segment VI ATM segment I Leukaemia with intact ATM Leukaemia with loss of ATM 1058delGT Tumour 1058delGT Skin 1058delGT Hair Stankovic et al, Lancet, 1999
  6. 6. ATM mutations in CLL alter DNA damage response 1. DNA damage response defect B-CLL47 B-CLL7 B-CLL35 B-CLL9 IR ATMdependent repair p53 Actin DSB p53 P CLL138 CLL37 CLL109 CLL169 0 24 0 24 0 24 0 24 ATM S1981P p53 S15P Mut WT WT WT WT Mut p=0.0019 % PARP1 at 24h 11q deletion and mutant ATM allele WT Mut 2. Defective IR induced apoptosis In vitro Fludarabine15µm urs of treatment + Pettit et al, Blood 2001, Stankovic et al, Blood 2002 3. DNA damage response defect requires inactivation of both ATM alleles 2 wild type ATM alleles ATM + - TP53 status Apoptosis 11q deletion and wild type ATM allele + + - DSB - ATM status ATM mut Activation of cell cycle check-points - 100 80 60 40 20 ATM wt ATM mutant p53 TP53 mutant Stankovic et al, Blood 2002 Austen et al, JCO 2007 SMC1 S966P SMC1 Actin Austen et al, JCO 2007
  7. 7. ATM mutations affect patients’ survival Unselected cohort (18/155) 12% p<0.0001 TP53 mutant (n=6) ATM mutant (n=15) ATM/TP53 wild type (n=133) 20 40 80 120 160 200 60 100 140 180 Time in months Proportion of patients alive 11q cohort (26/72) 36% p=0.0283 1.0 Overall survival 11q deletion and wild type ATM allele 11q deletion and mutant ATM allele 0.8 0.6 0.4 0.2 0.0 0 50 100 150 200 250 300 350 Months since diagnosis Time to First Treatment 90 p=0.0153 80 70 60 50 TP53 mutant (n=6) 40 ATM mutant (n=15) 30 ATM/TP53 wild type (n=133) 20 10 0 0 20 40 60 80 120 160 200 100 140 180 Time in months UK CLL4 –First line treatment: Chl vs F vs FC (36/224) 14.7% Percentage without progression Percentage alive 100 90 80 70 60 50 40 30 20 10 0 0 Percentage treatment free 100 Overall survival Progression Free Survival <0.001 No TP53 or 11q abnormality 11q deletion TP53 mutation or 17p deletion ATM mutation + 11q deletion TP53 mutation + 17p deletion
  8. 8. ATM null leukaemias require alternative, personalized treatment
  9. 9. Survival ATM defect DNA Damage tion combina s Re mologou Ho PARP inhibition (Olaparib) Single strand break repair Conversion of Single Conversion of Single Strand Breaks to Strand Breaks to Double Strand Breaks Double Strand Breaks
  10. 10. Mimicking a clinical trial in patients Victoria Weston Tumour size mm 3 2000 Ceri Oldreive No treatment (n=20) Olaparib (n=15) 1500 1000 500 0 ××× ×× 1 3 5 7 9 11 13 15 17 19 21 ×× ××× ××× ××× 23 25 27 29 31 Time post-treatment initiation (days) No treatment Olaparib
  11. 11. Guy Pratt Nicola Fenwick Phase I/II clinical trial to assess the efficacy and safety of Olaparib, a PARP-Inhibitor, in relapsed and refractory Chronic Lymphocytic Leukaemia patients with an 11q deletion or ATM mutation and relapsed/refractory patients with TProlymphocytic Leukaemia and Mantle Cell Lymphoma.
  12. 12. PICCLE Trial Patients with refractory CLL and 11q del Olaparib 200 mg bd->400mg bd 16 Weeks 1 ATM analysis Clinical and laboratory assessment Response rate at 16 weeks
  13. 13. Trial Objectives Primary Objective: – Phase I:To identify the maximum tolerated dose (MTD) of olaparib – Phase II: To assess the efficacy of Olaparib in patients with ATM-deficient CLL Exploratory Objective: – Develop biomarkers for the activity of this agent Planned Recruitment: – Phase I: 18 patients (maximum) – Phase II: 58 patients
  14. 14. From ATM gene to leukaemia patients: return to bedside ATM mutations in the most frequent blood cancer Clinical trial with Olaparib Clinical significance of ATM mutations ATM function Concept of synthetic lethality 1999 2011
  15. 15. Survival ATM defect DNA Damage
  16. 16. Acknowledgements Victoria Weston Ceri Oldreive Angelo Agathanggelou Anna Skowronska Gulshanara Ahmed Eliot Marston Katie Mapp Belinda Austen Malcolm Taylor Phil Byrd Paul Moss Guy Pratt David Oscier Chris Fegan Martin Dyer Pam Kearns Judy Powell KuDOS/Astra Zeneca Pharmaceuticals
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