Therapeutic implications of identification of mutations · PDF fileTherapeutic Implications of...

François Lemonnier, Institut Mondor

de Recherche Biomédicale,

INSERMU955 Equipe 9,

Créteil

Therapeutic Implications of Identification of

Mutations in Epigenetic Regulators in PTCL

TFH Derived Peripheral T Cell Lymphomas

TFH derived PTCL= the most

frequent PTCL – Angioimmunoblastic T cell lymphomas

(AITL),

– Follicular PTCL

– Nodal PTCL with TFH phenotype

Poor outcome

Recently FDA approved drugs have

a limited efficacy

New drugs are an unmet medical

need

OS

Years

ORR Median

PFS

Pralatrexate 29% 3.5 m

Romidepsine 25% 4 m

Belinostat 25% 1.6 m

Oncogenic Events in TFH PTCL

TFH

PTCL

RHOAG17V

(50-70%)

Epigenetic

regulators

(>70%)

Mutations in

TCR signaling

(50%)

Sakata-Yanagimoto et al, Nature genetics. 2014

TET2

IDH2R172

DNMT3A

Objectives

Mutations in epigenetic regulators are also present in

myeloid malignancies, where 5-azacytidine is effective

IDH2 inhibitors are effective in IDH2 mutated AML

Need to identify these mutations in TFH PTCL in

clinical practice

– FFPE samples

– Tumor cells are in minority among an abundant environment

in lymph node

– TET2 and DNMT3A are not mutated in hotspot

TENOMIC Biobank

32 centers

1020 PTCL patients (300 in clinical trials)

– Almost all with FFPE material (LYSA-P)

– 662 with frozen tissue (Tumor Biobank, Henri Mondor

university hospital)

– 550 with DNA/RNA extracted

– 30 TMAs built (LYSA-P)

– 140 with PBL DNA

– 221 (excl. ALCL) with GEP, MiRNA and aCGH

Project coordinator: V Fataccioli

CeVi collection

IDH2 Mutant is Restricted to Tumor Cells

Vallois et al. Blood 2016

IDH2R172K ICOS

CD8 IDH2R172K

IDH2 Mutation Identification

BM IHC

R172K 7 8

R172S 1 0

R172G 3 0

R172T 1 0

WT 14 18

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

NGS allele

specific

PCR

HRM Sanger

100 91,7

66,7 75

0 8,3

33,3 25

identifed mutation not identified mutation

IDH2R172K

-

Aurélie Dupuy

5hmC Loss is Frequent in PTCL

IDH2 and TET2 mut AITL

5hmC

5hmC

PD1

IDH2 and TET2 WT AITL Reactive lymph node

5hmC Loss is Frequent in PTCL

Number of cases High 5hmC in

tumor cells

High 5mC in

tumor cells

AITL 25 0 25

Mutated

AITL

14 0 14

WT AITL 11 0 11

PTCL-NOSa 10 0 10

ALK-ALCLb 3 0 3

ALK+ALCL 3 0 3

TypeI EATL 4 0 4

HSTL 3 3 3

ENKTCL 4 0 4

Total

Mut cases

WT cases

52

19

33

3

0

3

52

19

33

5-Azacytidine Efficacy in TET2 mut AITL

Cheminant et al. BJH. 2014

Delarue, Dupuis et al.

ORR: 75%

Perspectives

To study effect of these mutations

– In primary cells (single cell analysis)

– In mouse models (in collaboration with the group of Tak Mak,

University of Toronto)

– In PDXs models (in development)

To identify new therapeutic targets, especially in TCR

signaling

To evaluate prognostic impact of these mutations:

– Sequencing of clinical trial cohort (RAIL, REVAIL, AATT, Ro CHOP)

Contributors

TENOMIC