in partnership with

Drug development for Neuroblastoma – a preclinical hospital to drive trials and drug development for the field

Nov. 30, 2013

Ben Herring Trust

Felix White Foundation

Cole’s Family Foundation

Treatment for High-Risk Neuroblastoma(new interventions)

Prevention

Ultra-high risk

stratification

Targeted maintenance

Residual disease

eradication

X

Major Categories of New Therapeutics

• Chemotherapeutics• Small-molecule drugs

• Gene-targeted drugs• Oncoprotein-targeted drugs• Metabolic pathways• Differentiation pathways

• Immunotherapeutics – GD2, ALK, cellular• Radiotherapeutics – antibodies, metabolites

Panel Members

• Mark Gaze, UCLH, radiotherapy approaches

• John Anderson, GOSH, novel immunotherapies

• Hung Tran, CHLA, novel therapies through NANT

• Shakeel Modak, novel immune/therapies at MSKCC

• Rupert Handgretinger, Tubingen, immunotherapy/transplant

• Low number of drugs available for investigation in children • Clinical trials not optimally designed – do not Select the best drug  Ask a clear scientific question Select patients who might benefit from a new drug Understand what is happening in the tumour Compare with a standard treatment

• Clinical trials take a long time to develop

Why do new drug trials take so long to develop? 

Why do new drug trials take so long to develop? 

• Low number of drugs available for investigation in children • Clinical trials not optimally designed – do not Select the best drug  Ask a clear scientific question Select patients who might benefit from a new drug Understand what is happening in the tumour Compare with a standard treatment

• Clinical trials take a long time to develop• Pre‐clinical science and the hypotheses underpinning a therapy intervention take massive effort and funding to develop

• Without adequate science from pre‐clinical research, clinical trials are not hypothesis‐driven

New drug trials that are open

0

5

10

15

20

25

30

35

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Total number of openstudies

Molecular targeted agentstudies

First in Child

The Royal Marsden HospitalPaediatric Clinical Drug Development Team

Andy Pearson, Lucas Moreno, Lynley Marshall,  Lou Chesler, Giuseppe Barone, Susanne Gatz,Dominik Schrey, Fernando Carceller, Andrea Boast, Gill James, Tracey Crowe , Beth Leach & Research Nurse Team 

The Institute of Cancer ResearchBiology, Pre‐clinical Trials and Drug 

Development TeamLou Chesler, Lynsey Vaughan, Teeara Berry, Evon, Poon, Sanne Kuijpers, Zai Ahmad, Xiaodun Li, Karen Barker, Lizzie Cullis, Laura Glass, Giuseppe Barone, Albert Hallsworth, Michelle Garrett (Biomarkers)Simon Robinson  (Pre‐clinical Imaging)David Gonzalez (Clinical Assays)Paul Workman (Chemistry‐Drug Synthesis)

AACR Team Science Award 2012ICR/RMH Contributing of New Drugs to Cancer Trials

9

The AACR Team Science Award recognizes an outstanding interdisciplinaryresearch team for its innovative and meritorious science that has advanced orlikely will advance our fundamental knowledge of cancer or a team that hasapplied existing knowledge to advance the detection, diagnosis, prevention, ortreatment of cancer.

Major Advances in Pre-clinical Research

1. Sequencing of patients and identification of molecular targets

2. Medicinal development of targeted drugs

3. Development of pre-clinical target-driven cancer models

1. Molecular targets in neuroblastomaMutations are being rapidly identified

11

Mosse and Maris, U.Penn/CHOP NCI – TARGET, Versteeg, AMC Amsterdam

MYCN (sporadic) (Schwab et al., 1983) - “an undruggable target” ALK (familial, sporadic) (Mosse, George, et al., 2008) – “an eminently druggable target”

Drugs that target the specific molecules that are required for the growth of cancer tissue ‐ not present in normal tissue

Ideally “reduced” toxicityAdult Targets Lung Cancer – EGFR, EML4‐ALK GIST – c‐KIT Melanoma – BRAF  V600E Breast + Ovarian – BRACA1/2 Breast Cancer ‐ HER2

Neuroblastoma Targets – MYCN, ALK

Centre for Cancer Therapeutics at ICR – Paul 

Workman

2. Targeted Drugs for Neuroblastoma

13

Relevant clinical target

muscle‐tTA

X‐tTATRE MYCNLuc

Doxycycline

brain‐tTA

nerve‐tTA

X Medulloblastoma

Rhabdomyosarcoma

Neuroblastoma

Accurate in vivo models

OrthotopicsCell linesHT screens & pD assaysMouse hospital trials

PI103

+MYCN

-MYCN

3. Cancer models for Neuroblastoma

Drugs for MYCN and ALKThe two most common targets

1. MYCN – most common prognostically significant genetic change (gene amplification) –undruggable?

2. ALK – inherited and acquired mutations (most common single gene mutation) – druggable now (Crizotinib).

14

MYCN in neuroblastoma 15

• MYCN amplification in 25% of neuroblastoma

• MYCN amplification in infants and localised neuroblastoma – major prognostic factor –10% versus 85% survival

Years From Diagnosis

Amplified > 18 mo

Not  Amplified

Overall Survival in Neuroblastoma

Amplified < 18 mo

% S

urvi

val

The MYCN driven neuroblastoma Pre-clinical model

16

Human MYCN cDNATyrosine-OH promotor

Weiss and Bishop, EMBO J, 1997 Reviewed in, Chesler, SCB, 2011

kidney

tumour

IGF-1R

PI3K AKT

Ras/Raf

MEK/ERK

mTOR

DALO

BEZ235GDC0980

AT9283CCT137690

RIDAAZD8055 AurK

GSK‐’212

GSK-’436Vemurafenib

Chesler et al. Cancer Res 2006, ANR2010, AACR2010 AACR2011, Mol Cancer Ther 2011, ANR2012, CCR2012, Cancer Cell 2012

GDC0941

Functional Imaging

Targeting MYCN protein stability

Drugs that block MYCN 18

MYCN causes resistance to PI3Ki mTORC2 inhibitors degrade MYCN

19

Mycncl. C3

pAkt473pAkt308

AktpS6

S6GAPDH

Vehicle mTOR Vehicle PI3K

200

150

100

0

-100

-150

Perc

ent V

olum

e C

hang

e

250

200

150

100

0

-100

-150

Vehicle mTOR Vehicle PI3K

mTOR PI3K

Unpublished work

Four classes of MYC/N inhibitor

Type I – transcriptional inhibitorsJQ1, iBET, Pfi1, ICR compound/s, others

Type II – stabilization inhibitors (interact with MB1)(AKT, mTORC1/2, others)

Type III – proteasome complex inhibitors (AURKA, UBC, USP inhibitors)

Type IV – synthetic lethal/functional inhibitors(CDK2 and CHK1 inhibitors, metabolic inhibitors)

20

Clin Cancer Research, Nov. 2013

ALK mutations identified in NB 2009ALK GEMM-therapeutics 2012

21

TH-driven ALKF1174L expressionTH-ALKF1174L/MYCN GEMM

22

TH MYCN TH ALKF1174Lx

Berry, CA Cell, 2012

ALK mediates resistance to CrizotinibNo efficacy as a single agent

23

Berry, Ca Cell, 2012

Combination of Crizotinib with mTOR inhibition is effective against ALK

24

Teeara Berry, Louis Chesler, Rani George, Cancer Cell 2012

Targeting ALK – Combination approach 

Patient w/ germline R1275Q mutation Crizotinib (165-365 mg/m2), 7 courses

26

Mosse, ASCO, 2012

C1 C7

Neuroblastoma

ALCL

Development of Biomarkers

Yap et al, Nature Rev Cancer 2010; Yap , JCO 2011; Garrido‐Laguna Nat Rev Clin Onc 2011

MK2206

MK2206

Predictive ‐What is the best drug for an individual patient?

Vemurafenib

Pharmacodynamic ‐ Is the drug working in the way we expected?

MK2206

Future imaging – anatomic correlationTranslational imaging for clinical use

28

tk

TH-ALKF1174LMYCN

TH-MYCN

TH-ALKF1174L

MYCN

TH-MYCN

PET MRI MRI perfusion imaging

Simon Robinson Laboratory, ICR

Pharmacodynamic Biomarker

Ganglioneuroblastoma (7 years old)

Miyazaki, et al. ISMRM 2011

Glioblastoma (10 years old)

Implemented in the Beacon –Neuroblastoma  Trial

Is  the drug tumour targeting  tumour blood vessels?

DCE MRI

Models with multiple mutationsRepresentative of relapse patients

30

XTH MYCN

XMYCNTP53

ALK/ALKF1174L

p53ERTAMTH‐ALK/ALKF1174L

MYCNPhox2b

THPhox2B Sox2/10 dHand2Promotors:

Trial designs (single agent/combinations):• Intervention (induction)• Prevention• Survival extension• Chemo/Relapse• Chemo/MRD• Imaging is a key driver to all of these trials

Chemoresistant relapse mouse

Brain Tumour Cancer Models 31

D

Control NeuN Ki67 MYCN

0.E+00

5.E+09

1.E+10

2.E+10

2.E+10

3.E+10

1 8 15 22 28 32 39

Days post-implantation

500dox/CD133-

50 CD133+

500 CD133+

100 CD133+

Pre-clinical Drug Trials An Equivalent “HR” Trial

32

Models – Imaging – pK – online pathology – genomics - integrative dataflow – formalised reporting

Induction Consolidation Retrieval(phase I/II/III trial)

Chemo combinations

Targeted single / combinations

MRI/US BIOPSY MRD “biopsies”

Tumour Board

refractory

remission

MRD

XRT

HD-chemo

Surgery

Immunotherapy

Differentiation

Anatomic/functional imagingPharmacokinetics

Toxicity

Mol. PathologyGross and traditional Path

Genomics/sequencing

Chemo backbone

-/+ targeted agents

XRT

Relapse

Progression

A1

A2

A1

A2GEMM

Pre-clinical Drug PipelineFrom Mouse hospital trials

33

GENE TARGET/S COMPOUND/S COMPLETED CLINICAL TRIALPROPOSED

CLINICAL TRIAL INITIATION

MYCN PI3K ZSTK474, GDC0941 XPI3K/mTOR NVPBEZ235

GDC0980, Torin1/2XX

20122012

mTOR(kinase)

(rapalogue)

WY132AZD8055, AZD2014INK128RapamycinTemsirolimus

XX

XX

X

AURKA/B MLN8054MLN8237CCT690 (ICR)CCT736 (ICR)VX689AT9283

XXXXXX

XX

USA 2010

Spring 2010CDK2 AT7519 XBRD4 JQ1, iBET, Pfi1CHK1 CCT244747 X 2012PARP AZD2281 X 2012

ALK ALK crizotinib XLDK378 X X Feb 2013undisclosed

ALK immunotherapeuticALK/mTOR Crizotinib/temsirolimus

Critozinib/AZD2014XX

Late 2013

ALK/HSP90 AUY922 XVEGFR2 VEGFR2 mAb

VEGFR2 kinaseAvastinAZD2171

XX

Jan 2013

MDM2 MDM2 Roche pipeline X X Late 2014

Early Phase Studies Early 2013 Neuroblastoma

2013 2014 2015 2016 2017

• Ph I LEE011 CDK inhibitor (Novartis)

• Ph I/II Lutetium dotatate NBL (CR CTU)

• Ph IIb Beacon‐NBL (CR CTU)

• Ph I Abraxane (Celgene)

• Ph I Volasertib I (BI)

• Ph I/II Trametinib MEK inhibitor (GSK) 

• Ph I LDK 378 ALK inhibitor (Novartis)

• Ph I/II Abraxane (Celgene)

• Ph I/II Crizotinib + temsirolimus ‐ ALK (CTU)

• Ph I/II trial GD2‐CAR transduced T‐cells (UCLH)

• Ph I /II study  CI ch14.18/cho antibody and IL2 (CR CTU)

• Ph I/II Regorafenib (Bayer)

• PI3K Inhibitors• TORC1/2 Inhibitors• HSP90 Inhibitors• PARP Inhibitors

• Fusion Protein IL2 + GD2• ALK Vaccines• ALK CAR • Alk Antibodies

Earlier stages of planning

in partnership with

x

Centre for Pre-Clinical Drug Development, July 1 2011

in partnership with

x

x

Centre for Pre-Clinical Drug Development, Opens, July 1 2014

Translational drug developmentWorkflow in the ICR mouse hospital

37

in partnership with

Paul WorkmanAndrew PearsonPaul ClarkeJulian BlaggSpiros LinardopolousAlan AshworthChris LordMichelle GarrettSimon RobinsonSue EcclesJanet ShipleyChris JonesSergey PopovKhin Thway

Chesler labLynsey Vaughan Teeara BerryEvon PoonSanne Kuijpers

Clay GustafsonWilliam WeissYvan Chanthery

Fred Swartling

Martin Eilers

Rani GeorgeNathanael GrayNai-Kong Cheung (MSKCC)Wenchao WantScott RodigBandana Sharma

John MarisYael Mosse