targeted therapy in cancer - university of...

Targeted therapy in Cancer

S. AgelakiDept of Medical Oncology

University Hospital of Iraklion

Introduction

The concept of targeted Tx was originally described by the bacteriologist Paul Ehrlich in the late 1800s

He used the term ‘magic bullet’ to describe a chemical with the ability to specifically targetmicroorganisms

Classic anti-cancer Tx targets the loss of cell-cycle control and the genetic instability of cancer cells

Cancer cells suffer from genetic instability that results from loss of chromosome maintenance or DNA repair mechanisms

Traditional anticancer Tx mostly rely on agents (drugs and ionizing radiation) that damage DNA and the machinery that maintains chromosomal integrity

Such treatments preferentially kill certain kinds of cancer cells because these mutants have a diminished ability to survive the damage

Cytotoxicagents

Cell cycle and Cell cycle and cytotoxic cytotoxic opportunitiesopportunities

CELLCELLDIFFERENTIATIONDIFFERENTIATION

CELLCELLLIFE CYCLELIFE CYCLE

TIMETIME

CELLCELLDIVISIONDIVISION

GG22 PERIODPERIOD

(CHROMOSOME REPLICATION) (CHROMOSOME REPLICATION) SS--PHASEPHASE

GG11 PERIODPERIOD

Effects of Effects of RadiationRadiation TxTx on normal and cancer cellson normal and cancer cells

Cancer cells lack an ability to arrest the cell cycle and make the necessaryrepairs. Unfortunately, the same genetic defects may render some cancer cellsresistant to radiation treatment, as they may also be less prone at activatingapoptosis in the face of DNA damage.

CANCER CELLSCANCER CELLS NORMAL CELLSNORMAL CELLS

Loss of contact inhibitionIncrease in growth factor secretionIncrease in oncogene expressionLoss of tumor suppressor genesNeovascularization

Oncogene expression is rare

Intermittent or coordinatedgrowth factor secretion

Presence of tumor suppressor genes

Frequentmitoses

Nucleus

Blood vessel

Abnormalheterogeneous cells

Normalcell

Fewmitoses

Cancer cells are different from normalcells

The malignant genotypeActivated oncogenes

Down-regulated suppressor genes

Signal transduction/cell-cycle/apoptosis genes

These alterations result in– ↑ proliferation– ↑ angiogenesis– ↓ adhesion– ↑ invasion– ↓ apoptosis – ↑ survival

What is a “targeted” therapy?

Targeted therapy is a therapy directed at the molecular or physiologic concomitants of malignancy

This implies a DRUG acting on a MOLECULAR TARGET(necessary but not sufficient)

What makes a “drug”?

Nature Rev. Drug Discovery 4:161, 2005

What makes a MOLECULAR TARGET an IDEAL therapeutic target?

the MOLECULAR TARGET should be present in the majority of patients

the MOLECULAR TARGET should have a causative link with tumorigenesis

the MOLECULAR TARGET should have an essential function in tumor but not in normal cells

the MOLECULAR TARGET should be measurable in the clinic

measurement of the MOLECULAR TARGET should have a predictive impact on the therapy

Specific molecular targetsSignal transduction

Inhibition of tyrosine kinases (HER1, HER2, bcr-abl)Targeting of mutant oncogenes (Ras)Targeting of proteins that mediate the function of oncogenes (Raf)

Tumor supressor genes (p53, p16)

Cell cycle control (cyclin-dependent kinases)

Apoptosis regulators (Bcl-2)

Angiogenesis and metastasis (VEGF, VEGFR2, MMPs)

Targeted Cancer TxAdvantages

Selective: targets tumor cellsFewer systemic toxicities predictedDosing can be adjusted to biologicactivity of the drug May improve quality of lifeduring treatmentDramatic responses in select subsetsof patients

Approaches to block target activity

Gene therapy

Nucleus

Immuneeffectorcell

BispecificAbs

Anti-ligandMAbs

Ligand-toxinconjugates scFv-toxin

conjugates

Anti-receptorMAbs

ATP and substratecompetitors

Ribozymes and antisense oligonucleotides

Estrogen Receptor as a Success StoryRecurrence and Mortality Reductions from Tamoxifen

Early Breast Cancer Trialists’ Collaborative GroupLancet 351: 1451, 1998

Targeted therapies Some newer success stories

Bcr-Abl, c-kit

Her-2

The Gold Standard of Molecular Therapeutics: Imatinib

Tyrosine Kinases (TKs)Tyrosine phosphorylation is tightly regulated and modulates the activity of target proteins

Tyrosine kinases (TKs) are a family of enzymes thatcatalyses the phosphorylation of select tyrosine residuesin target proteins

The human genome contains ~90 TK and 43 TK-likegenes

Many proteins regulated by tyrosine phosphorylation areinvolved in cell cycle progression and/or survival

Classification of TKs

Receptor tyrosine kinases: EGFR, PDGFR, FGFR, IR Non-receptor tyrosine kinases: SRC, ABL, FAK and Janus kinase

TKs as targets in cancer therapy

Many proto-oncogenes encode protein tyrosine kinases

Protein tyrosine kinases can be hyperactivated by mutation, overexpression, structural rearrangements, and/or loss of normal regulatory constraints

TKs were implicated as oncogenes more than 25 yrs ago inretroviruses - induced animal tumors

The development of TKs inhibitors as an anticancer strategyhas been accelerated by the success of imatinib mesylate inCML

Activation of TKs

Cell membrane

Ligand binding

Activated receptor

Y Y

YYP

P

P

P

Proliferation Migration

Tumour growthand metastases

Survival

Signal transduction

Tyrosine kinase receptor

Tyrosine kinase domain

Strategies to target TKs in cancertherapy

Small molecule inhibitors occupie the TK ATP-binding site

High sequence homology in the ATP binding pocket of the kinasessuggested possible lack of selectivity

The development of STI-571 provided the proof- of-principle for the valueof TK inhibitors in cancer therapy

Cellular Selectivity of Imatinib (STI571, GLIVEC) IC50mM

Kinases Inhibited Kinases Not Inhibited

v-ABL 0.1–0.3 Flt-3 >10p210Bcr-Abl 0.25 c-Fms, v-Fms >10p185Bcr-Abl 0.25 EGF receptor >100TEL-Abl 0.35 c-erbB2 >100PDGF-R 0.1 Insulin receptor >100TEL-PDGF-R 0.15 IGF-I receptor >100c-Kit 0.1 v-Src >10

JAK-2 >100

Druker BJ et al. Nat Med. 1996;2:561-566.

Imatinib: GIST GISTs

– Infrequent tumour (~0.2% of all GI tumours)– Occur primarily in stomach (60%–70%) and small intestine with

liver metastases and peritoneal seeding – ~10%–30% malignant

Therapeutic Options– Surgery was the only effective modality– 0%–5% respond to chemotherapy with short time to failure

Outcomes– For unresectable/metastatic disease

• Estimated time to progression <2 months• Estimated survival <1 year

Imatinib: GIST Origin is linked to interstitial cells of Cajal (ICC)

Gastrointestinal pacemaker cells

Evolving definition of disease Historically difficult to distinguish from soft-tissue sarcomas

Now defined immunohistochemically c-Kit gain-of-function mutation Present in 95% of patientsc-Kit (CD117) is the causative abnormality of GISTs

KIT Mutations and GIST

•In frame mutation exon 11 (52%)•Point mutation exon 13 (1%)

•In frame duplication exon 9 (3%)

TK1

TK2

JM

THE ROLE OF KIT

Transmembrane receptor with tyrosine kinase activity

Stem cell factor is the ligand

Ligand-receptor binding leads to:

Kit dimerization, TK phosphorylation/activation signal transduction to the nucleus cell proliferation

Imatinib Mesylate in GIST:Rapid Response in Primary Tumor

CT

18FDG-PET

Pre-imatinib mesylate 4 weeks of imatinib mesylate

Courtesy of Dr. G.D. Demetri and Dr. A.D. Van den Abbeele.

Imatinib Mesylate in GIST:Rapid Response in Liver Metastasis

CT

18FDG-PET

Pre-imatinib mesylate 4 weeks of imatinib mesylate

Courtesy of Dr. G.D. Demetri and Dr. A.D. Van den Abbeele.

Randomized Phase II Trial of STI571 in Metastatic GIST

400 mg/day

Treat Dailyx 24

months

REGISTER

SCREEN

Progression

600 mg/day

STI - 571 in GIST: Pivotal Trial—Conclusions

147 patients randomized to 400 or 600 mg/d83% of patients showed a clinical benefit– 67% PR/CR– 16% stable disease (SD)

Median time to progression (TTP) was 84 weeksMedian overall survival (OS) has not been reached at median follow-up of 34 monthsImatinib mesylate has an acceptable safety profile in patients with GIST

Blanke et al. ASCO 2004 Gastrointestinal Cancers Symposium. Abstract 2.

Imatinib Mesylate in GIST Pivotal Trial — Overall Survival

100

Imatinib mesylate (pooled 400-mg +600-mg)

SWOG S8616/S9627

80

Surv

ival

(%)

60

40

20

00 1 2 3 4 5

Years after registration

• With a median follow-up of 34 months, median survival has not been reached


HER2 receptor signal transduction

Signaltransductionto nucleus

Nucleus

Binding site

Tyrosinekinase activity

Cytoplasm

Plasmamembrane

Growth factor

Gene activation CELLDIVISION

Indicators of increased HER2 production

1 = - gene copy number2 = - mRNA transcription3 = - cell surface receptor protein expression4 = - release of receptor extracellular domain

Normal Amplification/overexpression

Cytoplasm

HER2 receptorprotein

Cytoplasmicmembrane

Nucleus

HER2 DNA

HER2mRNA

1

2

3

4

Herceptin: Humanized Anti-HER2 Antibody

• Targets HER2 oncoprotein• High affinity (Kd = 0.1 nM)

and specificity• 95% human, 5% murine

- Decrease potential forimmunogenicity

- Increase potential forrecruiting immune-effector mechanisms

Scientific Rationale

Recruitment of immune cells to the tumor resulting in antibody-dependent cellular

cytotoxicity (ADCC)

First-line Herceptin®

monotherapy(H0650g)

Vogel C, et al. J Clin Oncol 2002;20:719–26

Patien

ts (%)

RR Clinical benefit rate

38

26

48

35

48

34

0

10

20

30

40

50

60 All IHC 3+ FISH+

First-line single-agent Herceptin®:

survival in all enrolled patients

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30 35 40 45 50

Prob

ability

of

surv

ival

Time (months)

Median survival: 24.4 months

Vogel C, et al. J Clin Oncol 2002;20:719–26

Adding Herceptin®

to chemotherapy improves survivalSummary of results of pivotal combination therapy trial

(H0648g)

H + AC(n=143)

AC(n=138)

H + P(n=92)

P(n=96)

H + CT(n=235)

CT(n=234)

Median TTP (months) All3+

7.8* 8.1*

6.16.0

6.9*7.1*

3.03.0

7.4* 7.8*

4.64.6

Response rate (%) 56*60

4242

41*49

1717

50*56

3231

Median duration ofresponse (months)

9.1* 9.3

6.75.9

10.5* 10.9

4.54.6

9.1* 10.0

6.15.6

Median TTF (months) 7.2* 7.1

5.65.1

5.8* 6.7

2.92.8

6.9* 7.0

4.54.4

Survival (months) 26.8 31*

21.421

22.125

18.418

25.1*29*

20.320

*p<0.05All: n=4693+: n=349 Slamon D et al. N Engl J Med 2001;344;783–92

Overall survival in IHC 3+ patients

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30 35 40 45 50

18 25

Time (months)

Herceptin® + paclitaxelPaclitaxel alone*

40%

Herceptin® + CT CT alone*p<0.05

1.0

0.8

0.6

0.4

0.2

020 29

0 5 10 15 20 25 30 35 40 45 50Time (months)

Prob

abili

ty o

f sur

viva

l

45%

Slamon D et al. N Engl J Med 2001;344;783–92

Prob

abili

ty o

f sur

viva

l

*~70% of patients receiving CT alonecrossed over to receive Herceptin®

upon progression

The addition of Herceptin®

to chemotherapyis associated with improved quality of life (QoL)

p=0.003 p=0.03p=0.07

p=0.08

QoL domains

No.

of p

atie

nts

impr

ovin

g (%

)

Herceptin® + CT CT alone

Global QoL Physical Role Social Emotional Fatigue0

10

20

30

40

50

60

Osoba D et al. Proc ASCO 2001;20:28a (Abstract 109)

Who benefits from Herceptin®

therapy?

Clinical trials have taught us that accurate assessment of HER2 status is essential to ensure that eligible patients are correctly identified for Herceptin

®therapy

Patients with IHC 3+ or FISH-positive disease achieve the greatest benefit with Herceptin

®

HERA TrialPrimary management

Surgery, (neo-) adjuvant chemoTx, RTx

RANDOMIZATION

No Herceptin®

Herceptin®

q 3 weeks x 1 year

Herceptin®

q 3 weeks x 2 years

LOADING: 8mg/kg MAINTENANCE: 6mg/kg every 3 weeks

Disease-free survival (ITT)Median FU 2 yrs

Patients(%)

100

Months from randomisation12 36

1 year trastuzumab

Observation

0 186 24 30

Events HR 95% CI p value

0.64 0.54, 0.76 <0.0001

3-yearDFS

80.674.3

218321

6.3%80

60

40

20

0

1703 1591 1434 1127 742 383 1401698 1535 1330 984 639

No. at risk 334 127

1703 1627 1498 1190 794 407 146

100

80

60

40

20

0

Patients(%)

Months from randomisation

Observation

Overall survival (ITT)

1 year trastuzumab

Events HR 95% CI p value

0.66 0.47, 0.91 0.0115

3-yearOS

92.489.7

12 360 186 24 30

5990

Median FU 2 yrs

2.7%

No. at risk 1698 1608 1453 1097 711 366 139

Targeted TxChallenges (I)

Biomarkers

Resistance

Side Effects

Why focus on biomarkers ?

Biomarkers have the potential to:

Improve the probability that the drugs which enter phase 2 aresuccessful by Designing phase 1 and 2 studies to include pharmacodynamic biomarkers

(making sure the drug hits the target)

Improve the probability that the drugs which enter phase 3 aresuccessful by Designing Phase 2 studies using biomarkers which are correlated with

clinical outcome Designing phase 2 and 3 studies which enroll higher-risk patients

(identified by prognostic biomarkers) likely to have a greater treatmentrespond (predictive biomarkers)

Improve our ability to identify toxicity signals (biomarkers whichare correlated with SAEs)

Her 2 Over-expression and The Development ofHerceptin : The Importance of a Predictive

Biomarker

Simulation of Phase III Trastuzumab Data

Phase III Trialin which 100% of patientsshow a treatment effect

Trial in which 50% of patientsshow a treatment effect

Trial in which 25% of patientsshow a treatment effect

Mark Pegram, UCLA

GIST: KIT Mutation Location Predicts Imatinib Mesylate Responsiveness

100PD/NE80

% o

f tot

al SD60 PR

40

200

KIT Exon 11(n=85)

KIT Exon 9(n=23)

No mutation(n=9)

KIT mutations are predictive of response to imatinib mesylateExon 11 mutants respond best


GIST: KIT Mutations Predict Overall Survival

0 100 200 300 400 500 600 700 800Days

KIT exon 11 (n=85)

KIT exon 9 (n=23)

No kinase mutation (n=9)

0102030405060708090

100

Ove

rall

surv

ival

(%)

Heinrich et al. J Clin Oncol. 2003;21:4342. Reprinted with permission from the American Society of Clinical Oncology.

Mutational hotspots in the Abl kinase domain conferringresistance to Imatinib

Src/Abl inhibitors include Dasatinib and others.100-300x more effective than Imatinib in blocking Bcr-Abl

tyrosine kinase autophosphorylationEffects extend to point mutations of Bcr-AblBind to active form of Abl (Imatinib binds inactive form)

Curr. Pharm. Biotechnology 7:371, 2006Leukemia 20:1542, 2006

Drugs Are NOT Safe…They Offer Benefit forRisk

Cardiotoxicity of Imatinib

Cardiac Dysfunction with Herceptin

H + AC(n=143)

AC(n=135)

H + P(n=91)

P(n=95)

Single agent(n=338)

% cardiac dysfunction 27.0 8.0 13.0 1.0 4.0NYHA III/IV (initial) 16.0 3.0 2.0 1.0 3.0NYHA III/IV (post-treatment) 6.0 0.7 0 0 1.5

% death due tocardiac dysfunction 0.7 0.7 0 0 0.9

Slamon D et al. N Engl J Med 2001;344:783–92Seidman et al. J Clin Oncol 2002; 20:1215-1221

Sunitinib related toxicitySkin toxicity

Sunitinib related toxicityHair discoloration

Success stories…. BUT….

EGFR

Angiogenesis

The Epidermal Growth Factor ReceptorThe Epidermal Growth Factor ReceptorTGFTGF-- ααAmphiregulinAmphiregulinEGFEGFBetacellulinBetacellulinEpiregulinEpiregulinHBHB--EGF..EGF..

LigandsLigands::

NeuregulinNeuregulinEpiregulinEpiregulinHBHB--EGFEGFBetacellulinBetacellulin

NoNoKnownKnownligands ligands NeuregulinNeuregulin

erberbB1 B1 HER1HER1EGFREGFR

erberbB2B2HER2HER2neuneu

erberbB3 B3 HER3HER3

No TKNo TKActivityActivity

erberbB4 B4 HER4HER4

Receptors:Receptors:

622 622 aaaa

22 22 aaaa

542 542 aaaa

CysteineCysteine--richrichDomainDomain

TyrosineTyrosine--KinaseKinaseDomainDomain

NeoplasticNeoplastic proliferationproliferation

EGFR expression in solid EGFR expression in solid tumorstumors

HeadHead & Neck& Neck(SCC)(SCC)

CRCCRC

NSCLCNSCLC

EGFR EGFR expressionexpression

HeadHead and Neck (SCC)and Neck (SCC) 90 90 -- 100100 %%

NSCLCNSCLC 40 40 -- 80 %80 %ProstateProstate cancercancer 40 40 -- 80 %80 %BreastBreast cancercancer 14 14 -- 91 %91 %

ColorectalColorectal cancercancer (25 ) (25 ) -- 80 %80 %

GastricGastric cancercancer 33 33 -- 74 %74 %

OvarianOvarian cancercancer 35 35 -- 70 %70 %

PancreaticPancreatic cancercancer 30 30 -- 50 %50 %

Invasive growthMetastasesAdvanced stageChemo-Resistance

EGFR expression – clinical significance

Neal (1985)PoorBladder

Sainsbury (1985)PoorBreast

Volm (1998)Veale (1993)Ohsaki (2000)Pavelic (1993)Increased

Decreased OSPoorPoor

NSCLC

Dong (1998)Yamanaka (1993)Decreased OS

PoorPancreatic

Grandis (1998)Maurizi (1996)

Decreased DFSDecreased OS

PoorHead and Neck

Mayer (1993)Hemming (1992)

IncreasedPoorColorectal

ReferencesRisk ofmetastases

SurvivalPrognosisTumor type

DFS = disease-free survival; OS = overall survival; NSCLC = non-small-cell lung cancer

© PW Dec 2002

MTTCMTTCMTTC

2-63

Gefitinib(IressaTM, ZD 1839)

Erlotinib (TarcevaTM, OSI-774)

ZD 1839OSI-774

N

HN

NOO

OO

HN

N

N

O

O

Cl

F

NO

EGFR Selective Small MoleculesTyrosine Kinase Inhibitors

EGFR tyrosine kinase activity requires ATPZD1839 and OSI-774 compete for ATP bindingReversible inhibitorsOrally bioavailable small molecules

EGFR TKIs in NSCLC

Based on promising data from phase I studies gefitinib and erlotinib were preferentially studied in NSCLC

Gefitinib 500 mg

Gefitinib 500 mg

Regimen PR Median Survival 1-yr survival

Gefitinib 250 mg

Gefitinib 250 mg19%18% 7.6 mo IDEAL1

12%9%

8.1 mo

6.1 mo6.0 mo

IDEAL 2

Trial

--------

29%

6%Best supportive care 0% 4.6 mo Shepherd Docetaxel 7.0 mo

19%29%

24%

Perez-SolerErlotinib 9.0 mo14% 40%

Combination therapy — Randomized phase III trials of EGFR TKIs

Four phase III trials trials with > 4000 NSCLC pts failed to show survival benefit when gefitinib or erlotinib were combined with standard CT

INTACT 1INTACT 2

TRIBUTE

The trials also failed to meet the secondary endpoints of RR and TTP

Erlotinib in Previously Treated NSCLCBR.21 Study Design

Erlotinib in Previously Treated NSCLCErlotinib in Previously Treated NSCLCBR.21 Study Design BR.21 Study Design

RANDOM I ZE

Erlotinib* 150mg daily

StratificationCentrePerformance status

0/1 vs 2/3Response to prior Rx(CR/PR vs SD vs PD)Prior regimens(1 vs 2)Prior platinum (yes vs no)

Placebo 150mg daily

*2:1randomisation

CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease

BR.21: Οverall Survival

Tarceva (n=488)

Placebo (n=243)

Median survival (months) 6.7 4.7

1-year survival (%) 31 21

42.5% improvement in median survival

Surv

ival

dis

trib

utio

n fu

nctio

n

Survival time (months)

HR=0.73, p<0.001*

1.00

0.75

0.50

0.25

00 5 10 15 20 25 30

Tarceva

Placebo

Shepherd F, et al. N EnglJ Med 2005;353:123–32

*HR and p (log-rank test) adjusted for stratificationfactors at randomisation and HER1/EGFR status

EGFR inhibitors – Why are 1 in 10 like this?

Somatic Μutations in the Tyrosine-Kinase (TK) Domain of

HER1/EGFR

EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy

Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M

Science, 29 April, 2004

Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung cancer to gefitinib

Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brian BS, Brannigan W, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA

New England Journal of Medicine, 20 May, 2004

EGFR mutations in NSCLC

Most common mutations (almost 90%)Exon 19 deletions (E746_A750)Missense mutations, exons 18 and 21 (L858R)

Challenges: EGFR in Lung Cancer

Phase III INTACT Trial

Phase II IDEAL Trial

J. Clin. Oncol. 23:8081, 2005

HER1/EGFR IHC

Scored positive if membranous staining (partial or complete) present in ≥10% of tumour cells

DAKO EGFR PharmaDxTM Kit

Disomy≤2 gene copies in >90% cells

Low Trisomy3 gene copies in >10% <40% cells

High Trisomy3 gene copies in ≥40% cells

Low Polysomy≥4 gene copies in >10% but <40% cells

High Polysomy≥4 gene copies in ≥40% cells

Gene AmplificationGene/chromosome ratio >2 or ≥15 gene copies in ≥10% cells

EGFR FISH Scoring Categories(Cappuzzo F, et al. J Natl Cancer Inst 2005;97:643–55)

The biology of EGFR mutant NSCLC Different kinetics of receptor dephosphorylation

Higher sensitivity to gefitinib inhibition

More potent stimulation of PI3K and STAT paths

Angiogenesis is required for solid tumor growth

1-2 mm3

The VEGF family are critical tumor-secreted angiogenic factors

Migration, permeability, DNA synthesis, survival

Lymphangiogenesis

– P– PP–

P–

– P– P

P–P–

– P– P

P–P–

VEGF-AVEGF-B

PlGF

VEGF receptor-1

VEGF-A

VEGF receptor-2

VEGF-CVEGF-D

VEGF receptor-3

Angiogenesis

Adapted from Ferrara N. Nat Med 2003;9:669–76

Avastin plus IFL (AVF2107g) as1st-line therapy of metastatic CRC

May receive Avastin beyond

disease progression

No Avastin beyond disease

progression

May receive Avastin beyond

disease progressionPreviously untreated

metastatic CRC(n=923)

IFL* + placebo(n=411)

IFL* + Avastin(5mg/kg, every

2 weeks)(n=402)

5-FU/LV† + Avastin(5mg/kg, every

2 weeks)(n=110)

Arm closed to enrolment

Hurwitz H, et al. N Engl J Med 2004;350:2335–42

• Primary endpoint: duration of survival*Bolus 5-FU/LV†Roswell Park regimen

Avastin plus IFL (AVF2107g): overall survival

Median survival (months)IFL + placebo: 15.6 (95% CI: 14.3–17.0) vsIFL + Avastin: 20.3 (95% CI: 18.5–24.2)HR=0.66 (95% CI: 0.54–0.81)p<0.001

1.0

0.8

0.6

0.4

0.2

00 10 20 30 40

Time (months)

IFL + Avastin

IFL + placebo

15.6 20.3

Prob

abili

ty o

f su

rviv

al

CI = confidence interval Hurwitz H, et al. N Engl J Med 2004;350:2335–42

Angiogenesis inhibitors

Are there any biomarkerscorrelated with clinical outcome?

Using Biomarkers/Surrogates which arecorrelated with clinical outcome

IFL/Placebo (n=412) RR=34.8%

IFL/Avastin (n=403)RR=44.8% p=0.004

1.0

0.8

0.6

0.4

0.2

00 10 20 30 40

Time (months)

IFL + Avastin

IFL + placebo

15.6 20.3

Prob

abili

ty o

f su

rviv

al

CI = confidence interval Hurwitz H, et al. N Engl J Med 2004;350:2335–42

Phase III MBC Trial With Avastin:Progression-free Survival

RR is not always a good biomarker though!

Cap/Placebo (n=230) RR=19.1%

Cap/Avastin (n=232)RR=30.2% p=0.006

DCE-MRI with Gadolinium: A Biomarker study for

PTK787 in Colorectal Cancer Patients

Morgan et al. JCO. 21:3955-64

Targeted therapiesChallenges (II)

Integration with other treatment regimens

Complexity in molecular targets

One specific target vs multiple targets

“Biological Effective Dose” rather than “Maximal Tolerated Dose”

Cell regulation: complex molecular interactions

WNT

Cell

ECM

Growth factors (e.g. EGF, amphiregulin TGFα)

Nuclear receptors(e.g. oestrogen)

Survival factors(e.g. IGF1)

Cytokines(e.g. ILs, IFNs)

Deathfactors

(e.g. FasL)

Anti-growth factors(e.g. TGFβ)

GPCR ligands

Frizzled Disheveled

GSK-3β

APC

Tubulin

TCF

Integrins

β-Cutenin β-Cutenin:TCFE-Cadherin

CdC42 PI3K Rac

Fak Cas CrkSrc

FynShc

NF1

RasRTK Grb2SOS Ral MEK MAPK MAPK

MEKK

PLC

PKC Mos MKKs JNKs

ELK

Myc:Max

Max:MaxFos

JUN

Abl

7-TMRCdC42 Rac Rho

G-Prol Ad Cycl PKA CREB

PKC NF-κB

NHR (e.g. ER)

NF-κB

P13K Akt Akka IKB

PTEN?

Stat 3.5

Stat 3.5

Stat 3.5

Bcl XL

Caspase 9

Cytochrome C

Jaks

Bad BidMitochondria

Bim, etc.Abnormalitysensor

Bcl 2

Cell Death(Apoptosis) Caspase 8

Fap

FADDBcl 2

Bax

ARF

p53

Mitochondria

MDM2

DNA damagesensorCell

Proliferation(cell cycle)

Changesin Gene

Expression

Cycl E:CDK2 p21

p27

E2Fs

Rb

p16

Cycl D:CDK+ p15 Smads

RTK

Cytokine R

Decoy R

Fas

SurfaceAg

TGFβR

HPVE7

Complexity

Analysis of 13,023 genes in 11 breast and 11 colorectal tumors

189 genes were significantly associated with the cancer process, affecting a wide range of cellularfunctions

An average of 11 mutant genes per tumor were cancer associated

Science 314: 268 - 274

One vs multiple targetsIn Defense of the “General” Molecular Target

Binding of Multiple Myeloma (MM)cells to bone marrow stromatriggers IL-6 release in aNF-kB dependent manner (1994)

Proteasome inhibitors inhibited NF-kB activationIn vivo inhibition of MM cells in SCID mice (1999)

Phase II trial of Bortezomib in refractory relapsed MM35% Response rates, Response duration of 14 monthsvs. 6-9 month expected survival

Approved 2003EJC Suppl. 2: 3-6, 2004

Other Targets of Proteasome Inhibitors

Nature Rev. Cancer 4: 349, 2004

Other Targets of Proteasome Inhibitors

Other “General” Molecular Targets

Histone deacetylase inhibitorsDNA methylation inhibitorsHsp90 inhibitors

How are tumor cells more sensitive to inhibition than normal cells?

Is there a single, dominant molecular pathway?Or is there partial inhibition of multiple pathways?

How do you follow this in a clinical trial?

Are multiple targets “better”?

Maximal tolerated vs biological doseRecommended phase II dose and primary reason for dose recommendation

Recommended phase II dose / Primary basis for recommendation No. of trials No. of agents

Not stated 6 6

Not recommended 2 1

RecommendedToxicity 35 19Pharmacokinetic data 11 7Other trial results (toxicity) 2 2Clinical activity* 1 1PBMC findings† 1 1Effect in tumor (target or response) 1 1Convenient dosing schedule 1 1

Total 60

Phase I trial design for solid tumor studies of targeted, non-cytotoxicAgents: Theory and practice. JNCI 96: 990, 2004

Targeted TxChallenges (III)

Consider Multiple Aspects of Tumor Progression— Cancer stem cells— Tumor dormancy— Micrometastatic disease

Consider additional steps in metastasis for therapeuticintervention

Normal stem cells:Extensive capacity for self renewal that allows maintenanceof the undifferentiated stem cell pool;Strict regulation of stem cell number;Abililty to undergo differentiation to reconstitute functional elements in the tissue

Cancer stem cell:A cancer cell that has the ability to self-renew giving rise to anothermalignant stem cells as well asundergo differentiation to give riseto phenotypically diverse nontumorigenic cancer cells

Curr. Opinion in Genetics & Development 14:43, 2004

Tumor Dormancy

B. Solitary tumor cell in liver d25

C-D. Solitary cells labeled withnanoparticles 11 w.

Cells labeled with flourescent nanospheres, which will be eliminated in 3 divisionsCells Ki-67 negativeCells can be harvested, grown in vitro, will form tumors upon re-injection

Cancer Res. 62:2162, 2002

Gross Metastases: Solitary Cells:

Breast Ca. Res. Trt. 2812-03: 1, 2003

What Steps In Metastasis Are Open for Therapeutic Intervention?

Future Cancer Treatment

20th century

Cytotoxic therapyRadiotherapy

Hormonal therapySurgery

21st century

Targeted therapy

Patient-specific therapy

Radiotherapy

Hormonal therapy Chemotherapy

Biologicaltherapies• Herceptin®

• IressaTM

• Glivec• ?

Tumour type

Disease stageTumor phenotype

Tumor genotype

Treatment

Target Discovery & ValidationAssay Development

High-Throughput Screens, Secondary and Tertiary Assays

Lead SelectionLead Optimization, Preclinical Efficacy

Preclinical Toxicity

Clinical Trial

0 1 2 3 4 5 6 7 8Years

Adapted from Nature, 2005

Drug development is getting and moreexpensive

Tufts Center for the study of Drug Development (CSDD)

Estimate of cost to develop a new drug (2003 study) –897 million in 2000 dollars

―Included in the cost are expenses of drug failuresand the impact that long development times haveon investment costs

―Estimates in prior studies was $802 million in 2001 and $231 million ($318 million in 2000 dollars) in1987

Driver for increasing costs thought to be clinical trialscosts

Declining success rates

How shall we achieve our goals towardstargeted Tx? (I)

Target identification…

The Achilles heelof cancer

How shall we achieve our goals towardstargeted Τx? (II)

Drugs that intervene in pathways mediating growth, deathmetastasis and resistance

Explore rational combinations More than limited preclinical experimentation Identification of biomarkers of efficacy

Molecularly based clinical trialsMolecular test for entryDevelop and validate biomarkers of activity

In conclusion…

Developing targeted therapyisn’t easy

The right thing for patients ismatching drugs with patients

that will benefit and not treatingthose that will not

Molecular biology should be incorporated into clinical trials

To this end

Tumor sample should be available for molecular analysis

targeted therapy in cancer - university of...

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