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Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response to anti-angiogenic agents: focus on Sunitinib Antonio Russo

Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

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Page 1: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

Università degli Studidi Palermo

DIPARTIMENTO DI ONCOLOGIA

SEZIONE DI ONCOLOGIA MEDICA(Dir. Prof. Nicola Gebbia)

Surrogate biomarkers in

evaluating response to

anti-angiogenic agents: focus on

SunitinibAntonio Russo

Page 2: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

• New technologies allowing large-scale measurement of genomic (and other) biomarkers

• Many new (targeted) therapeutic options emerging

• Optimizing and individualizing therapy becoming increasingly urgent and theoretically feasible

• However, very few potential biological markers developed to the point of allowing reliable use in clinical practice

CANCER BIOMARKERS

Page 3: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

PrognosticNatural history

regardless of treatment

Treatment decision

Predictive

CANCER BIOMARKERS

Ongoing treatment evaluation

Surrogate

DiagnosticScreening

RiskPredisposition

Page 4: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

MARKER +

MARKER -

No treatment or

Standard, non targeted treatment

CANCER BIOMARKERS as PROGNOSTIC

Prognostic

Single trait or signature of traits that separates different risk classes with respect to an

outcome of interest

Page 5: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

0 5

100

1 2 3 4

.

YEARS

LOW RISK

INT. RISK

HIGH RISK

80

100

20

RELA

PS

E-F

REE (

%)

40

60

PROGNOSTIC GOAL: “EARLY STAGE” CANCER

Under each curve → pts cured with local-regional therapy

Page 6: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

Single trait or signature of traits that separates groups with a different

outcome in response to a particular (targeted) treatment

Predictive

CANCER BIOMARKERS as PREDICTIVE

No treatment

or Standard

Targeted

treatment

MARKER +

MARKER -

Page 7: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

PREDICTIVE GOAL: “EARLY STAGE” CANCER

0 51 2 3 4

YEARS

RELA

PS

E-F

REE (

%)

LOW RISK

INT. RISK

HIGH RISK

100

20

60

40

80

SURGERY ALONE

SURGERY + CHEMOTHERAPY

Pts with residual micrometastases

SENSITIVE to adjuvant

CT/targeted therapy

Page 8: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

ENDPOINTS OF CANCER CLINICAL TRIALS:

Why are surrogate biomarkers necessary in determining the activity of targeted therapies?

Tumor Response (WHO, RECIST)

Time To Progression (TTP)Progression-Free Survival (PFS)

Overall Survival (OS)

Quality of Life (QoL)

Determining the efficacy of treatment

Determining the activity of treatment

Page 9: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

CANCER BIOMARKERS as SURROGATE ENDPOINT

The modulation of a trait or a signature of traits that reflects

the activity of a targeted therapy and is associated to

the clinical endpoint of interest

Surrogate Endpoint

Targeted therapy

Months

Response Lack of responseMark

er

lev.

Page 10: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

1. EARLY surrogate measures of benefit

2.Association with the clinical outcome of

interest

3.Minimally/non-invasive, reproducible,

reliable, cost-effective

4.More rapidly informative and with smaller

sample sizes than traditional endpoints

FEATURES OF BIOMARKERS as SURROGATE ENDPOINT

Page 11: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

PrognosticNatural history

regardless of treatment

Treatment decision

Predictive

Some Biomarkers

might have a Prognostic,

Predictive and Surrogate role

CANCER BIOMARKERS: summary

Ongoing treatment evaluation

Surrogate

Controlled studies are required to determine the contributions made by a particular marker

Page 12: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

ACTIVITY

EFFICACY

Biomarkers in the development of antiangiogenic therapies

Confirmation of the biological antitumor activity

Definition of optimalbiological dose and schedule

Early identification ofresponders VS non responders

PRECLINICAL

PHASE I

Early detection ofpts developing resistance

PHASE II

PHASE III

Page 13: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

PericyteEndothelial

cell

Capillary Vessel

Tumor and blood vessels

Page 14: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

VEGF and angiogenesis

Adapted from Kerbel RS NEJM 2008

NEUROPILIN

Page 15: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

ANG-2

VasostatinTHBS1/2

VasohibinEndostatin

The balance of angiogenesis

Anti-angiogenic

factors

Pro-angiogenic

factors

SDF-1 ANG-1

Leptin

PlGF

bFGFVEGF-B

PDGF

VEGF-D

VEGF-C

VEGF-A

Page 16: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

PDGFbFGF

PlGF VasohibinVasostati

nbFGF

PlGF-APDGF

VEGF-AVEGF-A

↑ VEGF and other pro-angiogenic factors (PDGF,

bFGF) and “escape” from therapy

ANG-1

Vasohibin

Vasostatin

THBS1/2

SDF-1 PDGFbFGF

VEGF-A

VEGF-A

Response to anti-angiogenic therapy

and normalized vasculature

VEGF-AVEGF-A

VEGF-A

VasohibinVasostati

nVEGF-AVEGF-A

VEGF-AVEGF-A

Early tumors show ↑ expression of VEGF

and associated abnormal

vasculature

Tumor angiogenesis & anti-VEGF therapy

Review of Literature 2008

Page 17: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

Molecular Marker

PtsGene

Alterations

Predicted Response

to treatment

VHL1 123Loss-of-function

mutationsGood response to

VEGF therapy

HIF-1/HIF-22 43High Expression

LevelGood response to

Sunitinib

Single Nucleotide Polymorphisms

(SNPs)3

42Various non

synonymous SNPsSignificant Sunitinib

toxicity

1. Choueiri TK et al. J Urol. 2008 Sep;180(3):860-52. Patel PH et al. ASCO 2008. Abstract 50083 Faber PW et al. ASCO 2008. Abstract 5009

VEGF-targeted therapies in RCC:are there PREDICTIVE BIOMARKERS?

Page 18: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

4400

8551 214 553 554 676 677

Ex 1 Ex 2 Ex 3

5’UTR 3’UTR

1 14 54 63 204155 213163114

VHL (Von Hippel-Lindau) is a tumor suppressor gene located on chromosome 3p25

3 codifing exons VHL genetic abnormalities present in 60-90% of patients with sporadic RCC

• VHL mutated in 50-70% of patients with sporadic RCC• VHL silenced by hypermethylation in an additional 5-20%

VHL gene and RCC

Review of Literature 2008

Page 19: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

Proximal nephron

Distal nephron

CLEAR CELL CARCINOMA (75%)

VHL mutation (70%)

Hypermetilation (20%)

Loss of Heterozygosity at 3p25

PAPILLARY CARCINOMA (15%)

Type 1

Type 2

c-Met mutation

FH mutation

Type 1

Type 2

ONCOCYTOMA (5%)

CHROMOPHOBE (5%)

Collecting duct, undifferentiated (rare)

RCC: histologic and molecular characteristics

Page 20: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

Role of VHL in RCC progression

EGF

PDGF

VEGF

Endothelial or stromal cell

EGF

PDGFVEGF

EGF PDGF

VEGF

Tumor cell

RAF

MAPK

Erk

RAS

PI3K

AKT

mTOR

eIF-4E

VHL mut

HIF1-a

Degradation by proteasome

Ub

α βHIF

RAF

MAPK

Erk

RAS

PI3K

AKT

mTOR

eIF-4E

α βHIF

Paracrin function

Autocrin function Tumor

cell

RAFM

APK

Erk

RAS

PI3K

AKT

mTO

ReIF-4E

VEGF

VEGF

VEGF

VEGF

VEGF

Intracrin function

Page 21: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

Targets of anti-VEGF therapies in RCC

EGF

PDGF

VEGF

Endothelial or stromal cell

EGF

PDGFVEGF

EGF PDGF

VEGF

Tumor cell

RAF

MAPK

Erk

RAS

PI3K

AKT

mTOR

eIF-4E

VHL mut

HIF1-a

Degradation by proteasome

Ub

α βHIF

RAF

MAPK

Erk

RAS

PI3K

AKT

mTOR

eIF-4E

α βHIF

Paracrin function

Autocrin function

TEMSIROLIMUS

BEVACIZUMAB

SUNITINIB

SORAFENIB

Page 22: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

Location of VHL mutation

Exon 3

27%Ex

on 1

42%

Exon 2

32%

N=19

N=25

N=16

Type of mutation

Frameshift

48%

Missense

22%

Splice

8%

Non sense10%

N=5N=13

N=7

N=6

N=29

Characteristics of VHL mutations in 60/123 (49%) mRCC pts

Adapted from Choueiri TK et al. J Urol. 2008 Sep;180(3):860-5

Page 23: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

FACTOR N* ORR (%) P-Value

Response 122 45/122 (37%)

VHL status

Mutated

Metilated

59

12

27 (46%)

2 (17%)

Wild Type 51 16 (31%)

41% ORR

31% ORR

vs p = n.s.

*one pts with inadeguate follow-up

VHL STATUS and RESPONSE to VEGF-targeted therapies

Adapted from Choueiri TK et al. J Urol. 2008 Sep;180(3):860-5

Page 24: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

FACTOR N* ORR P-value

“Loss Of Function” (LOF) mutations

(frameshift, non sense, splice and

inframe deletions/insertions)

4624/46 (52%)

vs

Wild type 51 16/51 (31%)

Types of VHL mutations and response to VEGF-targeted therapies

0.04

*one pts with inadeguate follow-up

Adapted from Choueiri TK et al. J Urol. 2008 Sep;180(3):860-5

Missense mutations were excluded because usually they don’t result in a LOF of the VHL protein

Page 25: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

VHL Status Sunitinib Sorafenib Bevacizumab

Mutated 18/32 (56%) 2/10 (20%) 4/9 (44%)

Methylated 2/6 (33%) 0/2 (0%) 0/3(0%)

Wild-type 13/25 (52%) 0/16 (0%) 0/5 (0%)

ORR by specific VEGF-targeted therapies

in relation to VHL status

Adapted from Choueiri TK et al. J Urol. 2008 Sep;180(3):860-5

Page 26: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

Adapted from Choueiri TK et al. J Urol. 2008 Sep;180(3):860-5

PFS in relation to VHL status

Page 27: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

First large study testing the impact of VHL mutation

and promoter hypermethilation on outcome of VEGF-

targeted agents in advanced RCC

No significant difference in ORR

Subset analysis generated a hypothesis that certain

types of VHL mutations (e.g. “LOF” mutations) may

identify a population of pts with a greater ORR to VEGF-

targeted agents

VHL status and response to VEGF-targeted therapies

CONCLUSIONS

Adapted from Choueiri TK et al. J Urol. 2008 Sep;180(3):860-5

Page 28: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

Molecular Marker

PtsGene

Alterations

Predicted Response

to treatment

VHL1 123Loss-of-function

mutationsGood response to

VEGF therapy

HIF-1/HIF-22 43High Expression

LevelGood response to

Sunitinib

Single Nucleotide Polymorphisms

(SNPs)3

42Various non

synonymous SNPsSignificant Sunitinib

toxicity

1. Choueiri TK et al. J Urol. 2008 Sep;180(3):860-52. Patel PH et al. ASCO 2008. Abstract 50083 Faber PW et al. ASCO 2008. Abstract 5009

VEGF-targeted therapies in RCC:are there PREDICTIVE BIOMARKERS?

Page 29: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

43 pts with metastatic clear cell RCC

Sunitinib treatment

Pretreatment snap-frozen RCC tumor available

Treatment outcome assessed

HIF-1α

HIF-2α

α-tubulin

Patients 1 2 3 4 5 6 7 8 9 10 11 12

HIF-α levels and response to Sunitinib

Adapted from Patel PH et al. ASCO 2008. Abstract 5008

Page 30: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

Resp

on

se R

ate

(%

)

2/15

4/15

12/13

High(> 50%)

Low(10-50%)

None(< 10%)

p-value 0.0001

Pre-treatment HIF levels by Western analysis and Sunitinib response in RCC patiens

15%27%

92%

HIF 2α

Adapted from Patel PH et al. ASCO 2008. Abstract 5008

Page 31: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

Detectable HIF-2

No Detectable HIF-2

p = 0.0085

PFS to SUNITINIB according to HIF-2

Adapted from Patel PH et al. ASCO 2008. Abstract 5008

Page 32: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

Molecular Marker

PtsGene

Alterations

Predicted Response

to treatment

VHL1 123Loss-of-function

mutationsGood response to

VEGF therapy

HIF-1/HIF-22 43High Expression

LevelGood response to

Sunitinib

Single Nucleotide Polymorphisms

(SNPs)3

42Various non

synonymous SNPsSignificant Sunitinib

toxicity

1. Choueiri TK et al. J Urol. 2008 Sep;180(3):860-52. Patel PH et al. ASCO 2008. Abstract 5008

3. Faber PW et al. ASCO 2008. Abstract 5009

VEGF-targeted therapies in RCC:are there PREDICTIVE BIOMARKERS?

Page 33: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

DNA sequence variation of a single nucleotide in the

coding region change in the aminoacid sequence

Arg – Pro - Phe

CGC – CCA - TTC

Arg – Thr - Phe

CGC – ACA - TTC

Non-Synonimous Single Nucleotide Polymorphism (nsSNP) and Sunitinib Toxicity

Adapted from Faber PW et al. ASCO 2008. Abstract 5009

nsSNPs can affect protein structure/function and thus impact drug metabolism and toxic effects

Page 34: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

23 nsSNPs were associated in 19/42 mRCC pts with Sunitinib-related G3-4 toxicities

9/23 genes were integrated in a network involving cytokines, transcription regulators and apoptosis regulators

No ≠ in the 3 nsSNPs for cytochrome P450 involved in Sunitinib metabolism

nsSNPs and Sunitinib Toxicity: RESULTS

Adapted from Faber PW et al. ASCO 2008. Abstract 5009

Page 35: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

VEGF-targeted therapies in RCC:are there SURROGATE BIOMARKERS?

MARKERS METHODS

INVASIVE MicroVessel Density (MVD) IHC (e.g. CD31) on tumor biopsy samples

MINIMALLY INVASIVE

Circulating endothelial GF

(e.g. VEGF, PlGF, VEGFR2)Plasma protein levels by ELISA

CECs & CEPs Blood concentration by Flow cytometry

NON INVASIVE Functional ImagingDCE-MRI

PET

Page 36: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

VEGF-targeted therapies in RCC:MICROVESSEL DENSITY as SURROGATE

BIOMARKER

LIMITATIONS

• invasive (tumor biopsies)• difficult to standardize• tumor tissue heterogeneity• reader-dependent variability

LOW MVD

MOD. MVD

HIGH MVD

Page 37: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

VEGFR2 levels

Adapted from Motzer RJ et al. J Clin Oncol. 2006

VEGF, PlGF & VEGFR2 levels during Sunitinib as SURROGATE BIOMARKERS

PlGF

VEGF VEGFR2

• Circulating levels of VEGF, PlGF and VEGFR2 in 63 mRCC pts receiving Sunitinib

• Biomarkers levels evaulation: Day 1 & 28 of each cycle of treatment

• RESULTS: significant differences between baseline and D28 biomarker levels through cycle 8 (p < 0.002)

Page 38: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

CECs & CEPs as SURROGATE BIOMARKERS

• Circulating endothelial cells (CECs) represent 1/1000-100000 of blood circulating cells in healthy people

• The majority (~95%) of mature CECs are terminally differentiated and frequently apoptotic cells (“anucleated carcasses”)

• Only a putative sub-population (<5%) of “stem-like” precursors (CEPs) might stimulate angiogenesis and contribute to tumor vasculogenesis

Page 39: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

CD31

CD146

CD105

VEGFR2

CD133

CD144

VEGFR3VEGFR1

• CD45 is used to exclude haematopoietic cells from analysis

• All CECs express CD31

• Sub-populations express endothelial markers e.g. CD146, CD105, VEGFR2, CD144

• Only CEPs express CD133 marker (also haematopoietic stem cells express CD133)

CECs & CEPs as SURROGATE BIOMARKERS

Page 40: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

CECs & CEPs as SURROGATE BIOMARKERS

CEPs = CD45-, CD31+, CD133+

CECs = CD45-, CD31+, CD117+

APOPTOTIC CECs = CD45-, CD31+, CD146+ & PI,

7AAD

Tumor

BM

Angiogenesis ONBONE MARROW

CEP ↓

Healthy

BM

Anti-VEGF therapies

Angiogenesis OFF

CEP ↓

CEP ↑

Page 41: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

New perspectives:MicroRNAs as SURROGATE BIOMARKERS

• MicroRNAs are a group of non-coding regulatory RNAs (20-25 nucleotides)

• They regulate proliferation, differentiation, apoptosis, cell metabolism and are involved in tumorigenesis

• They can regulate gene expression through translational repression or mRNA degradation of target genes

Page 42: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

New perspectives:MicroRNAs as SURROGATE BIOMARKERS

Hypoxia

Mir-20b

VEGF

CECs/CEPs

20b

?20b

20b

20b

Hua Z et al. PLoS ONE. 2006

Page 43: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

VEGF-targeted therapies in RCC:Functional imaging as SURROGATE

BIOMARKER

• Based on contrast-enhancement of vascular and tumoral structures

• NON INVASIVE

• Included in many antiangiogenesis studies

• No standard protocols available

Page 44: Università degli Studi di Palermo DIPARTIMENTO DI ONCOLOGIA SEZIONE DI ONCOLOGIA MEDICA (Dir. Prof. Nicola Gebbia) Surrogate biomarkers in evaluating response

CONCLUSIONS

o Objective Response Rate may not be a realistic estimate of activity of new targeted therapies

o Predictive biomarkers related to angiogenesis might be useful to predict therapy outcome

o Surrogate biomarkers of anti-angiogenic drugs activity are requested to monitor response and detect resistance during treatment

o No biomarkers of angiogenesis or antiangiogenic activity available for routine clinical use

o Non-standardized protocols are available