Antiangiogenics as Chemosensitizers:Out of the Frying Pan into the Fire?Dr. Urban Emmenegger

Potential Conflict of Interest

• Consultant / 2008 –– Amgen

• Research Grant – Consultant / 2007 –– Novartis

• Research Grant / 2007 –– Wyeth

MontrealMarch 27 & 28, 2009

1st Quebec Conference on TherapeuticResistance in Cancer

Antiangiogenics as Chemosensitizers: Out of the

Frying Pan into the Fire?

Urban Emmenegger, MD

Clinician-ScientistSunnybrook Odette Cancer Centre & Research Institute

Sunnybrook Health Sciences CentreDepartment of Medicine, University of Toronto

2075 Bayview Avenue, Toronto/ON M4N 3M5, Canadaurban.emmenegger@sunnybrook.ca

Disclosure

Consulting Fees: Amgen, Novartis

Research Funding: Novartis, Wyeth

Acknowledgements Sunnybrook Research Institute

Annabelle Chow

Bob Kerbel William Cruz

John Ebos Chris Folkins

Giulio Francia Kae Hashimoto

Christina Lee Shan Man

Tony Mutsaers Yuval Shaked

Terence Tang Ping Xu

D. Dumont M. Julius

Sunnybrook Odette Cancer Centre

Scott Berry

Edward Chow

Yoo-Joung Ko

Linda Rabeneck

Maureen Trudeau

University of Pisa, Pisa/Italy

Guido Bocci

Objectives

1) To review basic principles of tumor angiogenesis and antiangiogenic therapies.

2) To discuss the rationale for combining chemotherapy with antiangiogenic agents as a means to overcome/delay resistance.

3) To identify challenges of this approach.

Hippocrates… noticed that blood vessels around a malignant tumor looked like the claws of a crab. He named the disease karkinos (the Greek name for crab) … (http://medicineworld.org/cancer/history.html)

Tumor angiogenesis: therapeutic implications

Folkman J. N Engl J Med. 1971;285(21):1182-6

TAF inhibition reverses this process 3

2

1

VEGF-A

VEGF-B VEGF-C

VEGF-DPlGF

Sex hormones FGFs

PDGFsIL-8

EGF

angiogenesisangiogenesis

angiogenesis angiogenesisangiogenesis

Thrombospondin-1/2 Interferon-α

PEDFAngiostatin Endostatin Vasostatin Tumstatin Canstatin Arresten

…

Local (sprouting) angiogenesis

The VEGF Family And Its Receptors

VEGFR-3(Flt-4)

VEGFR-2(Flk-1/KDR)

VEGFR-1(Flt-1)

Angiogenesis‘Inflammation’

AngiogenesisLymphangiogenesisLymphangiogenesis

PlGF VEGF-A* VEGF-B VEGF-C VEGF-D206189165121

endothelial cell*VEGF-A = ‘VEGF’

‘Systemic’ angiogenesis (i.e., vasculogenesis)

Kerbel RS. N Engl J Med 2008;358:2039-2049

Agents Targeting the VEGF Pathway

VEGFR-2VEGFR-1P

PPPP

PPP

endothelial cellSmall-molecule

VEGFR kinase inhibitors (Sunitinib, Sorafenib, Axitinib, Cediranib … )

Anti-VEGFR

antibodies(IMC-1121b)

VEGFAnti-VEGF antibodies

(Bevacizumab)

Soluble decoy VEGF

receptors(VEGF-Trap)

mTOR inhibitors(Temsirolimus, Everolimus)

Sunitinib Sorafenib Vatalanib

http://www.kinomescan.com/show_data.asp

VEGFR1-3PDGFR alphaPDGFR beta

RETKIT

FLT-3

VEGFR1-3C-/B-RAF

PDGFR betaRETKIT

FLT-3

Delta-like Ligand 4 - Notch Pathway

Adapted from Hicklin DJ. Nature Biotechnology 25, 300 - 302 (2007)

Increased angiogenesis:functionally abnormal+++vasculature

reduced blood flow, severe hypoxia reduced blood flow, severe hypoxia

Decreased angiogenesis:vascular rarefaction

‘Accidental’ Anti-Vascular Agents

• chemotherapeutics• hormonal therapies• radiation therapy• COX-2 inhibitors• corticosteroids• thalidomide• LMW heparins• ACE inhibitors• propranolol• glitazones• doxycyclin• valproic acid• ...

Léauté-Labrèze C, N Engl J Med. 2008;358(24):2649-51.

Antiangiogenic Therapies: Phase III Success Stories

1971 FolkmanHypothesis

1983/89 VPF/VEGF

1997 Bevacizumab

2006 Non-small cell lung cancer: Bev + PC (PFS/OS)

2007 Colorectal Cancer: Bev + FOLFOX (PFS/OS) Breast Cancer: Bev + Paclitaxel (PFS) Renal Cell Cancer: Sunitinib (PFS/OS)

Sorafenib (PFS) Temsirolimus (PFS/OS) Bev + IFN-alfa 2a (PFS)

2004

2008 Hepatocellular Ca: Sorafenib (PFS/OS)Renal Cell Cancer: Everolimus (PFS)

Activity of Single-Agent Bevacizumab

Tumor Type (Ref)Objective

RR (%)SD

(%)

PFS/TTP

(median, m)Comments

CR Prostate Ca(Reese 01)

0 - 4Phase II, n=15,

10 mg/kg q2wks

Met Breast Ca(Cobleigh 03)

6.7 16 5.6Phase I/II, n=75,

3-10-20 mg/kg q2wks

Kidney Ca

(Yang 03)10 - 4.8

Phase II, n=39,

10 mg/kg q2wks

Recurrent NHL(Stopeck 05)

5 20 5Phase II, n=46,

10 mg/kg q2wks

Recurrent Ovarian Ca (Burger 05)

18 55 -Phase II, n=62,

15 mg/kg q3wks

Colorectal Ca (2nd line) (Giantonio 07)

3.3 - 2.7Phase III, n=243,

10 mg/kg q2wks

Metastatic Mela-noma (Varker 07)

0 - 3Phase II, n=5,

15 mg/kg q2wks

Activity of Bevacizumab & Chemotherapy

Ref

Hurwitz

mCRC

1st line

Giantonio

mCRC

2nd line

Sandler

NSCLC

1st line

Miller

ABC

1st line

TxIFL

+BIFL

FOL-

FOX4+B

FOL-

FOX4

P-C

+BP-C

P

+BP

Median

Survival (m)

20.3 15.6 12.9 10.8 12.3 10.3 26.7* 25.2*

1y survival (%)

74.3 63.4 - - 51 44 - -

Median PFS (m) 10.6 6.2 7.3 4.7 6.2 4.5 11.8 5.9

Overall RR (%) 44.8 34.8 22.7 8.6 35 15 36.9 21.2

mCRC = metastatic colorectal cancer, NSCLC = non-small cell lung cancer, ABC = advanced breast cancer, IFL = irinotecan-fluorouracil-leucovorin, FOLFOX4 = oxaliplatin-fluorouracil-leucovorin, P = paclitaxel, C = carboplatin , B = bevacizumab

Underestimation of the true potential?

• Antiangiogenics developed without biomarker guidance for optimal dosing:– flat dosing common for RTKIs– various bevacizumab regimens

• Lack of markers for patient selection

• Challenging integration into current standards of care

Rationale against Combination Therapy

• Antivascular effects I– inhibition of neo-angiogenesis– induction of endothelial cell

apoptosis– impaired mobilization of CEPs

and other bone marrow derived

cells– vasoconstriction

reduced blood flow → decreased pO2 and nutrients availability, low pH → ANTAGONISM: reduced chemotherapy drug deposition, diminished cytotoxic activity

de Bazelaire, C. Clin Can Res 2008;14:5548-5554

Rationale for Combination Therapy

• Antivascular effects I– inhibition of neo-angiogenesis– induction of endothelial cell

apoptosis– impaired mobilization of CEPs

and other bone marrow derived

cells– vasoconstriction

reduced blood flow → decreased pO2 and nutrients availability, low pH → SYNERGISM: impaired tumor cell repopulation

de Bazelaire, C. Clin Can Res 2008;14:5548-5554

Science 2005(307):58 – 62; Mol Can Ther 2008(7):3670-84

• Antivascular effects II– vascular ‘normalization’

Rationale for Combination Therapy

Rationale for Combination Therapy

• Antivascular effects III– disruption of ‘vascular niche’ → diminished

cancer stem cell compartment – impaired mobilization of CEPs and other bone

marrow derived cells → impaired vascular repair → augmentation of chemotherapy-related antivascular effects

Tumor Angiogenesis versus Physiological Angiogenesis

Conventional (MTD) Chemotherapy

Pla

sma

con

cen

trat

ion

of

cyto

toxi

c d

rug

Tumor cell cytotoxicity

Vascularrepair

Vascularrepair

Antivasculareffects

Antivasculareffects

3 weeks 3 weeks

An

tiva

scu

lar

effe

cts

Shaked et al. Cancer Cell. 2008;14(3):263-73.Bertolini et al. Nat Rev Cancer. 2006;6(11):835-45.

Metronomic Chemotherapy P

lasm

a co

nce

ntr

atio

n o

f cy

toto

xic

dru

g

Antiangiogenesis

An

tiva

scu

lar

effe

cts

3 weeks 3 weeks

Tumor cell cytotoxicity

Myelosuppression

Kerbel RS, Kamen BA. Nat Rev Cancer. 2004;4(6):423-36.Emmenegger U, Kerbel RS. Onkologie. 2007;30:606-608.

VEGF Targeting Agents: Beyond Antivascular Effects

• Direct anti-tumor effects• Immunomodulatory effects• Mitigation of ‘cancer-associated systemic

syndrome’

Xue et al PNAS2008 105:18513-518

Anti-VEGF agents confer survival advantages to tumor-bearing mice by improving cancer-associated systemic syndrome

Clinical Applications: Challenges • phase III failures

• pancreatic cancer: Bev + Gemcitabine• breast cancer: Bev + Capecitabine• colorectal cancer: Vatalanib + FOLFOX (1st and 2nd line)

• diminished PFS/OS benefit in ‘2nd generation’ trials

• > 50 agent(s) in clinical development• concurrent/sequential use? • continuous/intermittent use?• small molecule drugs or antibodies?• costs• side-effects• course of action in case of tumor progression?• intrinsic or acquired resistance

Mancuso et al. JCI 2006;116:2610–2621

Grothey et al. JCO 2008;26:5326-5334

Resistance to Antiangiogenic (Mono-)Therapy

EvasiveResistanceVascular

Remodeling Co-option

Reduced VascularDependence

Norden, Neurology 2008(70):779-787

Dissociation of antiangiogenic and anti-tumor effects

NS: 1 week

NS: 4 weeks

LDM CPA: 1 week LDM CPA: relapse

Emmenegger Cancer Res 66;1664-1674 (2006)

Reduced vascular dependence

Hypoxia,Starvation

Acute survival

Cell death ~• Necrosis• Apoptosis• Autophagy

Cytostasis• Autophagy

Proliferation

dual function

‘Macro-Autophagy’

Initiation

mTOR

mTOR inhibitors→ autophagy stimulation

Sequestration

Phagophore

Beclin1 (Atg6)UVRAGPI3kinase IIIAtg9

3-methyladenine→ autophagy inhibition

Docking & fusionwith lysosome

Lysosome

Cathepsins

ChloroquineBafilomycin A1→ autophagy

inhibition

Autophagosomeformation &maturation

Autophagosome

LC3 (Atg8)Atg5Atg12

Vesicle breakdown,degradation ofcontent, release of degradation products

Autolysosome

As a consequence of metabolic or treatment-related stress, autophagy is initiated and proceeds stepwise. Schematic presentation of the various steps of the autophagic cascade, the structures formed, important molecules involved and pharmacological modifiers of autophagy.

Step

Structure

MoleculesInvolved

Modifiers

‘Stress’

PC-3 LCR1.1

standard culture

conditions

metabolicstress

PC-3 LCR1.1

2%

5.26%19.47%

0.43%

Reduced vascular dependence: a consequence of impaired autophagy?

Promotion of tumor progression by antiangiogenic therapy?

Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis.Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Cancer Cell. 2009 Mar 3;15(3):232-9.

Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis.Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, Inoue M, Bergers G, Hanahan D, Casanovas O. Cancer Cell. 2009 Mar 3;15(3):220-31.

-7 0 7 14 21 28 35 42

106

107

108

Group AGroup B

Group C

120 mg/kg

Vehicle

120 mg/kg

i.v. tumor implantation

(LM2-4LUC+ Cells)

Days Postimplantation

Tu

mo

r B

urd

en

(Ph

oto

ns/s

)

Group A

1 2 3 4 5 6 7

Group B

1 2 3 4 5 6 7

Group C

1 2 3 4 5 6 7

Da

ys

Po

st T

um

or

Imp

lan

tati

on

7

21

30

27

Loges et al. Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell. 2009;15(3):167-70.

Conclusions I

• Antiangiogenic therapy is a clinical reality!• Angiogenesis is a highly regulated process.• Although the tumor vasculature is morpho-

logically and functionally aberrant, common regulatory mechanisms remain intact and represent promising treatment targets.

• Antiangiogenic agents can potentiate the anti-tumor effects of chemotherapeutics (and vice versa) but much remains to be learned to optimize the clinical benefit of such combinations.

Conclusions II

• The biological understanding of the process of tumor vascularization is rapidly evolving, but this is not yet matched by the way antiangiogenic agents are used in the clinic.

• There is an unmet need for biomarkers in order to optimize dosing of antiangiogenics, and for the selection of patients most likely to benefit from such agents.

• Various mechanisms of intrinsic or acquired resistance to antiangiogenic agents have been described.

Conclusions III• Resistance to combinations of cytotoxic and

antiangiogenic agents is less well characterized.• Stopping the administration of antiangiogenic

agents at progression might facilitate tumor growth acceleration.

• Novel findings suggest that antiangiogenic therapy might promote invasive tumor growth and metastatic disease progression.

• Tumor promoting effects could explain the yet limited overall survival benefit resulting from the use of antiangiogenic agents and are of special concern in the (neo)adjuvant setting.

‘The greater our knowledge increases, the greater our

ignorance unfolds.’John F. Kennedy