Improving Patient Outcomes by Targeting the VEGF/VEGFR Axis Wells Messersmith, MD, FACP Professor Director, Gastrointestinal Medical Oncology Program Co-Head,

Improving Patient Outcomes by Targeting the VEGF/VEGFR Axis

Wells Messersmith, MD, FACPProfessor

Director, Gastrointestinal Medical Oncology ProgramCo-Head, Division of Medical Oncology

Program co-Leader, Developmental TherapeuticsMay 2013

Conflict of Interest:

1. No employment, speaker’s bureaus, stock ownership, royalties, patents, etc

2. Data Safety Monitoring Board for Morphotek

3. Local PI of clinical trials by Genentech/Roche, GSK, AstraZeneca, EntreMed, Pfizer, Millenium, Bayer, Onconova, and NIH/CTEP.

Slides: S. Kopetz (MDACC), Chris Lieu (Colorado)

Outline/Objectives:

1. Introductiona. Angiogenesisb. Ongoing trials in GI cancers

2. Role of PlGF

3. Mechanisms of resistance

Angiogenesis

Angiogenesis Background- Observation that tumor growth can be accompanied by

increased vascularity was reported more than a century ago

- In 1939, Ide and colleagues first postulated the existence of a tumor-derived blood-vessel-growth stimulating factor

- In 1960s, experiments by Greenblatt and Shubik, and Ehrmann and Knoth, provided early evidence that tumor angiogenesis was mediated by diffusible factors produced by tumor cells

- In 1971, Folkman proposed that anti-angiogenesis might be an effective anticancer strategy

C. Lieu, Colorado

VEGF- VEGF family of growth factors and their receptor

tyrosine kinases mediate proangiogenic effects

- Normal endothelial cells engaged in angiogenesis express numerous VEGF receptors, but produce very little detectable VEGF

- Tumor cells express VEGF receptors and also produce VEGF (autocrine mechanisms)

- Classic signaling is via VEGF-A binding to VEGFR-2, stimulating the PI3K/Akt as well as Raf/MEK/MAPK pathways

VEGF Signaling

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

VEGF-A

VEGF-R1(Flt-1)

MigrationInvasionSurvival

VEGF-R3(Flt-4)

Lymphangiogenesis

VEGF-R2(KDR/Flk-1)Proliferation

SurvivalPermeability

PlGFVEGF-B

VEGF-C, VEGF-D

Fu

nct

ion

s

Y

BevacizumabYRamucirumab

Aflibercept (VEGF Trap)

PIGF = placental growth factor. Holash et al, 2002; Roy et al, 2006; Ghosh et al, 2000.

Large Molecule VEGF Inhibitors

Proposed Mechanism of Anti-Angiogenics

- Inhibition of new vessel growth and vascular regression

- Vascular normalization

- Vascular constriction

- Direct effects on tumor cell function

- Offsetting effects of chemotherapy inducing VEGF levels

ColorectalRecently reported:Regorafenib (“CORRECT”) – positiveAflibercept (“VELOUR”) – positiveBevacizumab 2nd line (“TML”) – positiveBrivinib (with cetux) – negative

OngoingRamucirumab (VEGFR-2 mAb; “RAISE”): NCT1183780

Phase III’s(selected anti-angiogenic agents)

Track Record of TKI’s in Colorectal

Total > 10,000Kopetz, MDACC

Track Record of TKI’s in ColorectalAgent FOLFOX

Irinotecan FOLFIRI

EGFRi + chemo

Other

Sunitinib Phase IIB Phase III Phase I/II

Vandetanib Phase IIB Phase IIB Phase I

Cediranib Phase II/III Phase IIB Phase I

Vatalanib Phase IIIs

Axitinib Phase IIB Bevacizumab

Semaxinib Phase III 5-FU, phase III

Motesanib Phase I Phase I Phase I

Sorafenib Phase IIB Phase IIB Phase I/II Bevacizumab

Pazopanib Phase I Phase I

Brivanib Phase I/II Cetux, Phase III

Regorafenib Phase II Phase II Phase III

Linifanib Phase IIB

Negative

Positive

Ongoing

Track Record of TKI’s in Colorectal

Kopetz, MDACC

Pancreas CancerGem +/- sorafenib “BYPAN” (NCT00541021) - negativeGem +/- bevacizumab (CALGB 80303) - negativeGem +/- Aflibercept (“VANILLA”) - negativeGem +/- axitinib (NCT00471146) – negative

Gastro-esophagealBevacizumab (“AVAGAST”) – negative (overall population)

Ramucirumab (VEGFR-2) vs BSC – positive

Pancreas Islet Cell / CarcinoidSunitinib (NCT00428597) – positiveBev vs Interferon, SWOG 0518 (NCT00569127)


HCC1st LineSorafenib (“SHARP”) – positiveDoxorubicin/Sorafenib vs S, CALGB 80202 (NCT00917384)

Sorafenib vs brivanib (“BRISK FL”) – negative

Sorafenib vs sunitinib (NCT00699374) – negative

Sorafenib vs linifanib (ABT-869) (NCT01009593)

2nd LineBrivanib vs BSC (“BRISK PS”) (NCT 01217034) – terminated

Ramucirumab vs BSC (“REACH”) (NCT01140347)


Outline/Objectives:


2. Role of PlGF


Angiogenesis

Role of Placenta Growth Factor- Angiogenic protein in VEGF family involved in cancer,

inflammation, pre-eclampsia, cardiovascular disease- Unlike VEGF, PlGF is undetectable in healthy tissues;

upregulated in tumors- Contributes to angiogenic and inflammatory “switch”- Produced by malignant cells, endothelial cells, smooth-

muscle cells, pericytes, cancer-associated fibroblasts, tumor-associated macrophages, and other stromal cells

- Serum PlGF is prognostic in colorectal cancer (Wei, 2009)

- Also prognostic in gastric cancer (Chen, 2004) and HCC (Ho, 2007)

Mechanism of Placenta Growth Factor

Loges et al, Clin Cas Res 2009. American Association for Cancer Research

Insights on PlGF- Four isoforms of PlGF in humans- PlGF transmits its own signal via VEGFR-1 (results is

phosphorylation of different residues than VEGF-A)- PlGF augments VEGF-A signaling by displacing it from

soluble VEGFR-1 (a negative regulatory mechanism), thereby increasing availability of VEGF-A

- PlGF also causes transphosphorylation of VEGFR-2- PlGF upregulates the expression of proangiogenic

molecules such as VEGF, FGF-2, and MMP-9- PlGF knock-out mice are healthy (unless challenged

with inflammation, cancer, etc)

Role of Placenta Growth Factor

Loges et al, Clin Cas Res 2009. American Association for Cancer Research

PlGF in bevacizumab resistance

Fan et al, British J Cancer. Cancer Research UK

- Colorectal cell lines that are chronically exposed to anti-VEGF-A therapy with bevacizumab show upregulation of compensatory pathways, including PlGF

- These “bev-adapted” cell lines are also more metastatic

PlGF and GI Toxicity

Hindryckx et al Lab Invest, ‘10, Fischer, Nat Rev Onc, ’08 ©

In chemically induced models of intestinal injury:Up to 6 fold increase in PlGF in the injured colon (minimal VEGF increase)In PlGF knockout mice (-/-), Substantial intestinal injuryHealing angiogenesis response is absentCan be rescued by PlGF

Increased weight loss and chronic intestinal injury

Wild-type

PlGFKnock-Out(severe injury)

S. Kopetz, MDACC

Outline/Objectives:


2. Role of PlGF


Angiogenesis

Resistance- Intrinsic Resistance

- Tumor cells can use existing blood vessels in vasculature-rich organs (lungs)

- Absence of VEGF or VEGF receptors in metastatic tumors

- Acquired Resistance- Induced pro-angiogenic factor substitution (FGF,

PlGF, etc)- Recruitment of bone marrow-derived cells to restore

neovascularization

Resistance Pathways

Numerous compensatory factors and cell typesEllis et al. Clin Cancer Res 2008;14:6371-6375

Preclinical Models of Resistance- Preclinical trials in a mouse model of pancreatic

neuroendocrine (islet cell) cancer, Rip1–Tag2

- Rip1–Tag2 mice were treated with a monoclonal antibody (DC101) that specifically blocked VEGFR signaling (in particular VEGFR2)

- Initial response denoted by tumor stasis and reductions in tumor vascularity

Casanovas et al. Cancer Cell 2005:8;299-309

Preclinical Models of Resistance- Response phase was transitory (10–14 days) and was

followed by tumor regrowth- Dense tumor vasculature restored


Preclinical Models of ResistanceThe relapsing tumors were found to express higher levels of the mRNAs for the pro-angiogenic factors fibroblast growth factor 1 and 2

Tumor-derived cells subjected to hypoxic conditions similarly upregulated most of the genes


Clinical Evidence

Hypothesis: resistance to angiogenesis inhibition should precede clinical progression

Kopetz; Lieu

0 3 6 9 12-50%

-40%

-30%

-20%

-10%

0%

Months on Trial

Tum

or M

easu

rem

ent

Prior to Progression

RECIST Measurements for Representative Patient

“AngiogenicActivity”

PlGF and bFGF are Increased Prior to Progression

Basel

ine

After B

evac

izum

ab

After F

OLFIRI+

B

Prior t

o Pro

gress

ion

0

20

30

40

ULN

*

*

*

PlG

F (

pg

/mL

)

Basel

ine

After B

evac

izum

ab

After F

OLFIRI+

B

Prior t

o Pro

gress

ion

0

10

20

30

ULN

p=0.04

p<0.01

bF

GF

(n

g/m

L)

p<0.01 compared to baselineULN = upper limits of normal for healthy controls

Kopetz. GI ASCO. 2009

Conclusion- Inhibition of angiogenesis results is modest but

meaningful benefit for multiple tumor types, including colorectal cancer.

- Dearth of biomarkers for who benefits; who is harmed; how resistance occurs

- VEGF-A has been the main focus, but the role other angiogenic signaling proteins (such as PlGF) under active study and drug development

- Overcoming resistance via multiple bypassing pathways may be challenging

Angiogenesis Overview

Thank [email protected]

Documents

Improving Patient Outcomes by Targeting the VEGF/VEGFR Axis Wells Messersmith, MD, FACP Professor Director, Gastrointestinal Medical Oncology Program Co-Head,