Beyond Angiogenesis: Blocking Invasion

Anti-Angiogenic Therapy for Brain

Tumors
FBTA 1.23.09

Steven Brem, M.D.

Moffitt Cancer Center
Tampa, Florida
steven.brem@moffitt.org
Swanson K, Acta Biotheoretica
Communication between
nerves and blood vessels

Lu P, Werb Z : Science 2008; 322-1506-9

Angiogenic Switch - Hypothesis

Brem S. Clin Neurosurg 1975

Glioblastoma are Endothelial-
Dependent

Brem S, Cotran R, Folkman J, JNCI, 1972

Angiogenic Switch
History of Angiogenesis Research
1970s Hypothesis of Folkman that tumor growth
depends on angiogenesis
1980s- Identification of vascular growth factors Proof
of concept in animal models
1990s Clinical Trials of angiogenic inhibitors Early
clinical failures - monotherapy
2004- FDA approval of bevacizumab for metastatic
colorectal CA
2007- Bevacizumab + irinotecan efficacious for
glioblastoma
 Current Angiogenic Inhibitors in
Clinical Use and Clinical Trials
Bevacizumab (Avastin)
Sunitinib (Sutent)
Sorafenib (Nexavar)
Cederanib (Recentin - AZD- 2171)
Cilengitide
VEGF-Trap
Many others in development
Bevacizumab- Efficacy in Clinical Trials
Metastatic Colorectal Cancer

From Ferrara N, Nat Rev Drug Discovery, 2004; Hurwitz et al, NEJM, 2004
Biology of Glioma
Angiogenesis
Cellular and Molecular Targets
Batchelor T, Brem S, Sorensen G, ANGIOGENESIS
Tumor Angiogenesis: A Balancing Act

Folkman J, Nature Drug Discovery 6:274, 2007

Potential Mechanism of Efficacy
Folkman Hypothesis Glioblastomas are
angiogenesis- dependent Growth advantage
Jain Hypothesis Normalization of vessels
Reduction of hypoxia, interstitial pressure, and
increased drug delivery
Stem Cell Hypothesis Glioma stem cells
promote angiogenesis via VEGF Vascular niche
protects stem cells (Bao et al., Cancer Res, 2006; 66:7843-8)
Different Mechanism of Action of 3
FDA- Approved Drugs

Folkman J, Nature Drug Discovery 6:274, 2007

Inhibition of Brain Tumor Growth in
the Brain

Brem S et al, Amer J Pathol, 1990

Bevacizumab + Irinotecan
 Patient 2
before and after (2 mos apart)

Courtesy Dr. Sajeel Chowdhary, Moffitt Cancer Center

 Response Rates
6-month PFS of 43% and median PFS of 24 weeks
compares favorably to historical controls (Wong et al., J. Clin.
Oncol., 1999) of 15% and 9 weeks, using 8 previous

chemotherapy regimens
Overall 1-year survival of 37% compares favorably
to historical control of 21% (Wong et al., 1999)
Temozolomide, in combination with other agents
(e.g., irinotecan, erlotinib, etoposide) produced modest
improvements in R.R. or O.S., but not as dramatic
as bevacizumab + irinotecan
Mechanism of
Resistance
 Patterns of Failure
with anti-VEGF Therapy
There are ~ 40 % that do not respond from
the outset - non-responders
Recurrence for responders different
phenotype angiogenesis-independent-
gliomatosis cerebri- diffusely invasive
40 yo M presents to MCC after a biopsy-GBM. 8.6.08
preop MRI with contrast. T-1 with Gd.
12.10.07 4Months post-op. Completed EBRT. Receiving temozolomide.
Postoperative scar. Increased periventricular enhancement. KPS-90
12.10.07 4Months post-op. Completed EBRT. Increased periventricular
enhancement. There is a finger nodule near the surgical site. KPS-90
6 months postop Completed 4 cycles of TMZ, s/p EBRT, now
recurrence with posterior nodule, periventricular, white matter
3.24.08 After 4 cycles (2 months) of CPT-11+ bevacizumab.
Complete response
8 months post-op 4 months after recurrence N.E.D. on T1-Gd in
tumor bed or in the periventricular spread. Some FLAIR abnormality
8.2008 One year after surgery, there is no evidence of contrast enhancement, but
the FLAIR images (right) are showing increasing infiltration
Nov. 2008. Patchy contrast enhancement appears after
resistance/cessation to VEGF. KPS-70. One-month after cessation of
Bevacizumab.
10.2008. 14 months after surgery; 10 months after BV + Irinotecan, there is no
evidence of C.E. tumor, but there is a marked increase in infiltrative, multifocal
tumor (middle cerebral peduncle, parahippocampal gyrus, pulvinar, and splenium
of the corpus callosum). Patient develops side effects of BV [hypertension, fatigue,
diarrhea] and is given a drug holiday.
Nov. 2008. The Flare on the FLAIR image. KPS-70. One-month after
cessation of Bevacizumab. Next step?
 Tumor Angiogenesis:
Multiple Angiogenic Factors

Folkman J, Nature Drug Discovery 6:274, 2007

Inhibition of Invasion are Linked

Brem S, et al, AJP, 1990

 Need for Second Generation
Angiogenesis Inhibitors
Bevacizumab limitations of cost, durable
response, responders vs. non-responders,
change in phenotype form angiogenic to
invasive
Toxicity of angiogenic inhibitors (wound
healing, hypertension, thrombosis), second
generation agents will be developed, more
effective, less toxic, affordable
Search for an effective, nontoxic,
affordable angiosuppressive drug
Rational Drug Design Based on known
molecular target and computational library
screening, in vitro testing in vivo testing
Endogenous Inhibitors Natural Angiostatin/
thrombospondin/ endostatin
FDA-drugs that are already shown to be
(relatively) safe in clinic, FDA-approved for other
indications (minocycline, penicillamine, captopril,
celebrex)
Current Treat of Glioblastoma
Surgery Maximal Safe Resection
Radiation Therapy 60Gy- Involved Field
Chemotherapy
Temozolomide Cytotoxic Penetrates BBB
Gliadel BCNU-Chemotherapeutic Wafer
Angiotherapy Antiangiogenesis Therapy
NCCN approval of bevacizumab-irinotecan 2008
NCCN approval of bevacizumab as single agent for
recurrent glioblastoma and anaplastic glioma -2009
Rubenstein JL et al., Neoplasia, 2000
 Laboratory Model Predicts Clinical Outcomes

Control G55 human gbm in

athymic rat (A) shows
discrete border
Treated tumors (anti-
VEGF Ab) show invasive
phenotype (B,C)

Normal vasculature of
basal ganglion with CD31
stain (A)
Treated rats show vascular
cooption (B)

Rubenstein JL et al., Neoplasia, 2000

 VEGF as a negative regulator of glioma invasion

Du R et al, HIF1alpha induces recruitment of BMDC to regulate tumor angiogenesis and

invasion. Cancer Cell 13:206-220, 2008.
Angiogenesis Invasive Switch
A proinvasive adaptation has been inferred
from MRI imaging in a subset of GBM patient
that had developed multifocal recurrence of
tumors during the course of anti-VEGF therapy.
These data implicate that GBMs impaired in
angiogenesis, for example, when targeted with
anti-VEGF agents, can evade from their
inability to induce angiogenesis by becoming
more invasive.
Du R et al: Cancer Cell 13:206-220, 2008.
 The Clinical and Biological Imperative-
Specific, Immediate, and Long-Term Objective

It will, therefore, be
instrumental to identify
pathways that simultaneously
block perivascular invasion
and angiogenesis to improve
current antiangiogenic
therapy in GBM and potentially
other tumors.
Du R et al: Cancer Cell 13:206-220, 2008.