Steven Brem, M.D.

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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_at_moffitt.org

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Swanson K, Acta Biotheoretica
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Communication between nerves and blood vessels
Lu P, Werb Z Science 2008 322-1506-9
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Angiogenic Switch - Hypothesis
Brem S. Clin Neurosurg 1975
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Glioblastoma are Endothelial-Dependent
Brem S, Cotran R, Folkman J, JNCI, 1972
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Angiogenic Switch
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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

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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

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Bevacizumab- Efficacy in Clinical Trials
Metastatic Colorectal Cancer
From Ferrara N, Nat Rev Drug Discovery, 2004
Hurwitz et al, NEJM, 2004
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Biology of Glioma Angiogenesis

• Cellular and Molecular Targets

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Batchelor T, Brem S, Sorensen G, ANGIOGENESIS
FOUNDATION, 2008
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Tumor Angiogenesis A Balancing Act
Folkman J, Nature Drug Discovery 6274, 2007
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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
  667843-8)

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Different Mechanism of Action of 3 FDA- Approved
Drugs
Folkman J, Nature Drug Discovery 6274, 2007
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Inhibition of Brain Tumor Growth in the Brain
Brem S et al, Amer J Pathol, 1990
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Bevacizumab Irinotecan
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Patient 2 before and after (2 mos apart)
Courtesy Dr. Sajeel Chowdhary, Moffitt Cancer
Center
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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

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Mechanism of Resistance
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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

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40 yo M presents to MCC after a biopsy-GBM.
8.6.08 preop MRI with contrast. T-1 with Gd.
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12.10.07 4Months post-op. Completed EBRT.
Receiving temozolomide. Postoperative scar.
Increased periventricular enhancement. KPS-90
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12.10.07 4Months post-op. Completed EBRT.
Increased periventricular enhancement. There is a
finger nodule near the surgical site. KPS-90
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6 months postop Completed 4 cycles of TMZ, s/p
EBRT, now recurrence with posterior nodule,
periventricular, white matter
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3.24.08 After 4 cycles (2 months) of CPT-11
bevacizumab. Complete response
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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
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8.2008 One year after surgery, there is no
evidence of contrast enhancement, but the FLAIR
images (right) are showing increasing infiltration
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Nov. 2008. Patchy contrast enhancement appears
after resistance/cessation to VEGF. KPS-70.
One-month after cessation of Bevacizumab.
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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.
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Nov. 2008. The Flare on the FLAIR image.
KPS-70. One-month after cessation of Bevacizumab.
Next step?
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Tumor Angiogenesis Multiple Angiogenic Factors
Folkman J, Nature Drug Discovery 6274, 2007
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Inhibition of Invasion are Linked
Brem S, et al, AJP, 1990
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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

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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)

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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

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Rubenstein JL et al., Neoplasia, 2000
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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
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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 13206-220, 2008.
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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 13206-220, 2008.
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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 13206-220, 2008.