Steven Brem, M.D.Moffitt Cancer CenterTampa, Florida steven.brem@moffitt.org

Beyond Angiogenesis: Blocking Invasion

Anti-Angiogenic Therapy for Brain Tumors

FBTA 1.23.09

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 1970’s – Hypothesis of Folkman that tumor growth

depends on angiogenesis 1980’s- Identification of vascular growth factors – Proof

of concept in animal models 1990’s – 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-TrapMany 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 FOUNDATION, 2008

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

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

Laboratory Model Predicts Clinical Outcomes

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.