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14th International Symposium on Anti-Angiogenic Agents

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By Francesco Bertolini, European Institute of Oncology

14th International Symposium on Anti-Angiogenic Agents, La Jolla, California, USA, February 2-4, 2012

Angiongenesis is an essential process in the growth of neoplasms and progression to metastasis. This year the annual state-of-the-art symposium on Anti-Angiogenic Agents continued the dialogue and interaction between research and clinical investigators by reviewing the current scientific understanding of vascular biology and angiogenesis.

The meeting is a comprehensive forum on neoplastic angiogenesis and anti-angiogenic therapies where cutting edge data from basic research and the results from relevant clinical trials are presented. As the registration and photographing of sessions was prohibited several new and unpublished data were presented.

The angiogenesis field has recently been sparked by the FDA approval of some new anti-angiogenic drugs and already approved drugs for new indications. These include Sutent (sunitinib) for neuroendocrine tumours, Caprelsa (vandetanib) for medullary thyroid carcinoma and Inlyta (axitininb) for renal cell carcinoma.

Also, a few days before the start of the meeting a number of press releases reported the clinical success of Avastin (bevacizumab) in both advanced metastatic colorectral cancer and as maintenance therapy in ovarian cancer and of VEGF Zaltrap (aflibercept) as second line therapy for colorectal cancer.

Some interesting phase I data presented at the meeting included evidence of clinical activity from PF03446962, an anti-alk-1 monoclonal antibody from Pfizer, which inhibits angiogenesis in way complementary to anti-VEGF therapies.

Also early results from a phase 1b trial with MEGF0444A (Genentech), a humanized monoclonal antibody against the epidermal growth factor-like domain 7, which is enriched in tumour vascular matrix after Avastin (bevacizumab) treatment look promising.

Hopefully these preliminary data will lead to new treatment options for solid tumours.

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Program Overview

Angiogenesis is an essential process in the growth of neoplasms and progression to metastasis. The angiogenic pathway is orchestrated by a range of pro- and anti-angiogenic factors that ultimately lead to the development of a neovascular blood supply to the tumor mass. Vascular endothelial growth factor (VEGF), which stimulates proliferation and migration of endothelial cells, plays a pivotal role in this process. For these reasons, the inhibition of VEGF and its receptor signaling system are attractive targets for therapeutic intervention. Indeed, the approval in 2004 of a neutralizing monoclonal antibody directed against VEGF - the first anti-angiogenic systemic drug to treat cancer – validated the notion introduced decades earlier that inhibition of tumor angiogenesis may be a valid approach to control tumor growth. This success has driven the search for new anti-angiogenic agents. For example, small-molecule multikinase inhibitors that target VEGF receptors have recently demonstrated efficacy in multiple tumor types. A number of other anti-angiogenic agents targeting an increasing variety of molecular tumor features are in clinical development. More recently, studies of powerful new genetic and cell biological approaches have provided unprecedented insights into how various molecular and pivotal to tumor growth and survival. As a consequence, a number of new angiogenic molecules, such as neuropilins, Tie-2, and Notch ligand delta-like 4, have emerged as promising targets.

Since its inception over 4 decades ago, investigators in the field of tumor angiogenesis research have made significant progress. Advancements in therapeutics have altered cancer treatment paradigms, and the next decade promises to be an exciting and productive time. This annual state-of-the-art symposium is designed to continue the dialogue and interaction between research and clinical investigators by reviewing the current scientific understanding of vascular biology and angiogenesis. In addition, this symposium provides a forum for presenting the most current preclinical and clinical data on emerging anti-angiogenic agents and regimens. Strategies that inhibit angiogenesis in colorectal, breast, lung, esophageal, gastric, genitourinary, neuroendocrine, central nervous system, hepatocellular and gynecologic malignancies will be discussed. In addition, biomarkers and resistance pathways will be addressed, and controversies in the field will be highlighted.

Educational Objectives

Define angiogenesis and its relevance to the treatment of cancer;

Outline the rationale for the development of anti-angiogenic agents, and explain why angiogenic signaling pathways are targets for inhibition;

Summarize data from clinical trials that support the use of currently available anti-angiogenic agents as monotherapy or in combination with other therapeutic modalities. This clinical trial data will ultimately assist the healthcare provider in making appropriate clinical decisions;

Discuss safety and efficacy results from recent clinical trials of investigational anti-angiogenic agents that will lead to better quality care for the oncology patient.

Target Audience

This symposium is designed for medical, surgical, and radiation oncologists, pharmacists, other providers of cancer care (PAs, RNs, etc.), and research scientists who have an interest in the biology, diagnosis, and treatment of cancer, as well as those who diagnose and treat patients with nonmalignant vascular diseases, such as arthritis and retinal neovascularization. As new and emerging data on anti-angiogenic therapy is presented at this symposium every year, it is necessary for this audience to be made aware of these findings so they can be utilized in their clinical practice.

The University of Texas MD Anderson Cancer Center

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Avastin (bevacizumab)-induced tumor calcifications can be elicited in glioblastoma microspheroid culture and represent massive calcium uptake death (MCAD) of tumor endothelial cells.

Larry Weisenthal, Summer Williamson, Cindy Brunschwiler, and Constance Rueff- Weisenthal

Bähr and colleagues reported that 22 of 36 glioblastoma patients treated with bevacizumab showed tumor calcifications on 8 week post therapy follow up with MRI. Early tumor calcification strongly predicted for response, time to progression, and overall survival (Neuro-Oncology, 13:1020, 2011, doi:10.1093/neuonc/nor099).

The authors didn't understand the mechanism, but speculated that it was vascular in nature.

At the 13th International Anti-Angiogenic Symposium (2011), we presented our discovery of the phenomenon of massive calcium accumulation death, wherein MCAD occurred in endothelial cells (tumor, circulating, and HUVEC), in response to VEGF depletion by bevacizumab and other putative anti-angiogenic agents, but not in response to non-specific cytotoxins.

In subsequent work, we have documented marked MCAD to occur in primary microcluster cultures from 6 fresh human glioblastoma biopsies, following 96 hours of VEGF depletion in vitro by Avastin (bevacizumab). The presence and degree of MCAD is strikingly dependent on the type of serum in the culture medium (RPMI-1640 + 25% serum) -- typically most striking in (very low VEGF) fetal calf serum, but inhibited (often) or enhanced (rarely) by 25% human serum from different patients or normal donors containing variable quantities of VEGF.

There was not a linear relationship between VEGF concentration and MCAD inhibition (or enhancement), suggesting that other pro-angiogenic (or anti-angiogenic) serum factors may play a role.

In epithelial metastatic tumors, circulating peripheral blood endothelial cells may be easily tested, using our methods, and the serum inhibition (or, rarely, enhancement) is faithfully reproduced on circulating endothelial cells, in comparison with the tumor cluster-associated endothelial cells.

We propose MCAD as the mechanism of glioblastoma calcification following Avastin (bevacizumab) and further propose that testing tumor microclusters and/or circulating endothelial cells, in the presence of autologous serum, could be a useful predictive biomarker and research tool.

Weisenthal, Larry. Bevacizumab-induced tumor calcifications can be elicited in glioblastoma microspheroid culture and represent massive calcium accumulation death (MCAD) of tumor endothelial cells. Available from Nature Precedings (2012)

http://precedings.nature.com/documents/7069/version/1

Weisenthal, Larry. Endothelial Massive Calcium Accumulation Death (MCAD): Mechanism, Target, and Predictive Biomarker for Anti-Angiogenic Therapy. Available from Nature Precedings (2011)

http://dx.doi.org/10.1038/npre.2011.6647.1

Poster Presentation

http://precedings.nature.com/documents/ ... 6647-1.pdf

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Biologic therapy is on the ascendancy. The possibility of eradicating cancer by selective destruction of tumor blood vessels may represent an attractive therapeutic avenue. It's going to take combination anti-vascular therapy to make a difference.

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Endothelial Massive Calcium Accumulation Death (MCAD): Mechanism, Target, and Predictive Biomarker for Anti-Angiogenic Therapy.

13th international symposium on anti-angiogenic therapy: recent advances and future directions in basic and clinical cancer research. LaJolla, CA. February 2011

When you culture endothelial cells (either pure cultures of endothelial cells or endothelial cells associated with fresh human tumor microclusters) with Avastin, all of the VEGF gets pulled out of the culture medium and the endothelial cells undergo what is called "massive calcium accumulation death."

Cytotoxic anticancer drugs (topotecan, vinorelbine, melphalan, doxorubicin, cisplatin) antagonize the ability of Avastin to kill endothelial cells through this specific cell death mechanism. The standard, traditional cytotoxic drugs all inhibited Avastin, but the new, "targeted" drugs either don't inhibit it or actually enhance it (e.g. lapatinib, erlotinib).

Clinical trials have shown that the combination of chemotherapy with Avastin generally works better than either alone (that is, in situations where Avastin works at all). But this is because Avastin has a very long half life (weeks) and it has the opportunity to work at times when the drug levels of the standard anticancer drugs go down to undetectable levels (where they won't antagonize the ability of low VEGF to cause death of the tumor endothelial cells).

It would be predictive that continuous chemotherapy with a drug like Taxol would be antagonistic; so that intermittent, lower dose therapy might actually work much better than continuous high dose therapy. This is a theoretical extrapolation from cell culture data.

The mechanism of antagonism is that the "MCAD" (massive calcium accumulation death of endothelial cells) is a bioenergetically active process. I'm sure that there's a specific pathway for it that someone will eventually work out and that non-specific cytotoxins inhibit this active process and, thus, the withdrawal of VEGF can't trigger this active, MCAD form of endothelial cell death.

Bibliography relevant to AngioRx/Microvascular Viability assay (MVVA)

1. Weisenthal, L. M. Patel, N., Rueff-Weisenthal, C. (2008). "Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood." J Intern Med 264(3): 275-287.

2. Weisenthal, L., Lee, DJ, and Patel, N. (2008). Antivascular activity of lapatinib and bevacizumab in primary microcluster cultures of breast cancer and other human neoplasms. ASCO 2008 Breast Cancer Symposium. Washington, D.C.: Abstract # 166. Slide presentation at: http://tinyurl.com/weisenthal-breast-lapatinib

3. Weisenthal, L. M. (2010). Antitumor and anti-microvascular effects of sorafenib in fresh human tumor culture in comparison with other putative tyrosine kinase inhibitors. J Clin Oncol 28, 2010 (suppl; abstr e13617)

4.Weisenthal, L., H. Liu, Rueff-Weisenthal, C. (2010). "Death of human tumor endothelial cells in vitro through a probable calcium-associated mechanism induced by bevacizumab and detected via a novel method." Nature Precedings 28 May 2010. from http://hdl.handle.net/10101/npre.2010.4499.1

5. Weisenthal, Larry. Endothelial Massive Calcium Accumulation Death (MCAD): Mechanism, Target, and Predictive Biomarker for Anti-Angiogenic Therapy. 13th international symposium on anti-angiogenic therapy: recent advances and future directions in basic and clinical cancer research. LaJolla, CA. February 2011

Available from Nature Precedings http://dx.doi.org/10.1038/npre.2011.6647.1

6. Weisenthal, L, Williamson, S, Ryan, K, Brunshwiler, C, and Rueff-Weisenthal, C. Massive calcium uptake in human endothelial cells, submitted for publication.

7.Bevacizumab-induced tumor calcifications can be elicited in glioblastoma microspheroid culture and represent massive calcium uptake death (MCAD) of tumor endothelial cells. Larry Weisenthal, Summer Williamson, Cindy Brunschwiler, and Constance Rueff-Weisenthal, 14th International Anti-Angiogenesis Symposium, LaJolla CA, Feb 2012. Available from Nature Precedings http://dx.doi.org/10.1038/npre.2012.7069.1

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