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16th International Symposium on Anti-Angiogenic Therapy
The 16th International Symposium on Anti-Angiogenic Therapy: Recent Advances and Future Directions in Basic and Clinical Cancer Research.
Date:February 6-8, 2014
Location:San Diego, California 92122, United States
Description: The field of anti-angiogenic therapy is quite complicated with various results with individual agents in different disease types. In fact, the efficacy of such agents in the advanced setting is different from that of an early stage in the adjuvant setting. In addition to learning more about the efficacy and appropriate use of these agents, it is also important for health care providers to understand new toxicities that have been recognized in association with the use of anti-angiogenic agents. This symposium will provide a comprehensive overview of the appropriate use of anti-angiogenic therapy in patients with solid malignancies. In addition, this symposium will review the appropriate use of anti-angiogenic agents and allow the learner to recognize toxicity and potential biomarkers. The main area of feedback focused on biomarkers and the appropriate use of therapy. This is an inherent challenge as we do not have any biomarkers that are validated. However we will continue to scan the literature and seek speakers who can address the issue of biomarkers and patient selection. We will also seek speakers and discuss resistance pathways, which overlap with the above issues.
One Laboratory Oncologist has the answer; will they listen?
Poster Presentation:
Massive calcium accumulation death (MCAD) of endothelial cells as a putative mechanism for Avastin (bevacizumab) anti-angiogenesis and acquired resistance to bevacizumab.
Larry Weisenthal, Summer Williamson, Cindy Brunschweiler, and Constance Rueff-Weiesnthal
We have discovered that human endothelial cells undergo two forms of cell death.
1. A non-specific form of cell death, similar to that of other normal and neoplastic cells.
2. A unique form of cell death, seen only in endothelial cells, associated with massive accumulation of calcium. We call this massive calcium accumulation death or MCAD.
MCAD may be identified by cytochemical staining with:
a. Fast Green alone
b. Fast Green/Hematozylin
c. Fast Green/Wright-Giemsa
d. Alizarin red S (most advantageous)
Sera from different patients is variably inhibitory of MCAD; circulating pro-angiogenic factors may be the mechanism of bevacizumab failure and a test called AngioRx assay may identify sera with such factors.
Here is what's new this year: We have discovered that MCAD occurs when endothelial cells deprived of VEGF begin to form massively calcified endosomes, which result in a unique form of cell death, specific to endothelial cells, and triggered only by pharmaceuticals known to have anti-angiogenic effects. It is not triggered by traditional cytotoxic agents. When many calcified endosomes are formed, the cells die and release massively calcified exosomes into the cellular millieu.
We isolated calcified exosomes produced by incubating circulating endothelial cells from a normal blood donor for 3 days in the presence of bevacizumab. We then incubated freshly drawn buffy coat leukocytes from the same normal donor and found that (1) neutrophils, monocytes, and lymphocytes clustered around these calcified exosomes and appeared to interact with them and (2) this resulted in the release of TNF into the culture medium. Besides being an inflammatory mediator, TNF has been shown to promote retinal vasculogenesis in various occular models and TNF inhibition has been shown to inhibit retinal vasculogenesis, in a manner similar to VEGF depletion by bevacizumab. We think that this provides a mechanism for bevacizumab resistance, to wit:
VEGF depletion --> MCAD, with formation of massively calcified endosomes and exosomes --> provoke phagocytosis and other direct interactions with inflammatory cells which result in the release of TNF (and probably other pro-angiogenic mediators; studies in progress) --> rescue of microcapillaries from the vasculotoxic effect of VEGF depletion.
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Hybrid Mode
