Biotech Values

[mskatiescarletohara]

Aslan/Dew--TrpRS therapy.

Perhaps Cheresh and his colleagues have determined blocking/inhibiting RAF1 is the route for delivering genes. If it works in cancerous tumors, it very well could work on blood vessels in the eye.

http://www.signaling-gateway.org/update/updates/200208/nrc870.html

David Cheresh and colleagues have destroyed tumors using a strategy of gene-delivery that blocks the endothelial signaling pathways required for new blood-vessel formation.

Although many drugs have been developed to interfere with tumour angiogenesis, it has been difficult to find ones that specifically target tumour blood vessels without affecting normal tissues. David Cheresh and colleagues have developed a gene-delivery strategy to block endothelial signalling pathways that are required for new blood-vessel formation, and report that this approach can be used to destroy established and metastatic tumours.


The angiogenic epithelium expresses several surface molecules that are potential therapeutic targets. One of these, the integrin alphavbeta3, is a particularly good candidate because it is involved in cancer-cell invasion and has also been shown to mediate virus internalization — meaning it could mediate entry of other ligands into vascular endothelial cells. Cheresh and colleagues report in Science that a cationic polymerized lipid-based nanoparticle (NP) coupled to a small, organic integrin alphavbeta3 ligand can be used to deliver therapeutic genes to angiogenic blood vessels. But what genes are best for stopping blood-vessel growth?

The angiogenic factors basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) signal through a RAF1-mediated pathway, and blocking this pathway induces endothelial-cell apoptosis. A mutant form of Raf1 that fails to bind ATP (ATP µ -Raf) has been shown to block endothelial-cell Raf1 activity and inhibit angiogenesis in vivo. The authors coupled this mutant gene to alphavbeta3–NP, creating alphavbeta3–NP/Raf(-). When mice bearing established M21-L melanomas received a single injection of alphavbeta3–NP/Raf(-), the vector specifically targeted tumour blood vessels, where it induced apoptosis within 24 hours. By 72 hours, concentric rings of apoptotic tumour cells were observed around each apoptotic vessel, and the tumours began to necrose.

Consequently, treated mice displayed rapid tumour regression — in four out of six mice the tumours completely disappeared, and the other two showed a 95% reduction in tumour mass and a 75% suppression of blood-vessel density. Tumour regression was sustained for over 250 days. M21-L cells do not express alphavbeta3, indicating that the tumour regressed as a result of anti-angiogenic effects, rather than due to a direct effect on the cancer cells themselves.

But is this therapy effective against metastases? The authors injected mice with CT-26 colon adenocarcinoma cells, which led to the formation of lung or liver metastases, and 10 days later injected alphavbeta3–NP/Raf(-). Mice treated with control vector developed extensive lung and liver metastases, whereas treatment with alphavbeta3–NP/Raf(-) caused a regression and disappearance of these tumours. NPs are less immunogenic than viral vectors, so this molecule should be safer than other cancer gene-therapy approaches, and can also be used to deliver other types of therapeutic genes to blood vessels.

Kristine Novak
References

1. Hood, J. D. et al. Tumor regression by targeted gene delivery to the neovasculature. Science 296, 2404 – 2407 (2002) / PubMed /
2. Hood, J. D. & Cheresh, D. A. Role of integrins in cell invasion and migration. Nature Rev. Cancer 2, 91 – 100 (2002) / Article /