June 6, 2011

New Strategy To Attack Tumor-Feeding Blood Vessels

Scientists at the Walter and Eliza Hall Institute have discovered a key molecule needed to kill the blood vessels that supply tumors.

The research team from the institute's Molecular Genetics of Cancer and Cancer and Haematology divisions found that for anti-cancer therapies that target tumor blood vessels to work the death- inducing molecule Bim is required. The finding could lead to improved anti-cancer treatments that are based on a two- or three-pronged attack on both the tumor and its blood supply. The research will be published online in the Journal of Experimental Medicine tonight.

The growth of solid tumors, such as lung cancer, breast cancer and melanoma, depends on nutrients and oxygen being provided by the tumor blood supply. Cancer cells encourage the growth of blood vessels to feed a tumor by producing the hormone-like protein, vascular endothelial growth factor (VEGF). The research by Drs Edwina Naik, Leigh Coultas and Lorraine O'Reilly, and Professors Jerry Adams and Andreas Strasser showed that VEGF produced by tumors blocks production of Bim in the cells that line the tumor blood vessels.

New "Ëœanti-angiogenic' medications that attack the blood vessels within tumors are showing promise in starving many types of cancers by reducing their blood supply.

In this study, in experimental melanoma, lung cancer and breast cancer models, Bim levels increased in the cells lining the blood vessels when VEGF was depleted by anti-angiogenic drugs, ultimately killing the blood vessel cells. VEGF depletion reduced the number of blood vessels in tumors, making the tumors shrink. However, in mice in which the blood vessels do not express Bim, VEGF depletion did not affect the number of tumor-associated blood vessels, and tumors grown in Bim-deficient mice did not respond to anti-angiogenic treatments.

Dr Strasser said this finding suggests that strategies for treating tumors by attacking the tumor blood supply could be optimized by incorporating drugs called BH3-mimetics that cause cell death by acting like Bim at a molecular level. "Similarly, therapies that increase the amount of Bim in tumor blood vessels could enhance the effects of anti-angiogenic agents," Dr Strasser said.

"BH3 mimetics may have two beneficial effects in cancer therapy. Our previous research had showed they can directly trigger death in tumor cells, particularly when the tumor is also attacked by chemotherapeutic drugs. We now think BH3-mimetics could also impact tumor cells indirectly by killing endothelial cells within tumors.

"This suggests that a promising new approach to the therapy of solid tumors may be to use a three-medication combination of a drug that specifically targets the tumor cell, an anti- angiogenic agent to impair the tumor blood vessels, plus a BH3 mimetic that will help the anti-tumor drug to directly kill the tumor cells and also will help the anti-angiogenic agent to kill the intra-tumoral endothelial cells, which in turn will starve the tumor, causing even more tumor cell death."


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