Preventing metastasis with molecular decoys

Many patients with colorectal cancer or non-small cell lung carcinoma are now treated with Genentech's monoclonal antibody Avastin (bevacizumab), the first in a new generation of drugs that inhibit the formation of new blood vessels that fuel tumour growth.

Angiogenesis inhibitors promise to have generic activity against a wide range of solid tumours. But molecular cancer biologist Professor Kari Alitalo, of the Finnish Academy at the University of Helsinki, says it's not enough just to inhibit angiogenesis.

Alitalo, a plenary speaker at last week's Lorne Cancer conference , says that ideally, the new inhibitors will also block lymphangiogenesis.

Cancerous cells secrete growth factors that stimulate formation of new lymphatic vessels, through which mutant cells can escape primary tumours and establish secondary, metastatic tumours elsewhere in the body.

Five years ago, Alitalo's team, working with researchers at the Helsinki, Stockholm and Melbourne centres of the Ludwig Institute for Cancer Research (LICR), cloned the gene for a new receptor for vascular endothelial growth factors (VEGFs).

The VEGF-C receptor appears to play a dual role in angiogenesis and lymphangiogenesis. It is activated by the VEGF-C and VEGF-D growth factors, which can stimulate both processes. Alitalo has collaborated with Marc Achen and Steven Stacker from the Ludwig Institute in Melbourne to characterise VEGF-D.

Structurally, VEGF-C is similar to VEGF-B, which the Helsinki team characterised in collaboration with Professor Ulf Ericsson at the Ludwig Institute in Stockholm.

VEGF-B selectively stimulates angiogenesis by a different pathway, and shows promise as a therapy for growing new coronary arteries after myocardial ischaemia.

Molecular decoy

The Helsinki team has now been experimenting with a promising approach that prevents about two-thirds of metastatic cancers in mice xenografted with human cancers.

It's a soluble form of the VEGF-C/D receptor that acts as a molecular decoy, competing with the native receptor to bind VEGF molecules secreted by cancerous cells.

"We have spliced out the part of the receptor that binds VEGF-C, so the signalling region is uncoupled from the region binding the growth factor," Alitalo says. "We then saturate tissues with this truncated form.

"We would be encouraged to try combination treatments with cytostatic therapy and other means of tumour inhibition. We think these combinations could be very effective."

Alitalo says that while the VEGF-C pathway is activated in a variety of solid tumours, the degree of activation varies.

"We have published data showing that the VEGF-C pathway is activated in nearly half of solid tumours, and we detect the receptor at levels which suggest that these types of tumours will be good targets for the new treatments," he says.

His team is also experimenting with monoclonal antibodies that selectively bind to and block the VEGF-C receptor.

"Both types of molecules should be suitable for treating cancer in the future, and we are about to proceed with clinical trials in human volunteers," he says.

"Recent experiments indicate that our monoclonal antibodies also inhibit tumour growth to a significant degree, and seem to have an effect on angiogenesis."

One of the first clinical trials will be in VEGF-C/D-expressing breast cancers.