A new angiogenesis inhibitor targeting multiple tyrosine kinases offers new hope for treating tumors

Jan KA guest blog from co-Editor-in-Chief of Vascular Cell, Jan Kitajewski, in which he discusses the potential of using the newly developed lenvatinib as an anti-angiogenic therapy in the treatment of thyroid cancer.

Blood vessels can be thought to function as do the roots of a tree, acting to nourish both near and far reaches of the living organism. Despite the amazing capacity of blood vessels to keep your tissues healthy, your blood vessels can be diverted toward more insidious purpose. Tumors attract and accept new blood vessels that they recruit from neighboring tissues. This process of tumor angiogenesis acts to assure that the growing tumor is nourished and provides a path for tumor cells to travel to distant sites.

Targeting tumors with anti-angiogenic therapy as an approach to treat human tumors has now passed the decade mark.Cancercell This began with the approval of bevacizumab (avastin), a therapeutic antibody that inhibits Vascular Endothelial Growth Factor (VEGF), for the treatment of colon cancer. This has been an era of promise achieved, with anti-angiogenic agents recognized for their success during treatment for kidney and colon cancer. However, the hope of using anti-angiogenic agents successfully to thwart growth of a variety of different tumor types has yet to be fulfilled. Novel drugs continue to be developed that offer unique inhibitory effects against tumor angiogenesis. These new agents provide new opportunities and more choices for cancer patients.

Lenvatinib is a recently developed chemical compound that hits a key angiogenic receptor known as VEGF Receptor (VEGFR). Unlike other similar agents in development, or which are approved for clinical use against tumors, lenvatinib has a unique range of activities. One could say that lenvatinib has an expanded capacity to work against the multitude of different ways that tumors stimulate new blood vessels.

Lenvatinib works by blocking a cohort of important angiogenic signals, mainly those signals that depend on cell receptors that promote blood vessel growth, such as VEGF and Fibroblast Growth Factor (FGF) receptors. Lenvatinib differs from other similar agents in the oncology clinic in that it successfully targets both FGF and VEGF. It also targets two receptors that can be active in cancer cells. Despite this broad range of activity, this potent compound can be tolerated when given to humans. Ongoing clinical trials look highly encouraging for the use of lenvatinib, particularly in thyroid cancer that did not respond to other treatments.

A recent article in Vascular Cell describes the preclinical studies that demonstrate why Lenvatinib is such a promising new compound. Yamamoto, Matsui and their colleagues from Eisai Co., Ltd. conducted a study to establish the mechanism of action of lenvatinib against angiogenesis. They proved that lenvatinib blocks angiogenesis promoted by either VEGF or FGF. This was in contrast to another anti-angiogenic agent, sorafenib, which was active against VEGF but not FGF.

Before going into the clinic, anti-angiogenic agents are tested against tumors grown experimentally in a mouse. The researchers report on evaluation of the response of several different tumor types to lenvatinib treatment in such experimental models. Their study includes representation of seven different tumor types found in humans: melanoma, pancreatic, lung, ovarian, colorectal, epidermoid and prostate cancer. Lenvatinib significantly inhibited the growth of all these tumor types at a high dose and five of the tumor types at dose that was 100 times less than maximal; a very encouraging profile.

A new terrain in cancer research is the study of why drugs work against some tumor types and not against others. This work is difficult when assessing anti-angiogenic agents where resistance mechanisms are poorly defined. The lenvatinib study looked for correlations between lenvatinib’s anti-tumor activity and the quality and quantity of tumor vasculature in 19 different mouse tumor models. The scope of this assessment helped the researchers establish that lenvatinib was more effective in tumors that have many blood vessels, or tumors with a large amount of blood vessel associated cells called pericytes. As a similar type of analysis can be done on biopsied human tumor samples, the research suggests that patients may one day be evaluated for their potential responsiveness to compounds like lenvatinib. The sophistication of newly emerging cancer drugs and the ability of predicting how a patient responds to these drugs is a positive force in the drive toward thwarting cancers. The study of lenvatinib in the preclinical setting, as described in this Vascular Cell research article, provides encouragement for similar assessments to be made in the oncology clinic.

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