Scientists have been able to prevent melanoma from metastasizing through increasing levels of a gene that is best known for its role in Alzheimer’s disease: apolipoprotein E (ApoE).

When they increased the levels of ApoE via activation of the liver X receptor (LXR), the authors saw an up to 80 percent reduction of the tumor sizes in mouse models of melanoma, and decreased metastases to the lung and brain by more than 90 percent.

Currently, there is no effective therapy for preventing melanoma metastasis, and even with the advent of Zelboraf (vemurafenib, Daiichi Sankyo Co. Ltd. and Roche AG) and Yervoy (ipilimumab, Bristol-Myers Squibb Co.), the majority of patients eventually relapse. The new findings suggest that drugs activating the LXR could be useful as an adjuvant therapy to prevent metastases in melanoma.

The work appeared in the Feb. 27, 2014, issue of Cell.

Scientifically, the findings expand the realm of how nuclear hormone receptors can be targeted therapeutically. Senior author Sohail Tavazoie of Rockefeller University explained that the rationale for targeting LXR is the opposite of the one that underlies targeting of nuclear hormone receptors in hormone-driven cancers. In estrogen receptor-fueled breast cancers, for example, targeting the receptor has the goal of shutting off estrogen signaling. The goal of LXR targeting, on the other hand, is “to turn on a metastasis suppressor,” he told BioWorld Today.

Tavazoie and his team had shown in previous studies that “highly metastatic melanoma cells shut down ApoE, and that allows them to metastasize.”

ApoE itself, however, would not work well as a therapeutic – the protein is too unstable. So Tavazoie and his team wanted to test whether spurring cells to increase their own production of the protein by activating the liver X receptor, which controls the production of ApoE, might halt melanoma metastasis.

In the experiments now published in Cell, Tavazoie, first author Nora Pencheva, and their team showed that activating the LXR increased ApoE levels, and that this increase had the ability to shrink primary tumors and prevent metastases from forming. ApoE affected both the melanoma cells themselves, keeping them from invading, and endothelial cells, by preventing their migration toward melanoma cells.

Tavazoie is the co-founder – with two of his siblings – of a start-up, Rgenix Inc., that aims to test LXR agonists in the clinic. The company was founded in 2010 and currently has lab space in the SUNY downstate incubator in Brooklyn, five employees and $3 million in received plus $1.5 million in committed angel funding.

Rgenix Inc. has identified and in-licensed a class of LXR agonists, Tavazoie said, that is not described in the Cell paper “but seems to be a better therapeutic.” Rgenix has filed method-of-use patents on that class of compounds, is doing toxicity studies and hopes to be in the clinical trials, he said, “within the next year.”

Tavazoie’s lab also is working out the molecular details of how ApoE prevents metastasis, and testing whether it might do so in other cancer types as well, since so far, their work has not turned up any reasons why the effect should be specific to melanoma.

Scientifically, the results also give new insights into the complex roles of ApoE. ApoE, Tavazoie said, “gets a bad rap” because of the association of certain variants with a high risk of developing Alzheimer’s disease and cardiovascular disease. But the work he and his team have now published in Cell show that at least in terms of melanoma, high levels of ApoE are a good thing.

“Our work has benefited from our understanding of Alzheimer’s and cardiovascular disease,” Tavazoie said, understanding ApoE’s role in melanoma “might give us some more insights into those diseases as well.”