New Pathway to Bone Metastasis Opens Door to Blockade

Pam Harrison

November 14, 2018

An intricate signaling pathway through which cancer cells likely metastasize to bone has been described, opening the door to its pharmaceutical blockade, and with it, the possibility of stopping metastatic disease spread.

The new findings were published online November 12 in Cancer Cell.

"We discovered that calcium influx from the osteogenic niche to cancer cells is essential for proliferation of early stage bone metastasis," the researchers write.

This is a new mechanism, that adds to the previously identified role of mTOR (mammalian target of rapamycin) signaling, they add.

"Blocking the calcium transfer that takes place through gap junctions as well as the activity of the mTOR pathway results in cancer cells dying or having difficulty growing because they are lacking the support of osteogenic cells," commented senior author Xiang Zhang, PhD, Baylor College of Medicine, Houston, Texas.

"And this observation suggested a potential Achilles heel in micrometastasis that could be targeted with medications to reduce the risk of full-blown metastasis," he said in a statement.

Building on Previous Research

Previous work (Cancer Cell. 2015;27:193-210) had shown that cancer cells and osteogenic cells — either osteoblasts or their precursors — activate mTOR signaling to promote the progression of bone micrometastases, the study authors explain.

Working with an experimental system in which researchers could mimic interactions between cancer cells and bone cells, the team determined that osteogenic cells and cancer cells establish a physical connection through gap junctions.

This connection works like a tunnel through which calcium travels from osteogenic cells to the cancer cell, they explain.

It is now known that it is calcium transfer that promotes the early outgrowth of tumor cells which could promote metastases in the bone, they add.

Small-Molecule Modulators

The team went on to screen a library of small-molecule modulators. They identified danusertib (PHA-739358, Cayman Chemical), a pan-aurora kinase inhibitor which inhibits the pathways involved in the promotion of bone metastasis, as well arsenic trioxide (Trisenox, Teva), a drug that possesses features similar to those found in danusertib.

Using these agents, either alone or together, opens up the possibility of eliminating bone micrometastases, they comment.  

However, since both mTOR and calcium signaling mediate early stage bone colonization with cancer cells, subsequent research indicated that an mTOR inhibitor such as everolimus (Afinitor, Novartis) plus either danusertib or arsenic trioxide might provide the most effective protection against micrometastasis to bone because both drugs affect calcium transport.

Using a mouse model of luminal breast cancer which has a strong affinity for bone, Zhang and colleagues showed that a very short interlude of treatment with everolimus plus arsenic trioxide significantly reduced relapses in these animals. The outcomes were even better when animals were treated with the combination than with everolimus alone.

"I think that conceptually, these results are telling us that when studying cancer biology, we cannot ignore the microenvironment," first author Hai Wang, MD, also from the Baylor College of Medicine in Houston, Texas, said in a statement.

"We need to consider the 'seeds' and the 'soil' in its entirety rather than studying the seeds separate from the soil," he observed.

Zhang and colleagues hope to persevere with this and related work so as to better understand the conversation between cancer and bone marrow and eventually come to stop cancer from spreading to bone and other organs.

The drugs used in these research studies — danusertib, arsenic trioxide, and everolimus — are already approved by the Food and Drug Administration for other indications, the researchers note. But they add that "there is still a number of steps that have to be fulfilled before they can be offered to treat micrometastasis in bone."

Zhang and Wang have reported no relevant financial relationships.

Cancer Cell. Published online November 12, 2018. Full text

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