Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-beta signaling

Administering a small amount of a potent but potentially toxic anticancer agent along with nanoparticles loaded with a second anticancer agent produced a dramatic inhibition of tumor growth in normally intractable cancers. These findings suggest a new approach to treating malignancies such as pancreatic cancer and diffuse gastric cancer.

Reporting its work in the Proceedings of the National Academy of Science, a team of investigators led by Kohei Miyazono, M.D., and Kazunori Kataoka, Ph.D., both at the University of Tokyo, described their experiments using an inhibitor of transforming growth factor beta (TGF-beta) to boost the antitumor activity of doxorubicin-containing nanoparticles. TGF-beta inhibitors have shown promise in stopping tumor growth and metastasis, but some experiments suggest that these inhibitors may trigger serious side effects, including the development of new tumors unrelated to the original cancer.

The investigators reasoned that sub-therapeutic doses of a short-acting TGF-beta inhibitor might interact with the blood vessels surrounding tumors in a way that might sensitize the tumors to a second therapeutic agent, in this case nanoparticles loaded with the anticancer drug doxorubicin. Indeed, experiments showed that very low doses of a short-acting TGF-beta inhibitor had no measurable effect on tumor biochemistry, but did lower the number of cells known as pericytes that normally coat the inside of newly growing blood vessels. With fewer pericytes present, the blood vessels surrounding tumors become even leakier than normal, allowing doxorubicin-loaded nanoparticles to escape from these vessels and accumulate at high levels within the tumors.

Experiments in animals with normally intractable cancers showed that this combination therapy was effective at inhibiting tumor growth. In somewhat of a surprise, the researchers also found that co-administering the TGF-beta inhibitor with a small molecule anticancer drug had no effect on tumor growth. Only the nanoparticle-inhibitor combination produced the desired boost in antitumor activity.

This work is detailed in a paper titled, “Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-beta signaling.” Investigators from the Osaka City University Graduate School of Medicine also participated in this study. This paper is available free-of-charge at the journal’s website. View paper.