3 Questions on...A New Way to Attack Metastatic Tumors

Daniel Heller, PhD: Daniel Heller, PhDP-selectin—a molecule on the inner walls of blood vessels—plays an important role in allowing tumors to metastasize. Researchers say they have now found a way to target the molecule using nanoparticles that they say may be key to better delivering anticancer drugs to stop those metastases. “The nanoparticles that we synthesized have affinity for P-selectin, which is present on or can be induced (via radiotherapy) to appear in the walls of tumor vasculature,” noted researcher Daniel Heller, PhD, Molecular Pharmacologist at Memorial Sloan Kettering Cancer Center, New York, N.Y. “The nanoparticles bind to the P-selectin, causing them to localize within the tumor microenvironment and deliver drug cargoes there, including precision medicines. “The drugs which we load into the nanoparticles are not new, but this technology may allow the development or rescue of drugs which have good anti-cancer properties but have poor pharmacologic properties,” Heller explained. This drug delivery process has a lot more testing to go before it reaches the bedside, including being tested in clinical trials. But the researchers say the strategy could be effective across almost any tumor type. The data were recently published in Science Translational Medicine (2016;8:345ra87). Here's what else Heller told Oncology Times about their findings. 1 Why target P-selectin? “It's not a conventional ‘drug target,’ but a new target that can be used to cause a drug carrier (i.e., the nanoparticle that carries drugs) to stick to a tumor site. This is true because the target appears in tumor blood vessels (that feed metastatic tumors). P-selectin often facilitates the metastatic process by causing circulating tumor cells to adhere to blood vessel walls, extravasate, and form new metastases. “We used P-selectin as way to target drugs to these metastases. We developed a new class of nanoparticles composed of the polysaccharide fucoidan, which has specific affinity to P-selectin. The fucoidan-based nanoparticles can be loaded with many different classes of drugs. “And we showed, using two metastatic tumor models, that doxorubicin-encapsulated nanoparticles targeted to P-selectin are much more effective than untargeted nanoparticles, or the same amount of doxorubicin given conventionally. A single injection of the nanoparticles resulted in complete tumor inhibition in 50-80 percent of the mice, depending on the metastatic model. 2 What advantages would this type of drug delivery have over existing modes of anti-cancer drug delivery? “New ‘targeted’ therapeutics and precision medicines, like MEK inhibitors, can be targeted using these nanoparticles, which can significantly reduce the side effects of these drugs. “Not only did we show that the nanoparticles allow us to give much greater doses of chemotherapeutic drugs to a tumor than could normally be administered, we also showed (in collaboration with the José Baselga Lab) that the pharmacokinetics, pharmacodynamics, toxicity, and efficacy of a personalized drug can be much improved by physically targeting these ‘targeted’ drugs. “We found that the tumor-targeted nanoparticles can localize MEK inhibitor in the tumor site, resulting in prolonged inhibition of pERK. MEK inhibitors can cause serious dermatologic side effects. We showed that the drug doesn't get to the skin and doesn't affect the skin when it is administered using the nanoparticles, but it is much more effective against the tumor.” 3 Your paper notes this strategy could be effective against almost any tumor type. Why? “This approach would work for any tumors that express P-selectin, which includes both primary and metastatic tumors. This would also work for any tumor that could be irradiated via ionizing radiation (radiotherapy). “[We also found that] radiation can be used to ‘guide’ these nanoparticles to the blood vessels of nearly any tumor, even if the target (P-selectin) doesn't naturally appear in the tumor because P-selectin is produced in blood vessels upon exposure to radiotherapy. Therefore, radiotherapy can be used to produce the target in the tumor before the nanoparticles are administered, ensuring that the target is present for the nanoparticles to stick to. “We don't have any indications whether this technology would work better or worse in metastatic tumors, but we found that metastatic tumors are good targets.”