Researchers at the University of North Carolina at Chapel Hill believe they have figured out why novel nanoparticle-based therapeutics have not improved overall survival rates for cancer patients despite high expectations. They think that failure may have less to do with the drugs and tumors than it does the tumor's immediate surroundings.
The research (“Effects of Tumor Microenvironment Heterogeneity on Nanoparticle Disposition and Efficacy in Breast Cancer Tumor Models”), published in Clinical Cancer Research, merges relatively old and new ideas in cancer treatment, on one hand underscoring the importance of personalized medicine and on the other, reinforcing a relatively new idea that the tumor microenvironment might affect the delivery of drugs to tumors. This finding may alter the ways scientists think about drug delivery from person to person, from cancer to cancer and even from tumor to tumor.
“Tumors create bad neighborhoods,” said William Zamboni, Ph.D., the study's senior author and an associate professor at the UNC Eshelman School of Pharmacy. “They spawn leaky, jumbled blood vessels that are like broken streets, blind alleys and busted sewers. There are vacant lots densely overgrown with collagen fibers. Immune-system cells patrolling the streets might be good guys turned bad, actually working for the tumor. And we're trying to get a large truckload of medicine through all of that.”
In their work, Dr. Zamboni and colleagues from the UNC Lineberger Comprehensive Cancer Center and the UNC School of Medicine joined forces to see how much of the standard small-molecule cancer drug doxorubicin and its nanoparticle version, Doxil, actually made it into two varieties of triple-negative breast-cancer tumor models created by UNC's Chuck Perou, Ph.D., the May Goldman Shaw Distinguished Professor of Molecular Oncology at the UNC School of Medicine and a professor at UNC Lineberger. Triple-negative breast cancer accounts for 10 to 17% of cases and has a poorer prognosis than other types of breast cancer.
At first, what they saw was no surprise: significantly more of the nanodrug Doxil made it into both triple-negative breast-cancer tumors compared with the standard small-molecule doxorubicin. “That's nothing new,” according to Dr. Zamboni. “We've seen that for twenty years.” They also saw the same amount of doxorubin in both tumors.
What did surprise them was that significantly more of the nanodrug Doxil—twice as much—was delivered to the C3-TAg triple-negative breast cancer tumor than to the T11 triple-negative breast cancer tumor.
“The tumor microenvironment and/or tumor cell features of breast cancer affected NP [nanoparticle] tumor delivery and efficacy, but not the small-molecule drug,” wrote the investigators. “Our findings reveal the role of the tumor microenvironment in variability of NP delivery and therapeutic outcomes.”
“If the differences in delivering nanoagents to these two tumors are so significant, we can only imagine what the differences might be between breast cancer and lung cancer,” pointed out Dr. Zamboni.
He and his team suggest that better profiling of tumors and their microenvironments would allow doctors not only to better identify patients who would most benefit from nanoparticle-based cancer therapy, but also that clinicians may need to learn more about a patient's tumor before prescribing treatment with one of the newer nanoparticle drugs.