Endometrial cancer (EC) is the most common gynaecological cancer in the US today, with patient outcomes worse today than they were in the 1970s. There are two main types of this cancer. The first is EC1, which can be detected early and successfully treated. In contrast, the second, EC2, which mainly includes uterine serous carcinoma (USC), is much more serious and often deadly. Indeed, although USC represents only 10% of all EC cases, it contributes to nearly 40% of all total deaths from EC.

USC contains mutations in the tumour suppressor p53, which is sometimes called “the guardian of the genome” because it controls cell cycle checkpoints to allow cells to repair damaged DNA or to induce apoptosis (programmed cell death). Researchers led by Kimberly Leslie and Aliasger Salem have now used biocompatible poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with the anti-cancer drugs paclitaxel (PTX), which is a type of chemotherapy used to treat endometrial cancer, and nintenadib or BIBF 1120, a relatively new drug used to restrict tumour blood vessel growth. Besides limiting blood vessel growth, nintedanib also targets tumour cells with a specific “loss of function p53”, or LOFp53, mutation. This LOF mutation interrupts the normal life cycle of tumour cells and makes them more resistant to the lethal effects of chemotherapy.

“The PTX/nintenadib combination works by specifically killing LOFp53 cancer cells because it makes them bypass a checkpoint called G2/M so that they cannot repair themselves,” explains Salem.

The nanoparticles were prepared using a nanoprecipitation method, which is a straightforward technique to produce small nanometre-scale particles with a narrow size distribution. These particles help the anti-cancer drugs better target tumour sites since they accumulate in them thanks to the so-called enhanced permeation and retention effect, which exists because tumours naturally have a defective “leaky” vasculature. “We also used the surfactant tocopherol glycol succinate (TPGS) as a drug efflux inhibitor that prevents drugs being pumped back out of the cancer cells once they are in there,” explains Salem.

The researchers hope their data will support future clinical trials using nanoparticles and combinations of anticancer agents chosen specially for a specific tumour genotype – in this case the mutational status of p53. “p53 mutations are the most common alteration in all cancers, and as a foundation mutation in many tumours, the allele frequency of mutant p53 in a tumour is very high," explains Leslie. "A high allele frequency means that most tumour cells have this mutation and will thus be vulnerable to treatment strategies capitalizing on the mutated p53 status. We have hence converted this common driver of carcinogenesis into an Achilles heel for cancer therapy.”

Optimizing nanoparticle delivery

Since both PTX and nintenadib are FDA-approved drugs and PLGA has a long track record of use in FDA-approved drug-delivery systems, we expect that our strategy could be readily translated to clinical applications,” Salem tells nanotechweb.org.

The researchers say that they will now be analysing data from both completed trials for their technique and new trials to confirm the findings reported in this work, which is published in Nature Nanotechnology doi:10.1038/s41565-017-0009-7. “From a fundamental perspective, we are also developing new combinations of agents that will target alternative forms of p53 mutations,” adds Leslie. “We will also continue to optimize the nanoparticle delivery strategy by adding targeting ligands to the nanoparticles, for example, to improve tumour-targeting further.”

The work could also revolutionize treatment of ovarian cancer, she states. “Nanoparticles may be particularly helpful when chemotherapy is delivered directly into the peritoneal cavity, but this approach is very toxic. Imagine if we were to use less toxic nanoparticles in this setting?

Even more interesting is a personalized approach that we could take – selecting the anti-cancer agents based on the specific mutations in a tumour.”