In order to accelerate this process, scientists at MIT have produced RNA-delivering nanoparticles that provide fast screening of the latest drug targets in mice. For their initial mouse study, conducted with scientists at Dana-Farber Cancer Institute and the Broad Institute, the researchers demonstrated that nanoparticles that target a protein called ID4 can reduce ovarian tumors.
The system, published in the online edition of Science Translational Medicine, could help overcome obstacles in the development of cancer drugs, according to Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science and a member of the David H. Koch Institute for Integrative Cancer Research at MIT.
"What we did was try to set forth a pipeline where you start with all of the targets that are pouring out of genomics, and you sequentially filter them through a mouse model to figure out which ones are important. By doing that, you can prioritize the ones you want to target clinically using RNA interference, or develop drugs."
William Hahn, an associate professor of medicine at Harvard Medical School, is the leader of Project Achilles, a collaborative attempt to discover potential innovative targets for cancer drugs from the avalanche of data coming from the National Cancer Institute's cancer-genome-sequencing project.
Some of those promising targets are regarded as "undruggable," for example, the proteins do not contain in which a medication could attach to them. The newest nanoparticles, which provide short strands of RNA that are able to turn off a specific gene, could help researchers pursue those undruggable proteins.
Hahn, who is also director of the Center for Cancer Genome Discovery at Dana-Farber and a senior associate member of the Broad Institute, said: "If we could figure out how to make this work [in humans], it would open up a whole new class of targets that hadn't been available."
Through Project Achilles, the team are examining the attributes of numerous genes damaged in ovarian cancer cells. Simply by exposing genes vital to cancer-cell survival, this method has refined the list of possible targets to several dozen.
Generally, phase two in discovering a good drug target is usually to genetically engineer a strain of mice that are absent (or overexpressing) the gene involved, in order to determine the way they react when tumors develop. However, this usually takes 2 to 4 years. A significantly quicker approach to examine these kind of body's genes is to switch them off after a tumor develops.
RNA interference (RNAi) provides a achievable technique of doing that. Within this naturally occurring phenomenon, short strands of RNA attach to the messenger RNA (mRNA) that delivers protein-building directions from the cell's nucleus to the other parts of the cell. Once attached, the mRNA molecules are demolished and their corresponding proteins never get produced.
Researchers have actually been pursuing RNAi as a cancer treatment since it was identified in the 1990's. However, researchers have experienced difficulties in discovering a approach to safely and efficiently target tumors with this treatment. One of their main challenges was finding a way to get RNA to enter tumors.
In this study, the teams goal was to develop a "mix and dose" technique that would allow scientists to mix up RNA-delivery particles that target a specific gene, inject them into mice and observe the outcome.
For their first attempt, the team focused on ID4 protein as it is overexpressed in approximately one third of high-grade ovarian tumors (the most invasive kind), although not in other cancer types. The gene, which codes for a transcription factor, seems to be connected to embryonic development: It gets de-activated early in life, then in some way reactivates in ovarian tumors.
To target ID4, the team developed a innovative type of RNA-delivering nanoparticle. These particles can both target and enter tumors, something that had not before been accomplished with RNA interference.
On their surface, the particles are marked with a short protein fragment that enables them to penetrate tumor cells. In addition, the fragments are attracted to a protein located on tumor cells, referred to as p32. This fragment and several comparable ones were identified by Erkki Ruoslahti, a professor at the Sanford-Burnham Medical Research Institute at the University of California at Santa Barbara.
Inside the nanoparticles, strands of RNA are combined with a protein that also assists them along their journey: When the particles penetrate a cell, they're exemplified in membranes called endosomes. The protein-RNA mixture can cross the endosomal membrane, enabling the particles to reach the cell's main compartment and begin deteriorating mRNA.
In a study of mice with ovarian tumors, the researchers discovered that therapy with the RNAi nanoparticles got rid of the majority of the tumors.
The team is currently utilizing the particles to examine additional potential targets for ovarian cancer in addition to other forms of cancer, such as pancreatic cancer. Furthermore, the team are considering the possibility of creating the ID4-targeting particles as a treatment for ovarian cancer.