Researchers at MIT and Skoltech have developed a new combinatorial therapy that could be used to treat liver cancer in humans, the fourth most common form of cancer. The researchers combine their new therapy with conventional chemotherapy in a mouse model with hepatocellular carcinoma and caused a significant decrease in tumor load.
Chemotherapy alone can be used to treat patients with liver cancer, but it is only effective in the early stages of the disease. Liver cancer is particularly aggressive in the latter stages of the disease, and those latter stages are resistant to all conventional chemotherapies currently in use.
There have been some advanced treatments developed, which have recently been approved for use in patients who have been treated with sorafenib and have progressed. The treatment uses a combination of the multiple kinase-inhibitor regorafenib with two check point inhibitors, but even the new treatment only increased survival, on average, by around 3 months. New treatments for advanced liver cancer are therefore needed.
The researchers’ technique uses an siRNA approach and lipid nanoparticle technology to prevent the production of specific proteins involved in the regulated program for cell death (apoptosis). By switching off a mechanism that prevents cell death, it makes chemotherapy more effective. “Once the mechanism is turned off, the cells become more susceptible to dying. This allows for the chemotherapy to be more efficient, killing more cancer cells, and preventing them from dividing,” explained Dominique Leboef, a Skoltech Ph. D student and first author of the study.
The siRNA used by the researchers will reach all liver cells, but it has the greatest effect in cancer cells which are dividing rapidly. Normal, healthy liver cells will survive chemotherapy.
The study was the result of close collaboration between Skoltech and MIT, and took advantage of the knowledge and strengths of both teams. Study lead, Professor Konstantin Piatkov had expert knowledge of the N-degron pathway, Professor Timofei Zatsepin has considerable expertise in siRNA, and Professor Daniel Anderson had an excellent understanding of oligonucleotide drug delivery. Dominique Leboef was able to confirm that the proposed molecular mechanisms would allow the selective killing of cancer cells, then the combinatorial approach was developed and shown to be effective at treating liver cancer in an animal model.
“Because the proteins targeted by our therapy are expressed in all types of cells, the combinatorial treatment developed in this study has the potential to be applied to all types of cancer,” said Piatkov. “Our approach is simple and universal, and we believe that it has the possibility of eventually improving the outcome for many cancer patients in the future.”
You can read more about the study in the paper – Downregulation of the Arg/N-degron Pathway Sensitizes Cancer Cells to Chemotherapy In Vivo – which was recently published in the journal Molecular Therapy. DOI: 10.1016/j.ymthe.2020.01.021