Many drugs are in the market for cancer treatment. However, the search for new drugs continues in order to get a better version or an efficient drug. ONC201 is one such drug used in cancer treatment. ONC201 is known to treat cancer but the exact mechanism of its action was not known to scientists. ONC201 prevents cells proliferation and kills tumors in cell and animal models. To understand this, multiple clinical trials have been conducted in the past few years.
The drug ONC201 is made by Philadelphia based company known as Oncoceutics. The company received a fast track designation from the FDA (Food and Drug Administration) for the treatment of Gliomas among adults. This month two studies have been published which shows the mechanism of action of the drug. It reveals that ONC201 activates an enzyme called ClpP, which breaks down the misfolded proteins in the mitochondria.
ONC201 originally when screened for potential cancer drug was thought to induce TRAIL gene which causes apoptosis in tumor cells. However, it was found that the same ONC201 doesn’t activate TRAIL gene in cancers cells for which it shows effectiveness.
“It’s important to understand how a drug works to understand how best to use it in patients, and in these two studies, they identified ClpP, a mitochondrial protease, as an important target of ONC201, which seems to account for some if not most of its clinical activity” said Stanely Lipkowitz, who is presently collaborating with the researchers.
A research paper published by Yoshimi Greer in Lipkowitz lab reported the activity of ONC201 against many cancer lines of breast cancer without activating TRAIL gene. Instead, the ONC201 was found to alter the mitochondrial functioning of the cancer cells. However, the understanding of its mechanism of action was not clear.
Understanding the mechanism of action
To understand the underlying mechanism of action of ONC201, Graves (Pharmacologist at University of North Carolina) studied it along with some other similar molecules. These molecules were referred to as ONC201 analogs generated by a company named as Madera Therapeutics. The scientist carried out affinity chromatography by using ONC201 analog TR-80 over the column against HeLa cells (Cervical cancer-derived cell line).
“We came at it from an old-fashioned affinity-chromatography approach—you know, ‘let’s make some bait and go fishing and see what we catch,’” said Graves.
Further analysis using Mass spectrometry found a protein ClpP to be associated with ONC201. The experiment was repeated using different cancer cell lines. It was found that ONC201 analogs bind to ClpP protein.
The study does not show that ONC201 killed cancer cells instead it shows that it prevents the growth of the cancer cells. Scientist tested all the analogs and observed an increase in the activity of ClpP to break down the mitochondrial proteins in the cells. To confirm this assay was carried out, where removal of ClpP nullified the effect of the analog drugs.
Another similar research was carried by a scientist – Michael Andreeff, a researcher at the University of Texas, who showed the increased activity of ClpP under the influence of drugs. More the ClpP, greater will be the effect of the drug. He also observed that the treatment using ONC201 causes degradation of proteins playing a role in the respiratory chain, impairing the mitochondrial function of cancer cells.
How the drug actually targets the cancer cells without affecting the normal cells was still a dilemma. Graves – “I think it comes back to the possibility that the tumor cells have a metabolic vulnerability,”. This indicates that mitochondria of cancer cells get altered in a way that it becomes more susceptible to the ONC201 drug. Whereas, the normal cell mitochondria remains unaffected.
The study can help scientist to identify more potential drugs targeting the pathway to prevent tumor proliferation and growth. The response of drug with respect to ClpP levels can be used to identify patients with a high response rate towards the drug.
This article has been adapted from the original content of The Scientist