Mantle cell lymphoma (MCL) and acute myeloid leukemia (AML) are two rare forms of blood cancer with a high unmet need. The majority of cases in these patient populations are still incurable.
“Anti-tumor agents with novel mechanisms of action are urgently needed.”
Researchers at the University of Texas have identified a new potential target to treat these rare conditions, even in patients who have p53 mutations, a common tumor suppressor.
Discovery in the Mitochondria
The research team uncovered that when caseinolytic protease P (ClpP) within the mitochondria of cells is activated, mitochondrial proteolysis occurs. Mitochondrial proteolysis causes the breakdown of proteins within the cell. Ultimately, this process causes the death of cancer cells.
In AML specifically, there have never been any reports of mutated ClpP or ClpP deletions. This indicates that ClpP could be a target across all subsets of AML. By investigating the levels of ClpP, researchers believe they could also determine which patients may be most responsive to the therapy. Early data has shown that patients who have low levels of ClpP have less of a reaction to its activation.
But how do we activate ClpP? Thankfully, the researchers found a new class of drug which can do so.
New Drugs
This class of drug is called imipridones and the two specific drugs investigated were called ONC201 and ONC212. The investigation was led by Michael Andreeff. Both in vivo and in vitro models were utilized to investigate these therapies. Not only did these studies show that the activation of ClpP was necessary, but the researchers were able to document the exact binding patterns/sites of the drugs in ClpP.
ONC201 is already in early clinical trials for both AML and other blood cancers after pre-clinical investigations showed the potential efficacy of the drug. However, the target behind its efficacy is still very much a mystery.
ONC212 has just finished pre-clinical toxicology studies and clinical trials for the drug should begin soon.
The results of this early research were published in Cancer Cell.
Of course, larger studies including a greater number of patients are essential. These additional studies should help researchers understand the thresholds of ClpP expressions needed to elicit response.
Overall, this class of drugs is still in very early development but researchers are excited about their potential for AML, MCL, and other blood cancers.
You can read more about this novel research here.
