Study Identifies New Therapy Target For Blood Cancers in Mitochondria of Cancer Cells

Researchers have identified a new target in the mitochondria of cancer cells that indicate the potential of a treatment class for certain blood cancers. According to the researchers, this new target offers insight into how impiridones, a novel class of small molecule anti-cancer compounds, work by inducing cancer cell deaths in blood cancers like acute myeloid leukemia (AML).

The target, caseinolytic protease P (ClpP) plays a central role in mitochrondrial protein quality by degrading misfolded proteins. Upon activation, ClpP breaks down proteins within the mitochondria in a process known as mitochondrial proteolysis. Impiridones have shown efficacy in activating ClpP.

Through both in vitro and in vivo models, the researchers were able to demonstrate that hyperactivation of the protease selectively kills cancer cells, independent of the presence of p53—the common tumor suppressor—by selective degradation of its repository chain protein substrates and disrupts mitochondrial structure and function. Nonmalignant cells were not affected.

“Despite newly developed targeted agents, the majority of hematologic malignancies and solid tumors are still incurable. This includes essentially all patients with p53 mutations,” said Michael Andreef, MD, PhD, professor of leukemia at The University of Texas MD Anderson Cancer Center, and author of the study, in a statement. “Therefore, anti-tumor agents with novel mechanisms of action are urgently needed. Our findings support the clinical development of imipridones and other ClpP activators for human cancers.”

These findings were demonstrated with the use of 2 drugs: ONC201 and ONC212. Throughout the study, the researchers found that knock-out or overexpression of inactivated mutant ClpP resulted in complete resistance against the 2 drugs, indicating that ClpP activation is needed for the drugs to work.

ONC201, which is currently in early clinical trials for AML and other cancers, has demonstrated pre-clinical efficacy in several cancer models.

“Deletions or mutations of ClpP have never been reported in primary AML, suggesting that ClpP could be an effective target across the spectrum of molecular and cytogenetic subsets of AML,” said Jo Ishizawa, MD, PhS, assistant professor of Leukemia at The University of Texas MD Anderson Cancer Center, and lead author of the study, in a statement.

According to Ishizawa, the study data indicated that samples with the lowest levels of ClpP were less sensitive to ClpP hyperavtivation, which suggest that levels of ClpP could serve as a biomarker to identify which patients with AML are most likely to respond to the treatment.

However, the direct target behind its effectiveness remains unclear. ONC212 is scheduled for clinical trials in the near future.

Reference

Ishizawa J, Zarabi S, Davis R, et al. Mitochondrial ClpP-mediated proteolysis induces selective cancer cell lethality [published online May 2, 2019]. Cancer Cell. doi: 10.1016/j.ccell.2019.03.014.