MODULATORS OF HUMAN MITOCHONDRIAL PROTEASE ClpP ACTIVITY FOR PEDIATRIC DIFFUSE PONTINE GLIOMA TREATMENT

Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem cancer and a leading cause of pediatric brain tumor-related death with the median survival of 10 months post-diagnosis. The sensitive location and infiltrative nature of the tumor makes full surgical resection unfeasible therefore targeted radiation has been the standard therapy to alleviate pain and transiently stabilize neurological functions. DIPG resistance to commonly chemotherapeutic agents, provided a pressing need for the development of novel therapeutics for this malignancy. Meantime, the compound ONC201 was discovered to reduce DIPG tumors size in DIPG H3K27M mutated and now is in phase III clinical trials. Efforts to better understand DIPG related mechanism have proposed a new cellular target, being the mitochondrial caseinolytic protease P (ClpP). ClpP is found in both mammalian and bacterial cells. It is a highly conserved serine protease which combines with an ATPase to form a proteolytic complex responsible for the degradation of misfolded proteins at cellular level. In view of the potential therapeutic applications of ONC201 and other to-be-developed molecules, it is crucial to understand the molecular mechanisms linking ClpP activity with DIPG tumor onset and progression. Currently, the effects of the newly identified small-molecule modulators are under evaluation on ClpP enzymatic activity by using purified, recombinant human ClpP protease in a fluorogenic in vitro assay. This study will help to gain insights into mitochondrial functions regulated by ClpP.