Chimerix is developing a new class of selective cancer therapies called imipridones. These drugs target specific G protein-coupled receptors (GPCRs) and mitochondrial caseinolytic protease P (ClpP), resulting in cancer cell death. The imipridone chemical scaffold provides an opportunity to target GPCRs and ClpP with tunable specificity and modality, which potentially enables broad therapeutic use for cancer and other diseases through selective modulation of distinct downstream mechanisms.
ONC201 is the founding member of the imipridone class of anti-cancer small molecules which selectively targets Dopamine Receptor D2 (DRD2) and ClpP. ONC201-mediated cell death occurs via induction of the integrated stress response and upregulation of apoptotic factors, such as tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). It is dosed orally and has been well-tolerated and shown clinical activity in Phase I and II trials for specific advanced cancers.
ONC201 has been shown to selectively induce cell death in cancer cells by binding to and differentially altering activity of DRD2 and ClpP as shown schematically below:
- ClpP normally degrades misfolded proteins in mitochondria
- ONC201 modifies ClpP conformation, promoting excess degradation of specific mitochondrial proteins important for cancer cell viability
- DRD2 is a G protein-coupled neuroreceptor that regulates Ras signaling
- ONC201 antagonizes DRD2, inhibiting Ras signaling pathways
H3 K27M sensitivity
- H3 K27M reduces methylation of histone H3, altering gene expression and increasing sensitivity to ONC201
Additional information on ONC201
Clinical trials of ONC201 in glioma patients with the H3 K27M-mutation are underway at several locations in the U.S. As many as 10% of patients with glioma have the H3 K27M-mutation. The H3 K27M-mutation is found in 50-90% of patients with midline glioma, including 80-90% of children with diffuse intrinsic pontine glioma or DIPG. The test for H3 K27M is commercially available either through immunohistochemistry (IHC) staining or gene sequencing..
ONC201 in brain and other CNS tumors
The development of ONC201 is focused on treating brain tumors with H3 K27M-mutations. This focus is based on both preclinical and clinical results that have shown the ability of single agent ONC201 to address this disease.
Neuro-Oncology and H3 K27M-mutations
Neuro-oncology is a category that includes all tumors of the brain and spinal cord, such as astrocytoma, glioma, ependymoma, and glioblastoma. Gliomas are tumors which arise from glial cells, forming the tissue that surrounds and protects other nerve cells found within the brain and spinal cord. The term H3 K27M refers to a specific mutation in genes that encode for proteins called histone H3, which occurs in a subset of these tumors. While the mutation can be found in tumor locations across the nervous system and across age groups, H3 K27M has a higher occurrence in midline brain locations (thalamus, brainstem, spinal cord) and in younger patients. The mutation can occur in several different types of brain tumors, including tumors that were traditionally called glioblastoma (GBM) or diffuse intrinsic pontine glioma (DIPG). Tumors with this mutation have no effective treatments after radiation and are associated with poor overall survival. Standard treatment for many patients consists of radiation and, when feasible, surgery. Chemotherapy is not curative for any of these brain tumors and has proven ineffective in clinical trials of some types of high-grade gliomas where the H3 K27M-mutation is found, such as DIPG.
About ONC201 in H3 K27M-mutant gliomas
In clinical trials and expanded access for ONC201, patients with brain tumors that have the H3 K27M-mutation have shown promising results, including significant tumor shrinkage. ONC201’s clinical activity against brain cancer is enabled by the drug’s ability to cross the blood brain barrier and achieve therapeutic concentrations within tumors. In clinical trials, ONC201 has been well-tolerated in patients. The drug antagonizes specific dopamine receptors (e.g., DRD2) that are overexpressed in some tumors that occur in the brain. Overall, ONC201-mediated DRD2 antagonism and ClpP agonism selectively induce tumor cell death which leads to tumor shrinkage and often other clinical improvements.
ONC201 in other cancers
ONC201 is being evaluated in tumor types that are generally enriched for specific predictive biomarkers or microenvironments. For example, ONC201 is being evaluated in neuroendocrine tumors in a Phase II clinical trial at the Cleveland Clinic. Tumor regressions in response to single agent ONC201 have been observed in an arm that exclusively enrolled patients with paragangliomas, which are adrenal-related tumors that can secrete dopamine and exhibit elevated DRD2 expression.
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