Abstract
A paucity of chemotherapeutic options for metastatic brain cancer limits patient survival and portends poor clinical outcomes. Using a CNS small-molecule inhibitor library of 320 agents known to be blood-brain barrier permeable and approved by the FDA, we interrogated breast cancer brain metastasis vulnerabilities to identify an effective agent. Metixene, an antiparkinsonian drug, was identified as a top therapeutic agent that was capable of decreasing cellular viability and inducing cell death across different metastatic breast cancer subtypes. This agent significantly reduced mammary tumor size in orthotopic xenograft assays and improved survival in an intracardiac model of multiorgan site metastases. Metixene further extended survival in mice bearing intracranial xenografts and in an intracarotid mouse model of multiple brain metastases. Functional analysis revealed that metixene induced incomplete autophagy through N-Myc downstream regulated 1 (NDRG1) phosphorylation, thereby leading to caspase-mediated apoptosis in both primary and brain-metastatic cells, regardless of cancer subtype or origin. CRISPR/Cas9 KO of NDRG1 led to autophagy completion and reversal of the metixene apoptotic effect. Metixene is a promising therapeutic agent against metastatic brain cancer, with minimal reported side effects in humans, which merits consideration for clinical translation.
| Original language | English (US) |
|---|---|
| Article number | e161142 |
| Journal | Journal of Clinical Investigation |
| Volume | 133 |
| Issue number | 24 |
| DOIs | |
| State | Published - Dec 1 2023 |
Funding
This work was supported by NIH grants P50CA221747, R35CA197725, R01NS87990, and R01NS093903 (all to MSL). Imaging work was performed at the Northwestern University Center for Advanced Microscopy, which is generously supported by National Cancer Institute (NCI), NIH grant CCSG P30 CA060553, awarded to the Robert H Lurie Comprehensive Cancer Center. Histology services were provided by the Northwestern University Research Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553, awarded to the Robert H Lurie Comprehensive Cancer Center. Pharmacokinetics experiments were conducted with the help of the Clinical Pharmacology Core at Northwestern University, which has received support from the NIH (1S10OD012016-01/1S10RR019071-01A1); Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-1542205); the State of Illinois; and the International Institute for Nanotechnology (IIN). The MD Anderson RPPA Core is supported by NCI grant CA16672 and Yiling Lu’s NIH R50 grant R50CA221675 (Functional Proteomics by Reverse Phase Protein Array in Cancer). We would also like to thank Yu Han for her technical support with in vivo studies.
ASJC Scopus subject areas
- General Medicine
