Expert Opinion on Therapeutic Targets最新文献

Introduction: The WRN gene is mutated in Werner syndrome (WS), a heritable premature aging and cancer predisposition syndrome. Recent work identified WRN as a therapeutic target in a subset of cancers, emphasizing the need to better understand physiologic and cancer-specific roles for WRN that can be leveraged in therapy.

Areas covered: We discuss WRN as a caretaker of the genome that can function as a tumor suppressor or tumor enabler, and review progress on targeting functional WRN in microsatellite-unstable (MSI) cancers. We discuss mechanisms and distinct properties of synthetic lethality between the loss of WRN and the MSI-high tumor status, and derive lessons that can be used to identify or improve upon other cases of WRN synthetic lethality. We highlight the properties of a new generation of WRN helicase inhibitors that may confer increased lethality to MSI cancer cells while sparing normal tissues. We also discuss targeting mutant WRN in Werner syndrome and in cancer.

Expert opinion: Significant gaps remain in understanding how WRN loss promotes pathogenesis. Filling these conceptual and informational gaps will allow better prediction of tissue-specific adverse effects of WRN helicase inhibition or WRN loss. We highlight important, unanswered questions in WRN biology and newly emerging research and translational opportunities.

Background: Breast cancer is a leading cause of cancer-related death among women worldwide. Aquaporin 7 (AQP7), a transmembrane protein facilitating the transport of glycerol, and/or water across plasma membranes, has been found the aberrant expression and dysfunction in various types of human cancer.

Research design and methods: In this study, we revealed an aberrant downregulation of AQP7 in basal-like breast cancer. We performed functional assays in vitro and in vivo using basal-like human breast cancer cells with or without expression of AQP7, including cancer cell stemness, cell migration and invasion, and tumorigenesis in mice.

Results: Overexpression of AQP7 showed a significant inhibition of cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and cancer cell stemness in vitro, and suppression of both tumor growth and lung metastasis in vivo. Consistencely, knockdown of AQP7 induced cancer cell stemness and migration and invasion. Pathway analysis of the AQP7-regulated genes indicated significant enrichment in pathways regulating the cell cycle and Wnt-β-catenin signaling, which were further experimentally validated.

Conclusions: The current study demonstrates a tumor-suppressive function of AQP7 in breast cancer through inhibiting the cell cycle, EMT, and cancer cell stemness. AQP7 holds potential as a therapeutic target to treat breast cancer.

Introduction: Parkinson's disease is among the most common age-related neurodegenerative disorders today and characterized by midbrain dopamine neuron degeneration. However, this cell loss is not uniform. Though most dopamine neuron loss occurs in the substantia nigra, some ventral tegmental area and dorsal-tier substantia nigra dopamine neurons are relatively resistant to degeneration in Parkinson's disease. Yet, the mechanisms underlying this dopamine neuron resilience remain unclear. Novel insights into neuronal resilience are provided by evidence of a midbrain dopamine neuron subpopulation that expresses the vesicular glutamate transporter 2, VGLUT2, and is more resistant to cell loss in both preclinical models and clinically in Parkinson's disease. Thus, VGLUT2 expression has emerged as a defining signature difference between vulnerable versus resilient dopamine neuron subpopulations.

Areas covered: Here, we review recent developments in the potential mechanisms of dopamine neuron resilience and the therapeutic potential associated with boosting cellular resilience via VGLUT2.

Expert opinion: We discuss approaches to maximize VGLUT2-mediated dopamine neuron resiliency. This includes increasing the efficiency of vesicular sequestration of dopamine to decrease generation of cytotoxic reactive oxygen species and increasing levels of neuroprotective antioxidant glutathione. Taken together, VGLUT2-mediated pathways represent original directions to treat Parkinson's disease symptoms and modify disease progression.