Autophagy and endolysosomal trafficking are crucial in neuronal development, function and survival. These processes ensure efficient removal of misfolded aggregation-prone proteins and damaged organelles, such as dysfunctional mitochondria, thus allowing the maintenance of proper cellular homeostasis. Beside this, emerging evidence has pointed to their involvement in the regulation of the synaptic proteome needed to guarantee an efficient neurotransmitter release and synaptic plasticity. Along this line, an intimate interplay between the molecular machinery regulating synaptic vesicle endocytosis and synaptic autophagy is emerging, suggesting that synaptic quality control mechanisms need to be tightly coupled to neurosecretion to secure release accuracy. Defects in autophagy and endolysosomal pathway have been associated with neuronal dysfunction and extensively reported in Alzheimer’s, Parkinson’s, Huntington’s and amyotrophic lateral sclerosis among other neurodegenerative diseases, with common features and emerging genetic bases. In this review, we focus on the multiple roles of autophagy and endolysosomal system in neuronal homeostasis and highlight how their defects probably contribute to synaptic default and neurodegeneration in the above-mentioned diseases, discussing the most recent options explored for therapeutic interventions.
Among the main aberrations occurring in GBM, those in MEK/ERK and PI3K/akt/mTOR pathways predominate and confer GBM Stem-like Cells (GSCs) sustained proliferation and resistance to therapy. A panel of eight patient-derived primary GSCs lines have been screened for their sensitivity to a small kinase MEK inhibitor (MEKi) with AnnexinV/PI staining. Among these, five display a sensitive phenotype with at least 50% reduction on cell viability after 72 hours of treatment. Then, four cell lines, two MEKi-sensitive (ICH001 and ICH003) and two MEKi-resistant (ICH013 and ICH027) were selected for a deeper molecular characterization based on MGMT methylation status, mesenchymal index and main hotspot mutations associated with GBM pathology MEKi incubation on GSC caused a prompt phospho-ERK reduction already after 3 hours. Of note, we report a concomitant activation of AKT and downstream molecules pointing to an ERK-mTOR redundant activity. To this end, we combined MEKi to PI3K/akt/mTOR inhibitor and we observed an increased cell death even in GSCs displaying moderate sensitivity to MEKi as single-agent (MEKi: 90% vs MEKi-PI3K/akt/mTOR inhibitor: 30% cell viability). Then, MEKi ability to cross the Blood Brain Barrier (BBB) and target GBM cells was investigated using a transwell BBB in vitro model. The PI3K/akt/mTOR pathway inhibitor, known from the literature to readily cross the BBB, was included as positive control. Obtained results showed MEKi inability to efficiently cross the BBB, thus limiting its utility as GBM therapy. These results suggest the need for a specific drug delivery strategy in the brain that might be therapeutically effective. Recently our laboratory has provided proof-of-concept of a combination strategy based on radiation and adjuvant drug-loaded liposomes (LPs) conjugated with a modified Apolipoprotein E-derived peptide (mApoE), known to facilitate BBB crossing. To strengthen therapeutic efficacy and to lower off-target effects, we implemented mApoE-LPs with a matrix metalloproteinases 2 and 9 sensitive lipopeptide (M2-9SLP) that allows controlled payload release only in the tumor microenvironment rich in MMPs. To this end, MEKi was encapsulated into the M2-9SLP/mApoE-LPs, and its capacity to promote cell death was evaluated. M2-9SLP/mApoE-MEKi-LPs caused in all the sensitive cell lines GSCs proliferation inhibition and induction of apoptosis upon 72h in vitro treatment indicating that the encapsulation process did not alter drug efficacy. In conclusion, our in vitro results support MEKi encapsulation into M2P/mApoE-LP as nanotherapeutic strategy that could guarantee specific delivery of MEKi in a MMP2-enriched tumor microenvironment without altering its capacity to inhibit GSC proliferation and survival. Funding by FRRB grant NEVERMIND (CP2_16/2018) Citation Format: Milena Mattioli, Elisabetta Stanzani, Valentino Ribecco, Marco Pizzocri, Eliana Lauranzano, Margherita Maria Ravanelli, Simone Olei, Maria Pia Tropeano, Pierfausto Seneci, Francesca Re, Federico Pessina, Michela Matteoli, Lorena Passoni. Smart encapsulation of a MEK inhibitor into M2-9SLP/mApoE-liposomes for specific GBM targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2711.
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