sirolimus

P4, N=20, Not yet recruiting, Sarepta Therapeutics, Inc.

Sixty female Sprague-Dawley rats were randomly assigned to six groups: control (sham exposure), autophagy inhibition (3-methyladenine, 3-MA), autophagy activation (rapamycin, RAP), +Gz exposure, +Gz exposure with autophagy inhibition, and +Gz exposure with autophagy activation...Excessive autophagy exacerbates ferroptosis via ferritinophagy-mediated iron release, whereas autophagy inhibition is protective against intestinal damage by preserving the Nrf2-GPX4 axis function. Targeting autophagy and ferroptosis may provide new therapeutic strategies for mitigating high-G-induced gastrointestinal injury in aerospace medicine.

Western blot analysis demonstrated inhibition of EGFR/PI3K/AKT/mTOR (mechanistic Target of Rapamycin) and STAT3/HSP90 signaling, along with marked downregulation of PI3K and phosphorylation levels of EGFR, AKT, and STAT3...These findings suggest that CDY exerts multi-targeted anti-cancer effects by modulating oncogenic signaling pathways and epigenetic regulators, supporting its potential as a promising bioactive lead for prostate cancer. Collectively, these findings demonstrate that CDY exerts mechanistically coordinated anticancer effects in vitro and in chorioallantoic membrane (CAM) models, warranting further validation in mammalian in vivo systems to assess translational relevance.

P1, N=53, Suspended, City of Hope Medical Center | Recruiting --> Suspended

P1/2, N=9, Recruiting, Astellas Gene Therapies

Tumor cells are highly dependent on branched-chain amino acids, which can activate mechanistic target of rapamycin complex 1, but the downstream catabolite branched-chain α-keto acids (BCKAs) are not well studied in this context...Mutation of the BCKA-binding site in Notch2 abolishes this effect in vivo. Together, these findings identify BCKAs as signaling metabolites that mediate tumor immunosuppression through direct sensing by Notch2.

P3, N=65, Terminated, University Hospital, Rouen | Completed --> Terminated; Difficulty in enrolling new patients

Its function was investigated through small interfering RNA-mediated silencing, lentiviral overexpression, pamidronate treatment, in vitro proliferation, migration, invasion, and apoptosis assays, xenograft models, phosphoproteomic profiling, and Western blot validation. FDPS knockdown was further associated with decreased B-cell lymphoma 2 expression, reduced phosphorylation of Caspase-9 at Ser196, increased cleaved Caspase-3, and reduced phosphorylation of mechanistic target of rapamycin at Ser2448. Collectively, these findings suggest that FDPS contributes to HCC progression and may serve as a candidate biomarker and therapeutic target.

Microsurgical resection of SEGA is a safe and effective therapeutic option, particularly in patients without hydrocephalus. Early surgical intervention may reduce the need for VPS and long-term complications, offering a valid alternative or complement to mechanistic target of rapamycin inhibitor therapy, with durable tumor control especially in unilateral cases.

The levels of phosphorylated-mechanistic target of rapamycin complex 1 (p-mTORC1)/mTORC1, p-v-akt murine thymoma viral oncogene homolog 1 (AKT)/AKT, and p-phosphatidylinositol-3 kinase (PI3K)/PI3K were significantly downregulated following GPR176 knockdown. GPR176 is upregulated in OS and is associated with a poor prognosis. GPR176 suppresses mitophagy to promote OS progression by facilitating mTORC1 activity via the PI3K-AKT pathway.

FA synthesis perturbation led to inactivation of TORC1 (mechanistic Target of Rapamycin Complex 1)-accompanied by activation of the catabolic process autophagy. Moreover, TORC1 activity cannot be fully restored by hyperactivation of upstream Insulin/PI3K signaling or inhibition of AMP-activated kinase (AMPK) in ACC-deficient tumor cells, but supplementation with ectopic oleic acid can partially increase TORC1 activity and tumor progression. In addition to their metabolic value, the role of FAs in promoting TORC1 gives us new insight into cancer cell dependence on de novo FA synthesis.

Importantly, inhibition of Golgi stress by exogenous spermine not only alleviates NDV-induced ferroptosis, but also demonstrates antiviral and cytoprotective effects, underscoring the translational potential of targeting the Golgi stress axis. Our findings uncover a previously unappreciated axis of virus-host interaction centering on Golgi stress and ferroptosis and suggest that modulation of organelle-specific stress responses represents a promising therapeutic strategy in both antiviral and cancer contexts.Abbreviations: AMPK: AMP-activated protein kinase; ARF1: ARF GTPase 1; ARF4: ARF GTPase 4; ATG7: autophagy related 7; BFA: brefeldin A; CGAS: cyclic GMP-AMP synthase; CHX: cycloheximide; CQ: chloroquine; CREB3: cAMP responsive element binding protein 3; DFO: deferoxamine; ER: endoplasmic reticulum; Fe2+: ferrous ions, GA: Golgi apparatus; GOLGA2/GM130: golgin A2; GPX4: glutathione peroxidase 4; GSH: glutathione; GSR: Golgi stress response; HCMV: human cytomegalovirus; HSV-1: herpes simplex virus 1; Lip-1: Liproxstatin-1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MDA: malondialdehyde; mtDNA: mitochondrial DNA; MTOR: mechanistic target of rapamycin kinase; NDV: Newcastle disease virus; NCOA4: nuclear receptor coactivator 4; PUFA: polyunsaturated fatty acid; ROS: reactive oxygen species; Rot: rotenone; SLC7A11: solute carrier family 7 member 11; SERPINH1/HSP47: serpin family H member 1; TFE3: transcription factor binding to IGHM enhancer 3; WT: wild-type.