sirolimus

PI3K-mTOR activation promotes the development of XRT-resistance in pediatric BRAFV600E glioma. Dual targeting of MAPK and TORC1 signaling significantly enhances the therapeutic efficacy of XRT, and can potentially prevent the development of XRT-resistance. (250 words).

We defined a nutrient signaling mechanism involving fatty acid-binding protein 5 (FABP5) and mechanistic target of rapamycin complex 1 (mTORC1) that is activated by the essential polyunsaturated fatty acid (PUFA) ω-6 linoleic acid (LA). FABP5 directly bound to the regulatory-associated protein of mTOR (Raptor) to enhance formation of functional mTORC1 and substrate binding, ultimately converging on increased mTOR signaling and proliferation. The amounts of FABP5 protein were increased in tumors and serum from triple-negative compared with those from receptor-positive breast cancer patients, which highlights its potential role as a biomarker that mediates cellular responses to ω-6 LA intake in this disease subtype.

Our results demonstrate the involvement of the autophagosome-late endosome/multivesicular bodies-exosome axis in regulating HBV production and release, highlighting amphisomes as a potential platform for HBV release.

P2, N=24, Recruiting, Medical University of South Carolina | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Feb 2025 --> Feb 2026

P2, N=62, Recruiting, Masonic Cancer Center, University of Minnesota

P2, N=33, Active, not recruiting, National Heart, Lung, and Blood Institute (NHLBI) | Trial primary completion date: Sep 2025 --> Apr 2025 | Recruiting --> Active, not recruiting | Trial completion date: Sep 2025 --> Apr 2025

P2, N=19, Recruiting, University of Michigan Rogel Cancer Center | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2026

P2, N=56, Active, not recruiting, National Heart, Lung, and Blood Institute (NHLBI) | Trial completion date: Dec 2024 --> Dec 2027

In addition, the high-risk group exhibited lower half-maximal inhibitory concentration values for specific chemotherapy medications, including bortezomib, luminespib, rapamycin, and 5-fluorouracil. Our study elucidates the diagnostic and prognostic value of mitochondria-related-lncRNAs in the promotion, suppression, and treatment of glioma.

Tolvaptan was initiated, and he remains under follow-up. Mutations in the PKD1/PKD2, which are responsible for ADPKD, affect intracellular signaling, including the mammalian target of the rapamycin (mTOR) pathway, leading to cyst formation and progression, while NF1 mutations overactivate the Ras proteins. His disease progression was more severe than that of his father with ADPKD alone, suggesting NF1 may have accelerated cyst enlargement. The co-occurrence of ADPKD and NF1 is extremely rare, with only a few cases reported in the past.

Our results revealed that the biomimetic strategy of MM@TPGS/F127@RAPA may be a good choice for the treatment of lung cancer patients with pulmonary fibrosis.

P1, N=4, Active, not recruiting, National Institute of Allergy and Infectious Diseases (NIAID) | Recruiting --> Active, not recruiting | N=30 --> 4

Regorafenib exerts a regulatory influence on the blood concentrations of sirolimus by inhibiting the activity of CYP3A4 and P-gp, potentially altering its pharmacokinetic profile. Given the potential for both excessive and inadequate immunosuppression to adversely affect patients with recurrent hepatocellular carcinoma post-liver transplantation, clinicians must maintain a heightened awareness of this drug-drug interaction.

P1/2, N=40, Active, not recruiting, National Heart, Lung, and Blood Institute (NHLBI) | Recruiting --> Active, not recruiting | N=90 --> 40 | Trial completion date: Nov 2033 --> Jan 2027 | Trial primary completion date: Nov 2032 --> Jan 2026

P=N/A, N=36, Recruiting, Fudan University

Multiple signalling pathways, such as the transforming growth factor-β (TGF-β) signalling pathway, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, inflammatory signalling pathways, neuromechanical signalling pathways, endoplasmic reticulum stress and glucocorticoids signalling pathways, regulate muscle atrophy...In this review, we summarized the known lncRNAs related to muscular dystrophy and muscle atrophy induced by denervation, ageing, weightlessness, cachexia and abnormal myogenesis, along with their molecular mechanisms. Finally, we explored the potential of using these lncRNAs as therapeutic targets for muscle atrophy and muscular dystrophy, including the methods of discovery and clinical application prospects for functional lncRNAs.

P4, N=84, Recruiting, Peking University First Hospital | Phase classification: P3 --> P4

P2, N=72, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2024 --> Oct 2025

Mechanistically, transferrin receptor activated the PI3K/AKT/mTOR signaling pathway, as its knockdown suppressed the pathway, and rapamycin, an mTOR inhibitor, reversed transferrin receptor-induced pathway activation and proliferation. Modulation of the labile iron pool by ferric ammonium citrate (FAC) or deferoxamine (DFO) rescued transferrin receptor-induced biological effects. Additionally, AURKA was identified as a regulator of transferrin receptor expression. These findings demonstrate the oncogenic role of transferrin receptor in endometrial cancer and suggest that targeting iron homeostasis and the PI3K/AKT/mTOR pathway may represent potential therapeutic strategies for endometrial cancer.

We also employed 3-MA (5mM) or rapamycin (100µM) to inhibit or promote autophagy...Additionally, we observed that ELAVL1 influenced EC cell proliferation, invasion, and migration through the regulation of LncRNA NEAT1-mediated regulation of Beclin1 expression. Moreover, in an animal study, we determined that ELAVL1 influenced endometrial cancer tumor growth through its interaction with LncRNA NEAT1, which mediated Beclin1 expression in vivo.In summary, our study showed that ELAVL1 regulated the malignant behavior of endometrial cancer cells through the modulation of LncRNA NEAT1-mediated regulation of Beclin1 expression.

Furthermore, when rapamycin is employed to impede EPS-induced autophagy, it results in an enhancement of apoptosis and cell death in HCT116 cells...Immunohistochemical analysis of tumors indicated increased expressions of LC3 and caspase-3, along with decreased levels of phospho-PI3Kinase, phospho-AKT, and P62, consistent with in vitro findings. Our study proved that EPSs have an inhibitory effect on colorectal cancer and can be used as a preventive and therapeutic drug for cancer.

P2, N=46, Active, not recruiting, Emory University | Recruiting --> Active, not recruiting | Trial completion date: Feb 2025 --> Jan 2026 | Trial primary completion date: Feb 2025 --> Jan 2026

P2, N=10, Completed, Unity Health Toronto | Active, not recruiting --> Completed

P2, N=95, Completed, Medical College of Wisconsin | Active, not recruiting --> Completed | Trial primary completion date: Sep 2024 --> Jan 2025

Mechanistic target of rapamycin-dependent loss of paraoxonase 1 drives autoimmunity and cirrhosis in TAL deficiency, while hepatocarcinogenesis hinges on polyol pathway activation via aldose reductase (AR). Accumulated polyols, such as erythritol, xylitol, and sorbitol, which are commonly used as non-caloric sweeteners, may act as pro-inflammatory oncometabolites under metabolic stress, such as TAL deficiency. The TAL/AR axis is identified as a checkpoint of pathogenesis and target for treatment of metabolic stress-driven systemic autoimmunity with relevance for inflammatory liver, renal and cardiovascular disorders, diabetes, carcinogenesis, and aging.

P2, N=7, Active, not recruiting, University of Pennsylvania | N=24 --> 7

P1, N=194, Not yet recruiting, The University of Texas Health Science Center at San Antonio | Initiation date: Jan 2025 --> May 2025

Remarkably, the effects of RA are modulated in the presence of autophagy inhibitors or stimulators. The present data indicate that RA-induced differentiation is concomitant with an increased autophagy.

Activating the inducible safety switch with rapamycin safely eliminated the engrafted cells. These results demonstrate that BDNF delivery via a novel hPSC-based platform incorporating safety switches could be a safe and effective HD therapeutic.

EAML develops sporadically or as part of the tuberous sclerosis complex (TSC), where mutations of the TSC1/2 genes result in increased activation of the mammalian target of the rapamycin (mTOR) signaling pathway...Subsequent surgical resection of the primary tumor and a course of ifosfamide monotherapy yielded a 36-month progression-free survival to date...Pathological re-evaluation confirmed the diagnosis of a metastatic retroperitoneal AML with complete response and no evidence of disease. This case underscores the invaluable role of next-generation sequencing testing in the differential diagnosis of retroperitoneal tumors, as well as the ability to identify precise therapeutic targets for the treatment of rare soft tissue cancer types within the realm of precision medicine.

Notably, cadherin 11 (CDH11), a specific marker for hybrid EMT cells, may exert its regulatory role in cellular function by interfering with branched-chain amino acids (BCAA) metabolism by inhibiting branched-chain ketoacid dehydrogenase to activate the mammalian target of the rapamycin pathway, thus making it a potential therapeutic target for SACC. Overall, these findings suggest a promising treatment strategy that targets hybrid EMT cells to mitigate lung metastasis in SACC. Celecoxib may serve as a promising clinical intervention for the treatment of lung metastases in patients with SACC.

P2, N=31, Active, not recruiting, Sarcoma Oncology Research Center, LLC | Trial completion date: Mar 2025 --> Mar 2028 | Trial primary completion date: Dec 2024 --> Dec 2027

Additionally, we treated cells with rapamycin to induce autophagy and then cotransfected them with circ-Vav3 and gga-miR-375...Moreover, cells cotransfected with circ-Vav3 and gga-miR-375 exhibited further autophagy inhibition after ALV-J infection, suggesting that circ-Vav3 is involved in inhibiting autophagy caused by ALV-J infection through the regulation of gga-miR-375/CIP2A/AKT. In conclusion, our results demonstrated that circ-Vav3 inhibited autophagy through the gga-miR-375/CIP2A/AKT pathway and mediated the suppression of ALV-J-induced autophagy.

Herein we observed that the overexpression of TPD52 (isoform 3) in LNCaP, PCa cells confers resistance to mTOR inhibitors, specifically everolimus and rapamycin. Above all, downregulation of both TPD52 and c-Myc enhanced the sensitivity of LNCaP-TPD52 cells facilitating apoptosis indicating a potential strategy to overcome resistance to mTOR inhibitors in PCa. Taken together, these findings underscore the role of TPD52 through c-Myc in conferring resistance to mTOR inhibitors and warrant further exploration of their molecular mechanisms in PCa treatment.

Fatostatin and rapamycin served as an inhibitor of sterol regulatory element-binding protein 1 (SREBP1) and an autophagy inducer, respectively...Kaplan-Meier analysis demonstrated that higher SREBP1 expression in patients with TNBC was associated with a worse prognosis, suggesting that SREBP1-mediated reprogramming of lipid metabolism and autophagy under hypoxia is essential for TNBC cell survival. The results of the present study indicate that strategies targeting SREBP1 could be exploited to treat TNBC and improve prognosis.

GSVA and GSEA highlighted the involvement of TME-related pathways, such as transforming growth factor beta (TGF-β) and mechanistic target of rapamycin (mTOR) signaling pathways...The in vitro experiment on the key genes showed a consistent result with the bioinformatics finding. Our study provides insights into the prognostic biomarkers and molecular mechanisms in BRCA, offering potential therapeutic avenues and guiding personalized treatment strategies for improved patient outcomes.

Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation...Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.

To date, genetic defects directly affecting B and T cell biology only account for a minority of identified causes of monogenic lupus, highlighting the importance of a tight regulation of mechanistic target of rapamycin and RAS (Rat sarcoma GTPase)/MAPK (mitogen-activated protein kinase) signaling in lupus...Observations from genetic studies in SLE and Behçet syndrome highlight the complexity of systemic inflammatory diseases in which distinct molecular defects caused by single-gene mutations can promote lupus or Behçet syndromes, often unrecognizable from their genetically complex "classical" forms. Insights gained from studying rare genetic variants enhance our understanding of immune function in health and disease, paving the way for targeted therapies and personalized medicine.

P1/2, N=75, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2024 --> Apr 2025

The mechanistic target of rapamycin (mTOR) pathway plays a critical role in cell growth and metabolic homeostasis...SRRM2 promotes CRC growth in vitro and in vivo. Combined, these data reveal an oncogenic role of SRRM2 in CRC through activating the mTOR-S6K pathway by two different approaches, further suggesting SRRM2 as a potential therapeutic target for CRC.

Phosphatase and Tensin Homolog (PTEN) is a dual-specific protein and lipid phosphatase that regulates AKT and downstream signaling of the mechanistic target of rapamycin (mTOR). Taken together, our results revealed in vivo and in vitro molecular and neuronal network mechanisms underlying neurological phenotypes of PHTS. Notably, pharmacologic mTOR inhibition by everolimus led to successful downstream signaling rescue, including mTOR complex 1 (mTORC1) site-specific suppression of S6 phosphorylation, correlating with phenotypic rescue found in our novel neuron-specific Syn-Cre/Pten HOM mice.

P3, N=140, Active, not recruiting, University of Kansas Medical Center | Recruiting --> Active, not recruiting | Trial completion date: Sep 2026 --> Dec 2026 | Trial primary completion date: Sep 2026 --> Dec 2026