sirolimus

P2, N=50, Recruiting, Emory University | Trial completion date: Sep 2025 --> Nov 2026 | Trial primary completion date: Sep 2025 --> Nov 2026

P2/3, N=130, Terminated, Tyme, Inc | Completed --> Terminated; Sponsor's decision

Additionally, NOP58 was linked to drug responses, including Methotrexate, Rapamycin, Sorafenib, and Vorinostat. Its expression level serves as a reliable prognostic biomarker and an actionable therapeutic target, advancing precision medicine for prostate cancer. Targeting NOP58 may enhance therapeutic efficacy and improve outcomes in oncology.

P2/3, N=150, Recruiting, West China Hospital

The tuberous sclerosis complex (TSC1/TSC2/TBC1D7) primarily functions to inhibit the mechanistic target of rapamycin complex 1 (mTORC1), a crucial regulator of cell growth...However, more recent studies have shown that TSC proteins can also promote tumorigenesis in certain cancer types. In this review, we explore the composition and function of the TSC protein complex, the roles of its individual components in cancer biology, and potential future therapeutic targeting strategies.

We studied this problem using cell lines representing diffuse large B-cell lymphoma (SUDHL-4 and OCI-Ly7), a genetically-encoded live-cell reporter of AKT activity, and 3 small-molecule inhibitors targeting different levels of the pathway: idelalisib (PI3Kδ), GSK2334470 (PDPK1), and ipatasertib (AKT)...Combining all 3 inhibitors produced sustained inhibition of AKT activity, was broadly synergistic at reducing viable cell number, enabled substantially lower doses of each inhibitor to be used, and was enhanced further by the mTOR inhibitor rapamycin...In a syngeneic mouse cell line model of lymphoma (A20), the triple combination showed antitumor activity and no evidence of toxicity. Our findings provide proof of concept suggesting further study of the safety and efficacy of low-dose multilevel PI3K/AKT pathway inhibition, for lymphoma and perhaps other cancers.

FBXO22 targets the serine 2448-phosphorylated form of mammalian mechanistic target of rapamycin (pS2448-mTOR) for ubiquitin-dependent degradation...These RAPA effects are correlated with the ability of RAPA to inhibit pS2448-mTOR, pS6K1, and p4E-BP1. Collectively, our data support a suppressive role for FBXO22 in colorectal inflammation signaling and CRC initiation by targeting pS2448-mTOR for degradation.

Metformin lowers the risk of tumour development through various mechanisms, including the adenosine 5'-monophosphate-activated protein kinase/liver kinase B1/mechanistic target of rapamycin (AMPK/LKB1/mTOR) pathway, insulin-like growth factor-1 receptor pathway, apoptosis, and autophagy. However, research findings are not entirely consistent. This article reviews the research progress of metformin in terms of lung cancer treatment within the past few years, aiming to provide a more comprehensive understanding of how metformin exerts its anti-cancer impact and how it can be clinically applied, as well as provide new insights for lung cancer treatment.

P1, N=194, Not yet recruiting, The University of Texas Health Science Center at San Antonio

Collectively, our findings suggest that the GCN2‒SLC7A11 axis regulates cell growth and survival upon arginine deprivation through coordinating autophagy, cell cycle arrest, and apoptosis in retinoblastoma cells. This work paves the way for the development of a novel treatment for retinoblastoma.

Although targeting the mammalian target of the rapamycin complex 1 (mTORC1) signaling pathway exerts potent anti-inflammatory activity, little is known about mTORC2's contribution to non-septic shock...The enhanced expression of the proteins mentioned above has been inhibited by JR-AB2-011. These data suggest mTORC2's promising role in ZYM-induced hypotension and systemic inflammation mediated via IKKα/IκB-α/NF-κB pathway.

Additionally, carnitine palmitoyltransferase 1 A (cpt1a), cytochrome c (cyt-c), adenosine 5'-monophosphate (amp)-activated protein kinase (ampk), the autophagosomal protein microtubule-associated protein 1 light chain 3c (lc3c), and the autophagy-related proteins beclin1, atg5, atg12 were significantly induced (P < 0.05) in the adenosine monophosphate-activated protein kinase/rapamycin (AMPK/mTOR) signaling pathway...The results confirm that deltamethrin exposure can induce hepatopancreatic injury by promoting mitochondrial autophagy, activating an immune response, and inhibiting lipid metabolism. Overall, this study provides multi-level information to reveal the toxic effects of deltamethrin on E. sinensis.

In summary, CH25H promotes autophagy and affects the malignant progression of LSCC through the PI3K-AKT pathway.

It underscores the importance of long-term follow-up in LAM patients, regardless of menopausal status, and demonstrates the efficacy of sirolimus in managing postmenopausal LAM progression. Further research is needed to understand the mechanisms driving LAM activity in the absence of high estrogen levels and to optimize treatment strategies for this patient population.

Trehalose did not affect the extracellular signal-regulated kinase (ERK) and mechanistic target of rapamycin complex 1 (mTORC1)/4EBP1 pathways, while it reduced the prosurvival mTORC2/AKT signaling...In conclusion, trehalose protects SH-SY5Y cells from 6-OHDA-induced oxidative stress, mitochondrial damage, and apoptosis through autophagy/p62-independent inhibition of JNK, p38 MAPK, and AMPK. The opposite effects of trehalose on the neurotoxicity of 6-OHDA and MPP+ suggest caution in its potential development as a neuroprotective agent.

Furthermore, it elucidated the molecular mechanism underlying the protective effect of ADAR1, the regulation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt)/mammalian target of the rapamycin (mTOR) signaling...The upregulation of ADAR1 expression alleviated high-glucose-induced endoplasmic reticulum stress, reduced HK-2 cell apoptosis, and reduced the expression of inflammation-related indicators (PI3K/AKT/mTOR). Taken together, the pivotal roles of ADAR1 in the progression of proximal renal tubulopathy and the mechanism of high-glucose-induced HK-2 injury in diabetic db/db mice suggest that ADAR1 may be a potential key factor in slowing the progression of diabetic kidney disease.

Elevated AMP:ATP ratio, a consequence of limited glucose levels, activate AMP-activated protein kinase (AMPK) while concurrently repressing the activity of mechanistic target of rapamycin (mTOR) and hypoxia-inducible factor 1-alpha (HIF-1α)...This metabolic adaptation prompts immune cells to turn down their effector functions, entering a quiescent or immunosuppressive state that may support tumor growth. This article discusses how tumor microenvironment alters the metabolism in immune cells leading to their tolerance and tumor progression, with emphasis on mitochondrial metabolism (OXPHOS and FAO).

The expression level of cNEK6 in the peripheral blood and tumor tissues correlated significantly and positively with the activation of the mTORC1 pathway and degree of glycolysis. Hence, the therapeutic effect of gemcitabine is limited in patients with high cNEK6 levels, and in combination with the mTORC1 inhibitor, rapamycin, can enhance sensitivity to gemcitabine chemotherapy.

P2, N=170, Active, not recruiting, St. Jude Children's Research Hospital | Recruiting --> Active, not recruiting | N=52 --> 170

This was followed by pronounced genetic diversity on both spatial and temporal levels, with parallel and convergent tumour evolution involving the ATRX/DAXX and mechanistic target of the rapamycin (mTOR) pathways...The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

We present a case of a man in his late 50s with RDD who experienced worsening cytopenias, including severe neutropenia and respiratory distress, despite an initial positive response to steroids, rituximab and lenalidomide. Sirolimus was initiated and led to complete radiological remission of the disease. This case adds strength to the growing evidence supporting the efficacy of sirolimus in refractory RDD cases.

P2, N=41, Completed, Nottingham University Hospitals NHS Trust | Active, not recruiting --> Completed

The combination of CHKI-03 and rapamycin demonstrates considerable therapeutic efficacy in PDO models resistant to gemcitabine. Our findings reveal a pivotal mechanism underlying PDAC metastasis regulated by mTORC1-CHKα loop-dependent choline metabolism reprogramming, highlighting the therapeutic potential of this novel regimen for treating PDAC metastasis.

This combination increased infectivity by augmenting the expression of coxsackievirus and adenovirus receptors and αV integrin on cancer cells and induced autophagy. Our findings suggest that combining a c-Met promoter-driven oncolytic adenovirus with rapamycin could be an effective lung cancer treatment strategy, offering a targeted approach to exploit lung cancer cells' vulnerabilities, potentially marking a significant advancement in managing this deadly disease.

Combination treatment with the GRP78 inhibitor DPT and pharmacological autophagy inhibitors will be a meaningful method of obviating osteosarcoma cells.

Sirolimus therapy was initiated, and at one month of follow-up after the treatment, his stridor had improved...However, as in our case, a large LM may cause recurrent airway obstruction, and the neck swelling may appear later. Atypical airway findings, especially endoscopic examination, in a child with stridor should be complemented with imaging to examine the possibility of extra-laryngeal mass or external compression.

cluster2 had higher immune cell infiltration levels and better prognosis, with greater sensitivity to Cyclopamine, Imatinib, MG-13, Paclitaxel, PHA-665752, Rapamycin, Sorafenib, Sunitinib, and VX-680. In contrast, cluster3 had higher TTN and PIK3CA mutations and greater sensitivity to AZ628, Dasatinib, Doxorubicin, HG-6-64-1, JQ12, Midostaurin, PF-562271, TAE684, and WH-4-023. In conclusion, we developed a feasible risk score model based on IPS-related genes for cervical cancer prognosis and identified potential drugs for different cervical cancer subtypes.

P1/2, N=16, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Recruiting --> Active, not recruiting | N=75 --> 16 | Trial primary completion date: Mar 2025 --> Sep 2024

For metastatic HER2-positive breast cancer patients with abnormal PAM pathway activation and previous trastuzumab treatment, the combination of inetetamab with sirolimus and chemotherapy is equivalent to the combination of pyrotinib and chemotherapy. Therefore, this regimen could be a treatment option for PAM pathway-activated metastatic HER2-positive breast cancer patients.

This study utilized the GBM cell membrane to construct a biomimetic targeted nanosystem (GMNPs@AMD/RAPA) that hierarchically releases the CXCR4 antagonist AMD3100 and the mTOR pathway inhibitor rapamycin (RAPA) for reprogramming the tumor immune microenvironment and suppressing the progression of GBM. Subsequently, through further cellular uptake and degradation of the nanoparticles, the mTOR pathway inhibitor RAPA was released, further suppressing the tumor progression. This study successfully combined chemotherapy and immunotherapy, achieving effective synergistic therapeutic effects, and suppressing the progression of GBM.

SIRT3 triggered SLC7A11-mediated ferroptosis in HCT-116 cells, reducing cell viability by activating the AMPK/mTOR pathway, and sulforaphane targets it to inhibit colorectal cancer.

P4, N=1200, Recruiting, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital; Sichuan Academy of Medical Sciences and Sichuan Provincial People’s

P3, N=140, Recruiting, University of Kansas Medical Center | Trial completion date: Feb 2024 --> Sep 2026 | Trial primary completion date: Feb 2024 --> Sep 2026

Then, the PPARγ inhibitor (GW9662), autophagy inhibitor (3-MA) and autophagy inducer (rapamycin; Rap) were used to further study the potential mechanism of YHD on TNBC...3-MA had the similar effects to GW9662. Collectively, YHD suppressed the malignant progression of MDA-MB-231 cells by inducing ferroptosis through PPARγ-dependent autophagy.

This study identifies GDF-15 as a novel biomarker of EHE aggressiveness and underscores the superior efficacy of sirolimus compared to doxorubicin in our experimental models. The observed inhibition of GDF-15 release by sirolimus suggests its potential as a biomarker for monitoring the drug's activity in patients.

P2, N=118, Recruiting, National Heart, Lung, and Blood Institute (NHLBI) | Trial completion date: Aug 2028 --> Jun 2030 | Trial primary completion date: Aug 2026 --> Jun 2030

P=N/A, N=150, Recruiting, Children's Hospital of Philadelphia | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

It also suppressed the activation of mechanistic target of rapamycin kinase (mTOR) and nuclear factor kappa B (NF-κB) and downregulated glutathione peroxidase 1 (GPX1), an antioxidant enzyme counteracting oxidative stress...The ROS inhibitor N-acetylcysteine attenuated the anti-proliferative and anti-CSC effects of OVA. Our findings suggest that OVA acts via ROS generation, leading to oxidative stress and DNA damage, culminating in cell cycle arrest and the suppression of CSC activity in EC. Therefore, OVA is a promising therapeutic agent for EC, either as a standalone treatment or an adjunct to existing therapies.

The advent of FLT3 tyrosine kinase inhibitors (TKIs), such as midostaurin and gilteritinib, has shown promise in achieving complete remission. Specifically, we provide evidence for integrating gilteritinib with mammalian targets of rapamycin (mTOR) inhibitors and interleukin-15 (IL-15) complexes. The combination of gilteritinib, mTOR inhibitors, and IL-15 complexes presents a compelling strategy to enhance the eradication of AML blasts and enhance NK cell killing, offering a potential for improved patient outcomes.

In Neuro2a cells, Na2WO4 increases protein synthesis by activating the mechanistic target of rapamycin (mTOR) and S6K kinases and GLUT3-mediated glucose uptake, providing the energy and protein synthesis needed for neurite outgrowth. These negative effects were corrected in both cell lines after incubation with Na2WO4. These findings support the role of Na2WO4 in neuronal plasticity, albeit further experiments using 3D cultures, and animal models will be needed to validate the therapeutic potential of the compound.

This enzymatic activity inhibits the phosphatidylinositol-3-kinase, protein kinase B and mammalian target of the rapamycin signalling cascade...The patient's nephritic symptoms, pleural effusion, dyslipidaemia and splenomegaly demonstrate systemic lupus erythematosus (SLE) multisystem involvement. The case report identifies an association between a PTEN mutation and a new diagnosis of SLE that might have been triggered by PTEN-associated immune dysregulation.

This study evaluated the impact of Morin on PC3 prostate cancerous cells by examining the AMPK/ mechanistic target of rapamycin (mTOR)/ ULK1 (UNC-51-like kinase 1) pathway and autophagy process...AICAR (an AMPK activator) enhanced the impact of Morin on apoptosis, cell growth, and expression of LC3B, p-AMPK, p-ULK1, and p-mTOR proteins in the PC3 cells. These findings suggest that Morin induces apoptotic and autophagic cell death by activating AMPK and ULK1 and suppressing mTOR pathways.