sirolimus

P1/2, N=54, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P2, N=65, Not yet recruiting, Rapa Therapeutics LLC | Trial completion date: Sep 2028 --> Sep 2029 | Trial primary completion date: Mar 2028 --> Mar 2029

Notably, repurposed drugs exhibit anticancer activity by modulating key pathways, including phosphatidylinositol 3-kinase/Ak strain transforming/mechanistic target of rapamycin, mitogen-activated protein kinase/extracellular signal-regulated kinase, wingless-related integration site/β-catenin signaling, as well as redox homeostasis and DNA response...With cancer causing one in six global deaths and marked by therapeutic resistance and molecular heterogeneity, drug repurposing provides a scalable solution. This approach bridged preclinical insight with clinical application, potentially transforming cancer therapeutics through rational, data-driven innovation.

The involvement of the mTOR pathway was further examined by combining MCCC2 knockdown with rapamycin treatment and leucine-deprivation experiments...MCCC2 promotes TNBC progression by activating the mTOR signaling pathway in a leucine-dependent manner. Targeting MCCC2 and its metabolic axis may represent a promising therapeutic strategy for TNBC.

Sequestosome 1 (SQSTM1)/p62, which functions as a signaling hub integrating nuclear factor kappa B (NF-κB), the mechanistic target of rapamycin complex 1 (mTORC1), and Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (NRF2) pathways, serves as a selective macroautophagy/autophagy receptor that binds ubiquitinated cargo proteins and recruits them to the autophagosome for subsequent degradation in the autolysosome. Furthermore, the phase separation of p62 is an important regulatory process in the autophagy mechanism, but recent studies have demonstrated that impaired or excessive autophagy mediated by p62 is associated with cancer development. This review summarizes the role of autophagy-including its types, mechanisms, and the pathway related to the ubiquitin-dependent selective autophagy receptor p62-in cancer progression.

The Phosphoinositide 3-kinase (PI3K), Protein kinase B (AKT) and mechanistic target of rapamycin (mTOR) pathway has been documented to regulate MPMCA-inhibited cell motility...Importantly, our in vivo data indicates that MPMCA reduces Snail and Slug expression and prostate cancer metastasis. Our evidence suggests that MPMCA is a novel therapeutic candidate for treating metastatic prostate cancer.

High CD44 expression was associated with advanced disease, immune cell infiltration, immune checkpoint gene expression, reduced sensitivity to gemcitabine, paclitaxel, rapamycin, and FMK, and distinct CTLA4/PD-L1 checkpoint profiles. CD44 exhibits compartment-specific regulation in PDAC, linking immune remodeling, exosome signaling, and therapeutic resistance to adverse clinical outcome.

The mechanistic target of rapamycin (mTOR) pathway is dysregulated in 55% of epithelial ovarian cancers, representing an appealing therapeutic target...In addition, FNIP1, a tumour suppressor gene implicated in mTOR dysregulation, was found to correlate with survival outcomes. We propose a model of dual activation of mTORC1 and autophagy in HGSOC as the metabolic rewiring enabling cancer progression under nutrient and cellular stress.

P1/2, N=32, Active, not recruiting, Prevail Therapeutics | Recruiting --> Active, not recruiting

Perinatal hypoxia suppresses mechanistic target of rapamycin complex 1 (mTORC1), essential for OPC maturation...In vivo, Lipin1 knockdown or HDAC2 inhibition enhanced myelin gene expression, promoted oligodendrocyte maturation, improved myelin ultrastructure, and alleviated motor deficits. Thus, a Lipin1-HDAC2 epigenetic axis mediates hypoxia-induced myelin gene repression, offering targets for white matter repair in preterm infants.

These include activation of AMP-activated protein kinase (AMPK), inhibition of the mechanistic target of rapamycin (mTOR), attenuation of oxidative stress, modulation of mitochondrial biogenesis, and reduction of low-grade systemic inflammation. While not a panacea, its favourable safety profile and multi-targeted actions make it a leading candidate for repurposing as an anti-ageing therapy. Continued clinical validation is essential to translate these insights into practice.

Remarkable progress has been made both in understanding the pathogenesis of TSC and in its clinical management, largely due to the discovery of the link between TSC1 and TSC2 and the mechanistic target of rapamycin (mTOR) signalling pathway...Approved drug treatments (rapalogues) exist for subependymal giant cell astrocytomas, renal angiomyolipomas, pulmonary lymphangioleiomyomatosis, facial angiofibromas and refractory seizures. However, there is still an unmet need for effective treatment of TAND and refractory epilepsy, despite the available medical and surgical options.