Overexpression of MICAL-L2 stimulated cell migration, proliferation, and rendered KIRC cells insensitive to sunitinib and everolimus, two traditional therapies for KIRC. Furthermore, MICAL-L2 overexpression accelerated cancer progression and resistance to therapy in KIRC cells by interacting with its downstream regulator α-actinin-4 (ACTN4) in a Rab13-dependent manner, which reduced the degradation of ACTN4, leading to increased Vimentin expression. All these findings indicate that MICAL-L2 plays a crucial role in the progression of KIRC and suggest that MICAL-L2 may serve as a potential therapeutic target for KIRC treatment.

This extensive data pool suggests significant benefit of CDK4/6i regimens after disease progression as compared with ET monotherapy. Our data also support current guideline recommendations of ET-based therapies over chemotherapy for treatment sequencing.

Besides BAY-293, BH1406 cells proved to be sensitive to the SOS1 inhibitors MRTX0902 and BI-3406...Additionally, the PI3K inhibitor dactolisib, the GSK-3 inhibitor BI-5521 as well as the bromodomain protein-directed PROTAC ARV-771 inhibited the growth of BH1406 cells significantly and showed synergistic interaction with BAY-293...BH1406 cells represent a novel cellular model suitable for the molecular characterization of SOS1 druggability. Such rare oncogenic driver genes are not included in standard NGS panels and need to be detected by expanded assays like WES.

Following these diagnoses, two patients underwent modifications in the management of care with the administration of intravenous immunoglobulin therapy (IVIG), the mTOR inhibitor sirolimus, or surgical procedures...In addition, these cases demonstrate beneficial changes in management and outcomes that can follow a definitive diagnosis, including the identification of targeted treatment options. Collectively, this case series supports the notion that underlying IEIs should be considered in the workup of early-onset or recalcitrant cytopenias, particularly in patients who present with a combination of hematologic and immunologic manifestations that are refractory to treatment, manifest at an unusually young age, or can be tied to family history.

P2, N=80, Not yet recruiting, Sun Yat-sen University

Among these inhibitors, capivasertib and alpelisib have received approval as targeted therapies for this indication. Additionally, the review discusses key considerations for integrating these inhibitors into clinical practice, such as timing and choice of PI3K/AKT/mTOR inhibitors, and management of treatment toxicities. By examining these different aspects, this review aims to provide valuable insights into optimizing the clinical utility of PI3K/AKT/mTOR inhibitors in HR+ advanced breast cancer.

Rapamycin (Rap) was a classic autophagy flux inducer that could attenuate the improvement effect of APS on H9C2 cell apoptosis under ionizing radiation stimulation. Finally, we found that APS could reverse the inhibition of PI3K/Akt/mTOR signaling pathway activity by ionizing radiation in vitro, thereby improving ionizing radiation-induced autophagy flux accumulation, cardiomyocyte apoptosis, and atrophy. All in all, this study provides important evidence for understanding the molecular mechanisms of the cross-talk between autophagy and apoptosis, and provides new directions and insights for APS combined with autophagy regulators as a therapeutic strategy for RIHD.

P1/2, N=60, Not yet recruiting, University of Texas Southwestern Medical Center

P2, N=20, Recruiting, Shanghai Jiatan Pharmatech Co., Ltd | Trial completion date: Dec 2025 --> Dec 2026

P=N/A, N=3150, Recruiting, Odense University Hospital | Not yet recruiting --> Recruiting

P3, N=84, Not yet recruiting, Peking University First Hospital

P1, N=15, Not yet recruiting, Xuanwu Hospital, Beijing

This meta-analysis revealed that dysregulation of mTOR signaling across pre- and post-natal periods of development can result in convergent and divergent consequences for brain volume among genetic syndromes. Further research employing advanced disease modeling techniques with human pluripotent stem cell-derived in vitro models is needed to further refine our understanding of between and within syndrome variability on early brain development and identify shared molecular mechanisms for the development of pharmaceutical interventions.

P4, N=3150, Not yet recruiting, Odense University Hospital

P3, N=325, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Oct 2025

P2, N=15, Recruiting, Palvella Therapeutics, Inc. | Not yet recruiting --> Recruiting

Previously, we identified that resistance to tamoxifen and rapamycin is associated with the suppression of DNMT3A. The coordinated suppression of NR6A1 and DNMT3A may contribute to sustaining the resistant phenotype in breast cancer cells. This pathway could serve as a predictive marker, helping guide the selection of optimal therapeutic strategies for breast cancer treatment in the future.

Mammalian targets of rapamycin (mTOR) and G1 to S phase transition 1 gene (GSPT1) are overexpressed in glioblastoma, regulating vital cellular functions...YB-3-17 can safely and effectively inhibit tumor growth in mice, offering a promising direction for precision treatment of glioblastoma, representing the first attempt to combine mTOR inhibition with GSPT1 degradation. This work also demonstrates that it is conceptually possible to successfully combine the properties of small molecule inhibitors and degraders into a single molecule, killing two birds with one stone.

P=N/A, N=60, Terminated, Harbin Medical University | Phase classification: P4 --> P=N/A | Unknown status --> Terminated; Difficulty in enrolling the required number of participants has made it impractical to proceed with the trial.

P2, N=333, Completed, Queen Mary University of London | Unknown status --> Completed

Regardless to decades passing since its discovery, HEHE still creates a dilemma due to its challenging clinical profile and lack of treatment guidelines. Raising awareness of HEHE in clinical practices improves the ability to diagnose this rare tumor at early stages and develop stronger research strategies and treatment guidelines to regulate the medical care provided to HEHE patients.

TSC1 and TSC2 encode the core components of the TSC1/2 complex (TSC1/2), a negative regulator of the mechanistic target of rapamycin (MTOR) complex 1 (TORC1)...Molecular diagnostics confirms the clinical diagnosis of TSC in a large proportion of cases. Functional assessment can help establish variant pathogenicity and is a useful adjunct to DNA analysis.

The combination of mTOR inhibitors and chloroquine represents a promising area of research in cancer therapy. It has the potential to enhance treatment efficacy through complementary mechanisms.

Background/Objectives: The ribosomal S6 kinase 2 (S6K2) acts downstream of the mechanistic target of rapamycin complex 1 and is a homolog of S6K1 but little is known about its downstream effectors. Silencing of S6K2 or p21 sensitized T47D cells to doxorubicin via c-Jun N-terminal kinase (JNK)-mediated downregulation of Mcl-1. S6K2 knockdown enhanced doxorubicin-induced apoptosis by downregulating the cell cycle inhibitor p21 and the anti-apoptotic protein Mcl-1 via Akt and/or JNK.

The upregulation of lncRNA WT1-AS could suppress the PI3K/Akt/mTOR pathway, which inhibits cell migration and cell cycle arrest while promoting autophagy in gastric cancer cells.

We screened PI-103 as the most promising candidate for patients with higher CupScore and confirmed its experimental evidence and clinical trial status...Cuproptosis has the ability to reprogram the tumor microenvironment (TME) in HGG, leading to the stratification of patients into two distinct molecular subgroups. The CupScore model emerged as a robust metric for predicting the prognostic and therapeutic benefits, as well as may therefore facilitate personalized treatment strategies for patients with HGG.

P1/2, N=100, Recruiting, Shanghai Jiatan Pharmatech Co., Ltd | Trial completion date: Mar 2025 --> Nov 2025 | Trial primary completion date: Mar 2025 --> Nov 2025

Surgical treatment is preferred for malignant PEComa affecting liver and kidney, especially with TSC; everolimus is effective postoperatively.

P3, N=43, Completed, Nobelpharma | Active, not recruiting --> Completed

Notably, mTOR signaling coupled tumor recognition to DETC trafficking, cytotoxicity and inflammatory programs, as rapamycin treatment impaired effector functions and therapeutic efficacy. Collectively, these findings establish DETCs as multidimensional antitumor effectors and provide insights for harnessing their unique biology for cancer immunotherapy.

Additionally, in vitro sensitivity to cisplatin and mTOR inhibitors was evaluated in SCLC cell lines harbouring RICTOR amplification and other mTOR pathway mutations...The importance of these alterations was confirmed both by the sensitising effect of vistusertib in vitro and the RICTOR copy number/expression changes in xenografts. Our study highlights the role of mTORC2 in SCLC progression. Early detection of RICTOR amplification in primary tumours and targeting mTORC2 in these cases may represent a promising novel strategy to develop personalised therapy for metastasis prevention.

P1, N=23, Terminated, MEI Pharma, Inc. | N=40 --> 23 | Active, not recruiting --> Terminated; Company decision to wind down operations, close all clinical programs and evaluate strategic options

The HFD groups subjected to RFM had significantly lower Insulin-like growth factor 1 (IGF-1) and mechanistic target of rapamycin (mTOR) serum, whereas AMPK, anti-inflammatory, and antioxidative stress serum levels were significantly higher...The data indicate that RFM can improve longevity and metabolic biomarkers and reduce pro-inflammation and oxidative stress. Also, RFM improves anti-inflammatory and antioxidant markers in HFD-induced obese rats.

Tuberous sclerosis complex (TSC) is targeted to the lysosomal membrane, where it hydrolyzes RAS homolog-mTORC1 binding (RHEB) from its GTP-bound to GDP-bound state, inhibiting mechanistic target of rapamycin complex 1 (mTORC1)...These structural advances provide a model by which WIPI3 and PIP-signaling networks coordinate to recruit TSC to the lysosomal membrane to inhibit mTORC1. The high-resolution TSC structure reveals previously unrecognized mutational hotspots and uncovers crucial insights into the mechanisms of TSC dysregulation in disease.

Among the alterations discussed, we focused on the ones that could be treated with already available drugs, such as MET-driven papillary RCC, mechanistic target of rapamycin altered chromophobe RCC, anaplastic lymphoma kinase-rearranged RCC, and fumarate-hydratase deficient RCC. Furthermore, we focused on the currently ongoing clinical trials and further evidence for all the other entities, such as SMARCB1-deficient RCC, TFE3 and transcription factorEB (TFEB)-altered RCC, and Elongin C (ELOC)-mutated RCC. The vast heterogeneity of nccRCC does not allow a one-size-fits-all solution; therefore, molecular characterization is the path toward effective therapies and fully personalized medicine for these entities.

P=N/A, N=500, Completed, Boston Scientific Corporation | Unknown status --> Completed

P=N/A, N=65, Recruiting, Johns Hopkins University | N=50 --> 65

Silencing RPS3A inhibited autophagy in U251 cells, whereas rapamycin, an activator of autophagy, reversed the inhibitory effect of RPS3A silencing on TAM M2 polarization...Overexpression of CSF1 promoted the proliferation and invasion of U251 cells and reversed the inhibitory effect of RPS3A silencing on TAM proliferation and invasion, but had no effect on TAM M2 polarization. The results of in vivo experiments showed that knockdown of RPS3A significantly inhibited glioma tumor growth and metastasis in vivo. This study revealed that RPS3A recruited TAMs by upregulating E4F1-mediated transcription activation of CSF1, and promoted the M2 polarization of TAMs through autophagy, promoting glioma cell malignant growth and tumor progression.

P2, N=70, Recruiting, Shanghai Jiatan Pharmatech Co., Ltd | Trial completion date: Jun 2024 --> Jun 2026 | Trial primary completion date: Jun 2024 --> Jun 2025

Mechanistic investigations revealed that the regulation of osteoblast and adipocyte differentiation by NKD2 involved Wnt/β-catenin and tuberous sclerosis complex subunit 1 (TSC1)/mechanistic target of rapamycin complex 1 (mTORC1) signaling pathways...This study provides evidence that NKD2 in mesenchymal stem/progenitor cells reciprocally regulates the differentiation of osteoblasts and adipocytes by modulating Wnt/β-catenin and mTORC1 pathways and inhibits osteoclast formation by down-regulating receptor activator of nuclear factor-κB ligand. It suggests that NKD2 up-regulation may ameliorate postmenopausal bone loss.

Internal validation cohort (PFS 18.4 vs 3.1 months, p = 3.6e-11, HR = 3.78, 95% CI = 2.49-5.74) and external validation cohort (PFS 13.5 vs 3.1 months, p = 2.9e-10, HR = 11.53, 95% CI = 4.68-28.37) confirmed its power for estimating clinical benefits of everolimus. A predictive model was successfully established to predict survival outcomes for everolimus in patients with HR+/HER2- ABC, which may provide references for the management of everolimus in Chinese patients with HR+/HER2- ABC.

This study enhances our understanding of PLAC1's role and molecular mechanisms in CCa progression, highlighting its potential as a diagnostic, prognostic, and therapeutic marker for the management of CCa.