P2, N=17, Active, not recruiting, National Cancer Institute (NCI) | N=209 --> 17 | Trial completion date: Jun 2024 --> Nov 2025

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.

P2, N=134, Completed, Imperial College London | Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Nov 2023 | Trial primary completion date: Dec 2022 --> Nov 2023

JR-AB2-011 affects leukemia/lymphoma cell metabolism via a mechanism independent of mTORC2.

In our study, we investigated how phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway inhibitors (TAK-228, everolimus and TAK-117) affect PD-L1 expression and function in preclinical bladder cancer cell models. These preclinical findings suggest that mTOR inhibition with TAK-228 can increase PD-L1 levels, potentially impacting the specific immune response against UC cells. This highlights the rationale for exploring the combination of mTOR inhibitors with ICIs in patients with advanced UC.

Furthermore, bioinformatics analyses showed that drugs such as erlotinib, OSI-027, and ibrutinib selectively targeted the CSC-specifically expressed genes. In conclusion, our results represent the first comprehensive characterization of CSCs properties in LSCC at the single-cell level.

Using a combination of functional and metabolic assays, we evaluated a panel of PC cell lines with different PTEN/PIK3CA status for their sensitivity to multi-node PAM inhibitors (PI3K/mTOR: gedatolisib, samotolisib) and single-node PAM inhibitors (PI3Kα: alpelisib; AKT: capivasertib; mTOR: everolimus). Gedatolisib, as a single agent and in combination with other therapies, reported promising preliminary efficacy and safety in various solid tumor types. Gedatolisib is currently being evaluated in a Phase 1/2 clinical trial in combination with darolutamide in patients with mCRPC previously treated with an AR inhibitor, and in a Phase 3 clinical trial in combination with palbociclib and fulvestrant in patients with HR+/HER2- advanced breast cancer.

P1, N=19, Completed, Avera McKennan Hospital & University Health Center | Active, not recruiting --> Completed | N=30 --> 19

mTOR signal pathway is poorly inhibited by imatinib and AZD2014 shows little effect on BCR::ABL1 signal pathway, which indicates that mTOR is involved in imatinib resistance via a BCR::ABL1 independent manner. Taken together, mTOR represents a potential target to overcome BCR::ABL1 independent imatinib resistance.

P1, N=28, Completed, AstraZeneca | Active, not recruiting --> Completed | Trial completion date: Feb 2025 --> Apr 2024 | Trial primary completion date: Feb 2025 --> Apr 2024

Inhibition of CK1α using short hairpin RNA (shRNA) and treatment of a CK1α inhibitor or an mTOR inhibitor, TORKinib, resulted in decreased β-TrCP interaction with LT, increased LT expression, and enhanced MCPyV replication...Therefore, cellular kinase pathways are indispensable for governing MCPyV polyomavirus infection and life cycle in coordinating with the immunosuppression environment at disease onset. Understanding the regulation mechanisms of MCPyV replication by viral and cellular factors will guide proper prevention strategies with targeted inhibitors for MCPyV-associated Merkel cell carcinoma (MCC) patients, who currently lack therapies.

Although the primary endpoint was no met, sapanisertib and paclitaxel combination demonstrated clinical activity in a heavily pretreated population of mUC. This trial generates insight for future combination of sapaniserib with immunotherapy and/or antibody drug conjugates.

P1; Recruiting --> Active, not recruiting

P1/2, N=37, Active, not recruiting, Kari Wisinski | Trial completion date: Apr 2024 --> Jul 2024 | Trial primary completion date: Apr 2024 --> Jul 2024

By using multiple functional assays, a panel of BC cell lines was evaluated for their sensitivity to four different PAM inhibitors: gedatolisib (pan-PI3K/mTOR inhibitor), alpelisib (PI3Kα inhibitor), capivasertib (AKT inhibitor), and everolimus (mTORC1 inhibitor). These results indicate that inhibition of multiple PAM pathway nodes by a pan-PI3K/mTOR inhibitor like gedatolisib may be more effective at inducing anti-tumor activity than single-node PAM inhibitors. A global Phase 3 study is currently evaluating gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- ABC.

P1; Trial completion date: Sep 2024 --> Jun 2025 | Trial primary completion date: Sep 2024 --> Jun 2025

P1, N=37, Completed, M.D. Anderson Cancer Center | Trial primary completion date: Jun 2022 --> Jul 2023

Collectively, our findings provide new insights into the tight connectivity of gene regulatory programs associated with cell cycle and cell fate regulation, and a rationale for sequential administration of WEE1 inhibitors with low toxicity inhibitors of pre-BCR signaling or metabolism.

Targeting HSP90 and mTOR has the potential to suppress breast cancer cell growth and progression by disrupting AKT signaling and inhibiting F-actin polymerization. This combination treatment may hold promise as a therapeutic strategy for breast cancer treatment that ameliorates adverse effects of a single treatment.

We treated cells from an OSCC cell line SCC131 with 5-Azacytidine, a DNA methyltransferase inhibitor, to reactivate tumor suppressor miRNA genes silenced/downregulated due to DNA methylation. Our results revealed that miR-6741-3p plays a tumor-suppressive role in OSCC pathogenesis, in part, by directly regulating SRSF3. Based on our observations, we propose that miR-6741-3p may serve as a potential biological target in tumor diagnostics, prognostic evaluation, and treatment of OSCC and perhaps other malignancies.

P1/2, N=159, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

Moreover, prediction results from the CellMiner database revealed great correlations between drug sensitivity (e.g., Vinorelbine and PKI-587) and prognostic genes. (Rev Invest Clin. 2024;76(2):116-31).

P2, N=49, Active, not recruiting, National Cancer Institute (NCI)

P2, N=39, Completed, Bradley A. McGregor, MD | Active, not recruiting --> Completed | Trial completion date: Aug 2024 --> Apr 2024

Dual targeting of Aurora A kinase and mTOR resulted in marginal clinical benefit in a population of patients with refractory solid tumors, including pancreatic adenocarcinoma, though individual patients experienced significant response to therapy. Correlatives indicate apoptotic response and tumor immune cell infiltrate may affect clinical outcomes.

P2, N=35, Active, not recruiting, National Cancer Institute (NCI)

P1/2, N=54, Recruiting, Celcuity Inc | Not yet recruiting --> Recruiting

P1, N=40, Terminated, National Cancer Institute (NCI) | Trial completion date: Mar 2025 --> Oct 2023 | Active, not recruiting --> Terminated; Other - Lapse in funding

These observations strongly indicate that TORin-1 acts as PAK1-blockers, instead of TOR-blockers, in vivo. Thus, it is most likely that melanogenesis in cell culture could enable us to discriminate PAK1-blockers from TORblockers.

Gedatolisib plus palbociclib and endocrine therapy showed a promising objective response rate compared with the published results for standard-of-care therapies and had an acceptable safety profile.

P2, N=16, Active, not recruiting, National Cancer Institute (NCI)

Moreover, our investigation has shown that AZD2014, SB505124, LJI308 and OSI-207 show a greater efficacy in patients in the low-risk category. Conversely, for the high-risk group patients, PD173074, ZM447439 and CZC24832 exhibit a stronger response...This innovative model provides a novel approach for forecasting prognosis and assessing drug sensitivity in HCC patients, driving a more personalized and efficacious treatment paradigm, elevating clinical outcomes. Nonetheless, additional research endeavours are required to confirm the model's precision and assess its potential to inform clinical decision-making for HCC patients.

In this research, we show that the long non-coding RNA MLLT4 antisense RNA 1 (lncRNA MLLT4-AS1) is induced by the MTORC inhibitor PP242 and rapamycin in cervical cells. Mechanically, MLLT4-AS1 was associated with the myosin-9 protein, which further promoted the transcription activity of the ATG14 gene. In conclusion, we demonstrated that MLLT4-AS1 acts as a potential tumor suppressor in cervical cancer by inducing autophagy, and H3K27ac modification-induced upregulation of MLLT4-AS1 could cause autophagy by associating with myosin-9 and promoting ATG14 transcription.

P1, N=40, Active, not recruiting, National Cancer Institute (NCI)

The combination of sapanisertib and ziv-aflibercept was generally tolerable and demonstrated anti-tumor activity in heavily pre-treated patients with advanced malignancies.

P1, N=83, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Jan 2025 --> Jan 2024

P1/2, N=159, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Jun 2024 --> Dec 2024

P1/2, N=37, Active, not recruiting, Kari Wisinski | Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2023 --> Mar 2024

P1, N=96, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Jan 2024 --> Jan 2025

P1/2, N=72, Active, not recruiting, Centre Leon Berard | Trial completion date: Dec 2023 --> Dec 2024

P1, N=83, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Jan 2025

P1, N=174, Terminated, Celgene | Active, not recruiting --> Terminated; Replaced with another clinical trial.