vistusertib (AZD2014)

We observed that trametinib, BKM120, AZD2014 and palbociclib increased the efficacy of each chemotherapy in SCC PDXs, in contrast to a non-insignificant or slight improvement in ADCs. Furthermore, we observed high efficacy of trametinib in KRAS-, HRAS- and NRAS-mutated tumors (ADCs and SCCs), suggesting that the MEK inhibitor may be useful in a wider population of NSCLC patients, not just those with KRAS-mutated ADCs. Our results suggest that the detection of pathogenic variants by NGS should be performed in all NSCLCs, and particularly in SCCs, to offer patients a more effective combination of chemotherapy and targeted therapy.

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

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.

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

P2, N=423, Active, not recruiting, University of Birmingham | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

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.

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

P2, N=1460, Active, not recruiting, UNICANCER | Trial completion date: Dec 2023 --> Dec 2024

P2, N=999, Completed, UNICANCER | Active, not recruiting --> Completed

P1, N=99, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2023 --> Sep 2028

On the contrary, patients with low cholesterol metabolism and high TIME often have better prognosis. Furthermore, we identified chemical compounds, such as BPD-00008900, ML323, Doramapimod, and AZD2014, which display better chemotherapy results for high-risk patients in specific sub-groups.

P1, N=156, Active, not recruiting, AstraZeneca | Phase classification: P1b --> P1 | Trial completion date: Sep 2023 --> Jun 2024

P1, N=54, Completed, AstraZeneca | Active, not recruiting --> Completed | Phase classification: P1/2 --> P1

Interestingly in an aggressive CLL-like disease model, rapamycin treatment reduced disease burden more effectively than AZD2014 (dual mTORC1/2 inhibitor), indicating a skew towards mTORC1 sensitivity with more aggressive disease. Rapamycin, but not ibrutinib, efficiently targeted the eEF2/eEF2K translation elongation regulatory axis, downstream of mTORC1, resulting in eEF2 inactivation through induction of eEF2 phosphorylation. mTOR inhibitor treatment of primary patient CLL cells halted proliferation, at least in part through modulation of eEF2K/eEF2 phosphorylation and expression, reduced protein synthesis and inhibited expression of MCL1, Cyclin A and Cyclin D2. Our studies highlight the importance of translation elongation as a driver of disease progression and identify inactivation of eEF2 activity as a novel therapeutic target for blocking CLL progression.

No abstract available

A fast and reliable QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) method for pre-processing combined with Ultra - high performance liquid chromatography - tandem mass spectrometry (UHPLC-MS/MS) was established for the analysis of five mammalian rapamycin target protein (mTOR) inhibitors (vistusertib, AZD8055, pictilisib, everolimus, temsirolimus)in human plasma. This method showed a high accuracy with high recovery rate and excellent stability. This method is fast, accurate and reliable, suitable for quantitative detection of mTOR inhibitors in human plasma.

This study furnishes a profound understanding of the contribution of m7G-related genes to the pathogenesis of OS. The discerned therapeutic potential of AZD2014, in conjunction with the identification of CYFIP1 and EIF4A1 as independent risk factors, opens novel vistas for the treatment of OS.

In murine and human myeloid leukemia, besides kinase-inhibitory on-target effects, AZD2014 displayed similar off-target and growth-inhibitory cytostatic effects. These studies provide new insights into kinase-dependent/-independent effects of mTOR in hematopoiesis and present a genetic means for precisely assessing the specificity of mTOR kinase inhibitors.

P1/2, N=159, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2023 --> Jun 2024 | Trial primary completion date: Jun 2023 --> Jun 2024

P1, N=27, Active, not recruiting, AstraZeneca | Trial completion date: May 2023 --> Feb 2025 | Trial primary completion date: May 2023 --> Feb 2025

P1/2, N=460, Recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Trial completion date: Jan 2022 --> Aug 2027 | Trial primary completion date: Jan 2022 --> Aug 2027

NF2-deficient tumors have constitutive activation of mammalian/mechanistic target of rapamycin (mTOR), and treatment with mTORC1 inhibitors results in growth arrest in a minority of tumors, with paradoxical activation of the mTORC2/AKT pathway. However, this dosing regimen for vistusertib was poorly tolerated. Future studies of dual mTORC inhibitors for NF2 should focus on optimizing tolerability and evaluating the relevance of tumor stability in participants.

In this randomized clinical trial of weekly paclitaxel and dual mTORC1/2 inhibition in patients with PR-HGSC, vistusertib did not improve clinical activity of weekly paclitaxel. isrctn.org Identifier: ISRCTN16426935.

P2, N=423, Active, not recruiting, University of Birmingham | Trial completion date: Mar 2023 --> Sep 2023 | Trial primary completion date: Mar 2023 --> Sep 2023

P1b, N=156, Active, not recruiting, AstraZeneca | Trial completion date: Mar 2023 --> Sep 2023

P1/2, N=72, Active, not recruiting, Centre Leon Berard | Trial completion date: Oct 2022 --> Oct 2023

P2, N=1460, Active, not recruiting, UNICANCER | Trial completion date: Dec 2022 --> Dec 2023

P1/2, N=54, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2022 --> Dec 2023

The combined treatment with AZD8186 and the mTOR inhibitor AZD2014 overcame resistance to PI3Kβ/δ inhibition and completely prevented outgrowth of lymphoma cells in vivo in cell line- and patient-derived xenograft mouse models. Collectively, our study reveals that subsets of DLBCLs are addicted to PI3Kβ/δ signaling and thus identifies a previously unappreciated role of the PI3Kβ isoform in DLBCL survival. Furthermore, our data demonstrate that combined targeting of PI3Kβ/δ and mTOR is effective in all major DLBCL subtypes supporting the evaluation of this strategy in a clinical trial setting.

P1/2, N=159, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Nov 2022 --> Jun 2023 | Trial primary completion date: Nov 2022 --> Jun 2023

P2, N=423, Active, not recruiting, University of Birmingham | Trial completion date: Oct 2022 --> Mar 2023 | Trial primary completion date: Oct 2022 --> Mar 2023

We selected 3 NET organoids (NET16, NET17 and NET18) to test the activity of select drugs: dovitinib (VEGFR inhibitor), vistusertib (mTOR inhibitor), cobimetinib (mitogen-activated protein kinase 1 inhibitor) and TAK243 (ubiquitin activating enzyme inhibitor). Tumor heterogeneity may be contributing to the differences seen in the drug response between the three NET organoids and requires further evaluation. Replication of these studies in a larger subset of patient samples and drug combination studies will be important for the advancement of therapeutics in NETs.

P1b, N=156, Active, not recruiting, AstraZeneca | Trial completion date: Sep 2022 --> Mar 2023

Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in the current study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.

P1/2, N=72, Active, not recruiting, Centre Leon Berard | Trial completion date: Oct 2021 --> Oct 2022

Notably, cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to prevent obesogenic diet-promoted HCC development. Moreover, suppression of hepatic cholesterol biosynthesis by a mammalian target of rapamycin (mTOR) inhibitor vistusertib preceded tumor regression, which was abolished by NKT inactivation but not CD8 T cell depletion. Mechanistically, sterol regulatory element-binding protein 2 (SREBP2)-driven excessive cholesterol production from hepatocytes induced lipid peroxide accumulation and deficient cytotoxicity in NKT cells, which were supported by findings in people with obesity, NAFLD and NAFLD-HCC. This study highlights mTORC1/SREBP2/cholesterol-mediated NKT dysfunction in the tumor-promoting NAFLD liver microenvironment, providing intervention strategies that invigorating NKT cells to control HCC in the obesity epidemic.

P1b, N=156, Active, not recruiting, AstraZeneca | Trial completion date: Feb 2022 --> Sep 2022

P1/2, N=159, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Nov 2021 --> Nov 2022 | Trial primary completion date: Nov 2021 --> Nov 2022