AVTX-006 / Avalo Therap, Astellas - LARVOL DELTA

Oncogenic β-catenin stimulation of cofilin 1-mediated macropinocytosis is druggable for cancer. (PubMed, Theranostics) - "Moreover, both excessive macropinocytosis induced by OSI-027 and macropinocytosis inhibition via CFL1 depletion suppressed β-catenin-driven tumor growth in orthotopic hepatocellular carcinoma model mice. Targeting macropinocytosis represents a promising therapeutic strategy for β-catenin mutant cancers."

Journal • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • CTNNB1

Deciphering the value of anoikis-related genes in prognosis, immune microenvironment, and drug sensitivity of laryngeal squamous cell carcinoma. (PubMed, Pathol Res Pract) - "Our prognostic signature effectively predicts LSCC prognosis, with MMP3 identified as a potential novel biomarker for LSCC treatment. Furthermore, our findings underscore the critical role of immune-based therapies in improving outcomes, especially for low-risk patients."

Journal • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • MMP3 • TIMP1

Comprehensive analysis of telomere and aging-related signature for predicting prognosis and immunotherapy response in lung adenocarcinoma. (PubMed, J Cardiothorac Surg) - "The risk score exhibited robust prognostic capabilities, offering novel insights for assessing immunotherapy. This will provide a new direction to achieve personalized and precise treatment of LUAD in the future."

Biomarker • IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Deptor protects against myocardial ischemia-reperfusion injury by regulating the mTOR signaling and autophagy. (PubMed, Cell Death Discov) - "These results revealed that OSI027 exerts a protective effect on myocardial ischemia/reperfusion injury in both an in vivo and in an in vitro model of I/R. These findings demonstrate that Deptor protects against I/R-induced myocardial injury by inhibiting the mTOR pathway and by increasing autophagy."

Journal • Cardiovascular • Myocardial Infarction • Myocardial Ischemia • Reperfusion Injury • DEPTOR • EIF4EBP1

Characterization of Cancer Stem Cells in Laryngeal Squamous Cell Carcinoma by Single-cell RNA Sequencing. (PubMed, Genomics Proteomics Bioinformatics) - "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."

Cancer stem • Journal • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ALDH1A1 • PROM1 • SOX4

Study on the effects of rapamycin and the mTORC1/2 dual inhibitor OSI-027 on the metabolism of colon cancer cells based on UPLC-MS/MS metabolomics. (PubMed, Invest New Drugs) - "For amino acids metabolism, although OSI-027 has a broad effect as rapamycin, their effects in degrees were not exactly the same. These findings address the knowledge gap regarding mTORC1/2 dual inhibitors and lay a foundation for their further development and research."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Clinical value of molecular subtypes identification based on anoikis-related lncRNAs in castration-resistant prostate cancer. (PubMed, Cell Signal) - "Four arlncRNAs were identified and a risk model was established to predict the prognosis of patients with prostate cancer. Immune infiltration and drug susceptibility analysis revealed a potential therapeutic strategy for patients with castration-resistant prostate cancer."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Molecular Expression and Prognostic Implications of Krüppel-Like Factor 3 (KLF3) in Clear Cell Renal Cell Carcinoma. (PubMed, Crit Rev Eukaryot Gene Expr) - "Based on GDSC database, KLF3 upregulation was identified to be associated with higher sensitivities towards PI3K-Akt-mTOR pathway inhibitors such as PI-103, PIK-93, and OSI-027. In addition, patients with down-regulated KLF3 expressions were found more sensitive towards Trametinib, Cetuximab, and Erlotinib. Collectively, our findings suggest that KLF3 may act as a suitable biomarker for prognosis prediction, tumor microenvironment (TME) phenotype identification, thereby helping ccRCC patients to make better therapeutic decisions."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • KLF3 • TGFB1

Reconstructing the immunosenescence core pathway reveals global characteristics in pan-cancer. (PubMed, Cancer Immunol Immunother) - "We found that OSI-027 was a potential sex-specific drug in HNSC tumors, which tended to be more effective in male HNSC by targeting the MTOR gene in the PI3K-Akt signaling pathway. In conclusion, our study provided a systematic understanding of immunosenescence pathways and revealed the global characteristics of immunosenescence in pan-cancer. We highlighted MTOR gene could be a powerful immunosenescence biomarker of HNSC that helps to develop sex-specific immunosenescence drugs."

Journal • Pan tumor • Oncology • Squamous Cell Carcinoma • mTOR

Three generations of mTOR kinase inhibitors in the activation of the apoptosis process in melanoma cells. (PubMed, J Cell Commun Signal) - "The following inhibitors were used: protein kinase inhibitors such as AKT-MK-2206, MEK-AS-703026, mTOR-everolimus and Torkinib, as well as dual PI3K and mTOR inhibitor-BEZ-235 and Omipalisib, and mTOR1/2-OSI-027 inhibitor in single-mode and their combinations with MEK1/2 kinase inhibitor AS-703026. There is a need for research on the search for new therapeutic strategies aimed at particular groups of patients. Effect of three generations of mTOR kinase inhibitors on caspase-3 activity, apoptosis and proliferation in melanoma cell lines."

Journal • Melanoma • Oncology • Solid Tumor • CASP3 • MAP2K1

Phenotypic Screening Using High-Content Imaging to Identify Lysosomal pH Modulators in a Neuronal Cell Model. (PubMed, ACS Chem Neurosci) - "Overall, data from this phenotypic HTS screen may be used to explore novel regulatory pathways of lysosomal pH regulation. Additionally, OSI-027 and PP242 may serve as useful tool compounds to enable mechanistic studies of autophagy activation and lysosomal acidification as potential therapeutic pathways for neurodegenerative diseases."

Journal • CNS Disorders • Neuroblastoma • Oncology • Solid Tumor

Combined inhibition of BET bromodomain and mTORC1/2 provides therapeutic advantage for rhabdomyosarcoma by switching cell death mechanism. (PubMed, Mol Carcinog) - "Thus, the bromodomain inhibitor RVX-208 significantly augmented the therapeutic effects of the dual mTORC1/2 inhibitors, OSI-027 and PP242, both in vitro and in a human xenograft murine model. While single RVX-208 treatment induces apoptosis and a single mTORC1/2 inhibitor induces macropinocytosis, their combined treatment led to necroptosis-mediated cell death. These data suggest that combined treatment with drugs targeting BRD4 and mTORC1/2 may be an effective therapeutic intervention for drug-resistant RMS."

Journal • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • BRD4 • CCND1

Optochemical Control of mTOR Signaling and mTOR-Dependent Autophagy. (PubMed, ACS Pharmacol Transl Sci) - "Herein, we designed a photoactivatable OSI-027 prodrug, which allowed the release of OSI-027 after light irradiation to inhibit the mTOR signaling pathway, triggering autophagy and leading to cell death. This photoactivatable prodrug can provide novel strategies for mTOR-targeting cancer therapy and act as a new tool for investigating mTOR signaling and its related biological processes."

Journal • Oncology

A Pharmacokinetic, Pharmacodynamic, Safety and Tolerability Study of CERC-006 in Adults With Complex Lymphatic Malformations (clinicaltrials.gov) - P1b | N=0 | Withdrawn | Sponsor: Cerecor Inc | N=10 ➔ 0 | Recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • FLT4 • PIK3CA

OSI-027 inhibits the tumorigenesis of colon cancer through mediation of c-Myc/FOXO3a/PUMA axis. (PubMed, Cell Biol Int) - "OSI-027 attenuates colon cancer progression through mediation of c-Myc/FOXO3a/PUMA axis. Thereby, this research might shed new insights on exploring the strategies against colon cancer."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor • FOXO3 • MYC

Dual Inhibition of mTORC1/2 Reduces Migration of Cholangiocarcinoma Cells by Regulation of Matrixmetalloproteinases. (PubMed, Front Cell Dev Biol) - "Moreover, survival as well as anti-apoptotic signaling was impaired upon the use of OSI-027 as determined by AKT and MAPK blotting. Dual targeting of mTORC1/2 might therefore be a viable option for anti-neoplastic therapy in CCA."

Journal • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • MMP2 • MMP9

hnRNP C modulates MERS-CoV and SARS-CoV-2 replication by governing the expression of a subset of circRNAs and cognitive mRNAs. (PubMed, Emerg Microbes Infect) - "Treatment of MERS-CoV- (IC: 0.618 µM) or SARS-CoV-2-infected (IC: 1.233 µM) Calu-3 cells with the mTOR inhibitor OSI-027 resulted in significantly reduced viral loads. Collectively, our study identified hnRNP C as a key regulator of MERS-CoV-perturbed circRNAs and their cognate mRNAs, and the potential of targeting hnRNP C-related signalling pathways as an anticoronaviral strategy."

Journal • Infectious Disease • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Solid Tumor • HNRNPC

A Pharmacokinetic, Pharmacodynamic, Safety and Tolerability Study of CERC-006 in Adults With Complex Lymphatic Malformations (clinicaltrials.gov) - P1b; N=10; Recruiting; Sponsor: Cerecor Inc; Trial completion date: Dec 2021 ➔ Jun 2022; Trial primary completion date: Dec 2021 ➔ Jun 2022

Clinical • Trial completion date • Trial primary completion date • FLT4 • PIK3CA

A Pharmacokinetic, Pharmacodynamic, Safety and Tolerability Study of CERC-006 in Adults With Complex Lymphatic Malformations (clinicaltrials.gov) - P1b; N=10; Recruiting; Sponsor: Cerecor Inc; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • FLT4 • PIK3CA

Rapamycin and trametinib: a rational combination for treatment of NSCLC. (PubMed, Int J Biol Sci) - "In addition, rapamycin synergized with another ERKi, MEK162, and in turn, trametinib synergized with other mTORi, Torin1 and OSI-027. In xenograft mouse model, co-administration of rapamycin and trametinib caused a substantial suppression in tumor growth without obvious drug toxicity. Overall, our study identifies a reasonable combined strategy for treatment of NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EIF4EBP1

A Pharmacokinetic, Pharmacodynamic, Safety and Tolerability Study of CERC-006 in Adults With Complex Lymphatic Malformations (clinicaltrials.gov) - P1b; N=10; Not yet recruiting; Sponsor: Cerecor Inc

New P1 trial • FLT4 • PIK3CA

Effects of rapamycin and OSI-027 on α-SMA in lung tissue of SD rat pups with hyperoxic lung injury. (PubMed, Biochem Biophys Res Commun) - "In hyperoxia lung injury, inhibiting the activation of mTOR signaling pathway can effectively reduce the expression of α-SMA; however, only mTORC1/2 dual inhibitor OSI-027 exhibited an anti-proliferative effect, and alleviated hyperoxia-induced lung injury and fibrosis in SD rat pups."

Journal • Preclinical • Fibrosis • Immunology • Respiratory Diseases

Multi-omics characterization and validation of MSI-related molecular features across multiple malignancies. (PubMed, Life Sci) - "Our pan-cancer study provides a valuable predictive model and a comprehensive atlas of tumor MSI, which may guide more precise and personalized therapeutic strategies for tumor patients."

Journal • Oncology • BRCA • MSI

OSI-027 alleviates oxaliplatin chemoresistance in gastric cancer cells by suppressing P-gp induction. (PubMed, Curr Mol Med) - "Moreover, OSI-027 exhibited synergistic cytotoxic effects with oxaliplatin in vitro, while a P-gp siRNA knockdown significantly inhibited the synergistic effect. In summary, our results suggest that dual mTORC1/mTORC2 inhibitors (e.g., OSI-027) should be further investigated as a potential valuable treatment for gastric cancer."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CCND1 • CDK4 • EIF4EBP1

Prolonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons. (PubMed, Nat Commun) - "Here, we explored autophagy as a mechanism to reduce tau burden in human neurons and, from a small-molecule screen, identify the mTOR inhibitors OSI-027, AZD2014 and AZD8055. These compounds are more potent than rapamycin, and robustly downregulate phosphorylated and insoluble tau, consequently reducing tau-mediated neuronal stress vulnerability...Notably, single-dose treatment followed by washout leads to a prolonged reduction of tau levels and toxicity for 12 days, which is mirrored by a sustained effect on mTORC1 inhibition and autophagy. This new insight into the pharmacodynamics of mTOR inhibitors in regulation of neuronal autophagy may contribute to development of therapies for tauopathies."

Journal • CNS Disorders