AVTX-006 / Avalo Therap, Astellas - LARVOL DELTA

Changes in Melanoma Cell Morphology Following Inhibition of Cell Invasion by Third-Generation mTOR Kinase Inhibitors. (PubMed, Int J Mol Sci) - "The study used mTOR kinase inhibitors: Everolimus and Torkinib; dual PI3K/mTOR inhibitors BEZ-235 and Omipalisib; and the mTORC1/2 inhibitor OSI-027. These compounds were used both as monotherapy and in combination with the MEK1/2 inhibitor AS-703026...The morphology of cells also changed significantly: their thickness, volume, roughness, convexity of shape, and irregularity, which may be a good diagnostic and prognostic factor for the response to treatment. Our studies to date on the effect of three generations of mTOR kinase inhibitors on the inhibition of the invasion process, the activation of apoptosis, and the reduction in cell proliferation suggest that they may be an important target for anticancer therapy."

Journal • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • MMP2 • MMP9

WZ4003 sensitizes hepatocellular carcinoma to OSI-027 by inhibiting ARK5-mediated autophagy. (PubMed, Cancer Lett) - "Notably, both chloroquine treatment and ULK1-S757E transfection abolished the OSI-027/WZ4003 synergy. Moreover, elevated ARK5 expression was observed in HCC specimens and was independently associated with an unfavorable recurrence-free survival (RFS). Our findings propose a novel strategy for augmenting sensitivity to OSI-027 in HCC, further underscoring the significance of ARK5 and autophagy as cancer therapeutic targets."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • NUAK1

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