Clinical study of oral PI3K/mTOR inhibitor P7170 in patients with advanced refractory solid tumors. The primary objective is to determine the maximum tolerated dose and dose limiting toxicity of oral PI3K/mTOR inhibitor P7170 in patients with advanced refractory solid tumors

开始日期2012-09-01

申办/合作机构

Piramal Enterprises Ltd.

CTRI/2012/07/002787 / Suspended临床1期

An Open Label Multicentric Phase 1 Study of Oral PI3K/mTOR Inhibitor P7170 in Patients with Advanced Refractory Solid Tumors

开始日期2012-07-16

申办/合作机构

Piramal Enterprises Ltd.

100 项与 mTOR x ALK1 x PI3K family 相关的临床结果

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100 项与 mTOR x ALK1 x PI3K family 相关的转化医学

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0 项与 mTOR x ALK1 x PI3K family 相关的专利（医药）

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项与 mTOR x ALK1 x PI3K family 相关的文献（医药）

2021-12-20·Bioengineered4区 · 生物学

Uncovering the action mechanism of homoharringtonine against colorectal cancer by using network pharmacology and experimental evaluation

4区 · 生物学

ArticleOA

作者: Li, Junyi ; Qu, Muwen ; Yuan, Lingling

Homoharringtonine (HHT), an Food and Drug Administration (FDA)-approved anti-leukemia drug, exerts anti-tumor activity in several solid tumors, including colorectal cancer (CRC). However, its mechanism of action in CRC progression has not been comprehensively elucidated. The drug-disease targets were obtained using publicly available databases. Protein-protein interaction (PPI) network, Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed to reveal the core targets, biological processes and signaling pathways of HHT against CRC. Cell and animal experiments were performed to validate the inhibitory effects of HHT on CRC. A total of 98 overlapping target genes of HHT and CRC were predicted. Through PPI network and topology analysis, we screened out 23 hub genes. Enrichment assays showed 163 biological processes (BP), 18 cell components (CC), 35 molecular functions (MF), and 85 related pathways. Functionally, HHT inhibited CRC cell proliferation, cell cycle progression, colony formation, migration and invasion, and promoted apoptosis. HHT treatment resulted in the inactivation of PI3K/AKT/mTOR signaling in CRC cells. Moreover, activation of PI3K/AKT/mTOR signaling by 740Y-P abated the suppressive effects of HHT on cell malignant phenotypes. Furthermore, HHT repressed CRC tumor growth in nude mice. Our current study demonstrated that HHT repressed CRC progression at least partly by inactivating PI3K/AKT/mTOR signaling pathways, highlighting HHT as a potential therapeutic agent for CRC patients.

2020-01-21·Journal of Clinical Investigation1区 · 医学

Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models

1区 · 医学

Article

作者: Choi, Hyunwoo ; Metz, Christine N ; Diao, Li ; Chatterjee, Prodyot K ; Papoin, Julien ; Blanc, Lionel ; Campagne, Fabien ; Patel, Radhika ; Wang, Ping ; Al-Abed, Yousef ; Gillen, Matthew ; Marambaud, Philippe ; Nomura-Kitabayashi, Aya ; Chandakkar, Pallavi ; Ruiz, Santiago ; He, Mingzhu ; Oh, S Paul ; Zhao, Haitian

Hereditary hemorrhagic telangiectasia (HHT), a genetic bleeding disorder leading to systemic arteriovenous malformations (AVMs), is caused by loss-of-function mutations in the ALK1/ENG/Smad1/5/8 pathway. Evidence suggests that HHT pathogenesis strongly relies on overactivated PI3K/Akt/mTOR and VEGFR2 pathways in endothelial cells (ECs). In the BMP9/10-immunoblocked (BMP9/10ib) neonatal mouse model of HHT, we report here that the mTOR inhibitor, sirolimus, and the receptor tyrosine kinase inhibitor, nintedanib, could synergistically fully block, but also reversed, retinal AVMs to avert retinal bleeding and anemia. Sirolimus plus nintedanib prevented vascular pathology in the oral mucosa, lungs, and liver of the BMP9/10ib mice, as well as significantly reduced gastrointestinal bleeding and anemia in inducible ALK1-deficient adult mice. Mechanistically, in vivo in BMP9/10ib mouse ECs, sirolimus and nintedanib blocked the overactivation of mTOR and VEGFR2, respectively. Furthermore, we found that sirolimus activated ALK2-mediated Smad1/5/8 signaling in primary ECs - including in HHT patient blood outgrowth ECs - and partially rescued Smad1/5/8 activity in vivo in BMP9/10ib mouse ECs. These data demonstrate that the combined correction of endothelial Smad1/5/8, mTOR, and VEGFR2 pathways opposes HHT pathogenesis. Repurposing of sirolimus plus nintedanib might provide therapeutic benefit in patients with HHT.

2014-06-01·Current Treatment Options in Oncology2区 · 医学

Therapy of Advanced Squamous Cell Carcinoma of the Skin

2区 · 医学

Review

作者: Eve Maubec ; Claudia Bejar

Advanced unresectable squamous cell carcinoma of the skin (SCCS) is a rare condition, which is difficult to treat. Because of its rarity, few therapeutic trials are available. Moreover, SCCS often occur in elderly. Conventional treatment options for advanced SCCS are chemotherapy mainly with cisplatin-based regimens. Immunotherapy with interferon alpha and retinoids combination was also shown to be efficient. Toxicity of these treatments limits, however, their use in elderly patients and an initial work up for a global assessment is needed in order to adapt the choice. More recently, epithelial growth factor receptor (EGFR) targeted therapies have been developed and induced interesting response rates in small series of patients with unresectable SCCS. Their efficacy in SCCS must be confirmed by larger phase III trials and the identification of predictive biological factors of response is warranted. New therapeutic approaches combining EGFR inhibitors either with IGFR inhibitors, or immunomodulators or inhibitors of the PI3K/AKT/mTOR pathway are currently under evaluation in head and neck carcinomas and might represent valuable therapeutic approaches for unresectable SCCS. Moreover, there are several new molecular candidate treatment targets for unresectable SCCS including somatic NOTCH1 or NOTCH2 inactivating mutations, ALK1, which could be a good candidate for antiangiogenic therapy and matrix metallopeptidase 7, which enhances proliferation, migration, and invasion of cancer cells. Organ transplant recipients often develop SCCS and in some patients, SCCS are rapidly progressing. Management of SCCS in this subgroup of patients includes both carcinologic treatment and modification of immunosuppression. Specific treatment is generally the same as in immunocompetent patients. Switching from calcineurin inhibitors to sirolimus or reducing immunosuppression has to be considered.