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Methods and compositions for treating cancer
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A technology of composition and use, applied in the fields of medicine, molecular biology and genetics, and cell biology, which can solve problems such as unpredictable clinical outcomes
Inactive Publication Date: 2015-08-19
AGENCY FOR SCI TECH & RES
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Although small-molecule mTORC1 inhibitors, such as rapamycin and its analogs, have shown reasonable promise in cancer therapeutic applications and have been approved for clinical use (Guertin and Sabatini, 2007; Hudes et al., 2007), but these inhibitors have had only limited success and clinical outcomes are unpredictable
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[0232] Methods for the preparation of rapamycin are disclosed in US Patent Nos. 3,929,992 and 3,993,749 to Sehgal et al. In addition, monoacyl and diacyl derivatives of rapamycin and methods for their preparation are disclosed in US Patent No. 4,316,885 to Rakhit. In addition, U.S. Patent No. 4,650,803 to Stella et al. discloses water-soluble prodrugs of rapamycin, namely rapamycin derivatives including the following rapamycin prodrugs: glycineprodrug, propionic acid prodrug and pyrrolidinylbutyrate prodrugs.
[0233] The methods and compositions described herein include the use of natural and synthetic rapamycin, genetically engineered rapamycin, and all derivatives and prodrugs of rapamycin, such as the aforementioned U.S. Patent Nos. 3,929,992, 3,993,749, 4,316,885, and 4,650,803, the contents of which are incorporated herein by reference.
[0234] Rapamycin is a 31-membered macrolide C 51 h 79 NO 13 , with a molecular weight of 913.6Da. Due to the hindered rotation ...
Embodiment 1
[0469] Example 1: Test Methods - Samples, Cell Lines and Agents
[0470] Human tissue samples were obtained from the Singapore Tissue Network (Singapore Tissue Network) according to the local ethics committee as previously described (Jiang et al., 2008). Cancer cell lines used in this study were purchased from the American Type Culture Collection (Manassas, VA).
[0471] HCT116 cells with genetic disruption of DNMT1 and DNMT3B (HCT116DKO) were kindly provided by Dr. Bert Vogelstein (Johns Hopkins University, MD). HEK-TERV cells were kindly provided by Dr. W.C. Hahn, Dana-Farber Cancer Institute. 5-AzaC and doxycycline were purchased from Sigma.
[0472] Rapamycin and PI-103 were purchased from Alexis (San Diego, CA). The PDK1 inhibitor BX912 and the PIK3CA inhibitor PIK90 were obtained from Axon Medchem (Groningen, The Netherlands).
[0474] The full-length PPP2R2B coding region was isolated by RT-PCR using 100 ng of total RNA from normal colon tissue and the following primers: 5'-GGTACCACCatggaggaggacattgatacc-3' and 5'-CTCGAGCAgttaaccttgtcctgga-3'. PCR products were cloned into pcDNA4 / myc-hisB between the Kpn I and Xho I sites for overexpression studies, or into pcDNA4 / TO / myc-hisB for inducible systems.
[0475] Full-length PDK1 was amplified by RT-PCR using 100 ng of total RNA from HEK293 cells and the following primers: 5'-tcGAATTCgccaggaccagccagc-3' and 5'-GAGAATTCctgcacagcggcgtccgg-3'. The PCR product was cloned between the EcoRI of the pHA.CE vector and sequenced. In order to produce PPP2R2B Tet-on-inducible cell lines, first isolate DLD1 or HCT116 stable cells expressing pcDNA6-TR (Invitrogen) and using blasticidin (Blasticidin, 10 μg / ml) according to the instructions of the T-Rex System Kit (Invitrogen). Cell l...
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Abstract
The present invention describes methods for detecting whether cancer cells are likely to be resistant to mTOR inhibitor treatment. The method may comprise detecting PPP2R2B (GenBank Accession Number: NM_181678) in or in the cell. Alternatively or additionally, the method may comprise detecting PDK1 (GenBank accession number: NM_002613) in or in the cell. The method may comprise detecting methylation of the PPP2R2B promoter in or in the cell. The method may comprise detecting PPP2R2B expression and / or activity in or in the cell. The method may comprise detecting PDK1 mediated Myc phosphorylation activity. The present invention also provides methods for selecting treatment for an individual having or suspected of having cancer, methods for determining whether an individual having or suspected of having cancer will respond to mTOR inhibitor therapy, methods for increasing cancer A method for the sensitivity of cells to treatment with an mTOR inhibitor for the treatment or prevention of cancer in an individual having or suspected of having cancer. The present invention further provides a combination of an inhibitor of PDK1 expression and / or activity and an mTOR inhibitor for use in a method of treating or preventing cancer.
Description
technical field [0001] The present invention relates to the fields of medicine, cell biology, molecular biology and genetics. The present invention relates to the field of medicine. In particular, the invention relates to the treatment and diagnosis of diseases such as cancer, and compositions for this application. Background technique [0002] Proteinphosphatase 2A (PP2A) functions as a multimeric enzyme comprising a catalytic subunit C, a structural subunit A, and one of a number of regulatory subunits B. Eukaryotic cells contain more than 200 biochemically distinct PP2A complexes derived from different combinations of A, B, C, and other subunits. Regulatory subunits are expressed in a tissue-specific manner, resulting in the presence of distinct PP2A complexes in different mammalian tissues (Virshup and Shenolikar, 2009). Furthermore, it is these regulatory subunits rather than the catalytic subunits that provide substrate specificity and catalyze different dephosphor...
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