Compositions and methods APC, CREB, and BAD pathways to assess and affect cancer
View Patent ↗Disclosed are compositions and methods for assessing the apoptosis and survival BAD phosphorylation pathway (BAD pathway); and/or (2) the cell cycle role of APC in cell cycle regulation pathway (APC pathway); and/or (3) the transcription CREB pathway (CREB pathway) and for using these pathways to assess, treat, monitor, prognose, diagnose, etc. subjects with cancer. Also disclosed are compositions and methods for identifying molecular pathways that are common to one or more chemotherapeutic agents for the treatment of an oncological disorder, for screening for compounds or agents that can be used to treat ovarian cancer, and for selecting for compounds or agents that can enhance the cytotoxic response of cisplatin, carboplatin, and/or paclitaxel against a cancer cell, such as an ovarian cancer cell or cell line.
1. A method for screening for compounds that can be used to treat ovarian cancer comprising
(a) contacting ovarian cancer cells with a test compound;
(b) measuring expression levels of at least 50% of the following genes of the transcription CREB pathway in the cancer cells; ADCY1, ADRB1, ADRB2, ADRB3, AKT1, AKT2, AKT3, CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1I, CACNA1S, CACNA2D1, CACNA2D2, CACNA2D3, CACNB1, CACNB2, CACNB3, CACNB4, CACNG1, CACNG2, CACNG3, CACNG4, CACNG5, CACNG6, CACNG7, CACNG8, CALM1, CALM2, CALM3, CAMK2A, CAMK2B, CAMK2D, CAMK2G, CAMK4, CCND1, CDO1, CREB1, DRD1, DRD5, EXOC7, GNAS, GRB2, HPD, HRAS, HRH1, HRH2, HTR4, HTR6, HTR7, HTR7P, IFI6, IGF1R, IGH@, IGHA1, IGHA2, IGHD, IGHG1, IGHG2, IGHG3, IGHM, IGHV4-31, IL8, IRS1, KCNIP3, LDHA, LOC730418, MAP2K1, MAP3K11, MAPK1, MAPK11, MAPK12, MAPK13, MAPK14, MAPK3, PDPK1, PDYN, PIK3CA, PIK3CB, PIK3CD, PIK3R1, PIK3R2, PIK3R3, PPP1CA, PPP1CB, PPP1CC, PPP2CA, PPP2CB, PRKACA, PRKACB, PRKACG, PRKAR1A, PRKAR1B, PRKAR2A, PRKAR2B, PRKCA, PRKCB1, PRKCG, RAC1, RAF1, RPS6KA1, RPS6KA2, RPS6KA3, RPS6KA4, RPS6KA5, SHC1, SIX6, SOS1, SOS2, TRPC1, TRPC3, and ZCWPW2;
(c) obtaining a CREB pathway gene expression signature score of the expression levels of the genes of the transcription CREB pathway that were measured, wherein the pathway signature score is determined by
Σw i x i , wherein x i represents gene i expression level and w i is the corresponding weight (loading coefficient) with Σw i 2 =1,
(d) selecting the test compound as a compound that can be used to treat ovarian cancer when the CREB pathway gene expression signature score is decreased from the CREB pathway gene expression signature score of the expression levels of the same genes of the transcription CREB pathway in control ovarian cancer cells cultured in the absence of the test compound; and
(e) repeating steps (a), (b), (c), and (d) a plurality of times each with a different test compound.
2. A method for selecting for compounds that enhance the cytotoxic response to an active agent selected from the group consisting of cisplatin, carboplatin, paclitaxel, and combinations thereof, against a cancer cell, comprising
(a) contacting cancer cells with (i) cisplatin, carboplatin, paclitaxel, or combinations thereof, and (ii) a test compound;
(b) measuring expression levels of at least 50% of the following genes of the transcription CREB pathway in the cancer cells: ADCY1, ADRB1, ADRB2, ADRB3, AKT1, AKT2, AKT3, CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1I, CACNA1S, CACNA2D1, CACNA2D2, CACNA2D3, CACNB1, CACNB2, CACNB3, CACNB4, CACNG1, CACNG2, CACNG3, CACNG4, CACNG5, CACNG6, CACNG7, CACNG8, CALM1, CALM2, CALM3, CAMK2A, CAMK2B, CAMK2D, CAMK2G, CAMK4, CCND1, CDO1, CREB1, DRD1, DRD5, EXOC7, GNAS, GRB2, HPD, HRAS, HRH1, HRH2, HTR4, HTR6, HTR7, HTR7P, IFI6, IGF1R, IGH@, IGHA1, IGHA2, IGHD, IGHG1, IGHG2, IGHG3, IGHM, IGHV4-31, IL8, IRS1, KCNIP3, LDHA, LOC730418, MAP2K1, MAP3K11, MAPK1, MAPK11, MAPK12, MAPK13, MAPK14, MAPK3, PDPK1, PDYN, PIK3CA, PIK3CB, PIK3CD, PIK3R1, PIK3R2, PIK3R3, PPP1CA, PPP1CB, PPP1CC, PPP2CA, PPP2CB, PRKACA, PRKACB, PRKACG, PRKAR1A, PRKAR1B, PRKAR2A, PRKAR2B, PRKCA, PRKCB1, PRKCG, RAC1, RAF1, RPS6KA1, RPS6KA2, RPS6KA3, RPS6KA4, RPS6KA5, SHC1, SIX6, SOS1, SOS2, TRPC1, TRPC3, and ZCWPW2;
(c) obtaining a CREB pathway gene expression signature score of the expression levels of the genes of the transcription CREB pathway that were measured, wherein the pathway signature score is determined by
Σw i x i , wherein x i represents gene i expression level and w i is the corresponding weight (loading coefficient) with Σw i 2 =1,
(d) selecting the test compound as a compound that can be used to enhance the cytotoxic response to the active agent when the CREB pathway gene expression signature score is decreased from the CREB pathway gene expression signature score of the expression levels of the same genes of the transcription CREB pathway in control cancer cells cultured with (i) cisplatin, carboplatin, paclitaxel, or combinations thereof, but in the absence of (ii) the test compound; and
(e) repeating steps (a), (b), (c), and (d) a plurality of times each with a different test compound.