A plateau has been reached in the effectiveness of current treatments for cancer. Given that most major cancers remain refractory to therapy radically new approaches to preventing and treating cancer are clearly needed. To this end our approach is based on the fact that the distinguishing feature of a cancer cell compared to a normal cell is the presence in the cancer cell of mutated or overexpressed oncogenes and the loss of tumor suppressor genes. The only known function of oncogenes is to code for proteins that are components of growth factor signalling pathways, which causes the cancer cell to receive an unrestrained signal to grow. Thus, cancer can be considered a disease of deranged intracellular signalling. Redundancy among intracellular signalling pathways allows selective inhibition of oncogene.activated pathways while leaving unaltered alternative pathways necessary for the normal functions of a cell. The objective of our studies is to use oncogene-activated intracellular signalling pathways as targets for the rational development of novel chemotherapeutic and chemopreventive anticancer drugs. The signalling targets we will use include enzymes of phospholipid signalling (phosphatidylinositol phospholipase C, phosphatidylinositol-3-kinase and phospholipase D), protein serine/threonine kinases (Raf-1 kinase, MEK kinase and MAP-kinase) and enzymes that regulate the cell cycle (cdc25 phosphatase and Cdk4 kinase). We have developed multiwell plate high volume screening assays in addition to cell based secondary assays for each of these targets. The sources of compounds we will use for screening are Chinese traditional medicinal plant extracts, combinatorial natural product based progenomers and pure fermentation products. We will use bioassay targeted fingerprinting as a rapid way to identify active lead compounds. The active compounds we identify will be tested for their in vitro cytotoxicity against a panel of human tumor cell lines and the most active compounds will be tested for in vivo activity against a panel of transplanted murine and human tumors in mice. Preclinical development of promising lead compounds and high throughput screening of selected targets against a chemical library will be carried out by our commercial collaborator.
| Ihle, N T; Powis, G; Kopetz, S (2011) PI-3-Kinase inhibitors in colorectal cancer. Curr Cancer Drug Targets 11:190-8 |
| Liu, Enbo; Knutzen, Christine A; Krauss, Sybille et al. (2011) Control of mTORC1 signaling by the Opitz syndrome protein MID1. Proc Natl Acad Sci U S A 108:8680-5 |
| Gwak, Ho-Shin; Shingu, Takashi; Chumbalkar, Vaibhav et al. (2011) Combined action of the dinuclear platinum compound BBR3610 with the PI3-K inhibitor PX-866 in glioblastoma. Int J Cancer 128:787-96 |
| Leone, Marilisa; Barile, Elisa; Vazquez, Jesus et al. (2010) NMR-based design and evaluation of novel bidentate inhibitors of the protein tyrosine phosphatase YopH. Chem Biol Drug Des 76:10-6 |
| Ihle, Nathan T; Powis, Garth (2010) The biological effects of isoform-specific PI3-kinase inhibition. Curr Opin Drug Discov Devel 13:41-9 |
| Koul, Dimpy; Shen, Ruijun; Kim, Yong-Wan et al. (2010) Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma. Neuro Oncol 12:559-69 |
| Ihle, Nathan T; Powis, Garth (2010) Inhibitors of phosphatidylinositol-3-kinase in cancer therapy. Mol Aspects Med 31:135-44 |
| Ihle, Nathan T; Powis, Garth (2009) Take your PIK: phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy. Mol Cancer Ther 8:1-9 |
| Tomko Jr, Robert J; Azang-Njaah, Ndang N; Lazo, John S (2009) Nitrosative stress suppresses checkpoint activation after DNA synthesis inhibition. Cell Cycle 8:299-305 |
| Gaitonde, Supriya; De, Surya K; Tcherpakov, Marianna et al. (2009) BI-69A11-mediated inhibition of AKT leads to effective regression of xenograft melanoma. Pigment Cell Melanoma Res 22:187-95 |
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