The success of a cancer therapy generally depends on its ability to target certain unique requirements of the cancer cells that are distinct from those of the normal cells in the body. Current targeted cancer therapies at different stages of development mostly focus on inhibiting the deregulated oncogenic pathways. clinical studies of tyrosine kinase inhibitors such as Gefitinib and Gleevec (inhibitors of EGFR and Abl tyrosine kinases, respectively) revealed two general properties of these targeted cancer drugs: 1) they are generally only effective to a small subset of cancers with genetic alterations that make these cancers "addicted" to the deregulated oncogenic signaling being targeted;2) cancers that are resistant to these inhibitors will eventually develop. These observations suggested the need to have large number of cancer drugs that target different features of cancer cells. In this case, different combinations of targeted cancer drugs can be used to specifically target different subsets of cancers and to prevent the development of resistant cancers. In addition to deregulated oncogenic activation, cancer cells also often have inactivation of tumor suppressor genes. However, very little effort has been devoted to develop therapeutic approaches that target such loss of tumor suppressor function in cancers. The main difficulty with targeting the loss of function tumor suppressors is the lack of straightforward approaches to either restore the lost tumor suppressor function in all the cancer cells or to specifically kill cancer cells with inactivated tumor suppressors. The Rb tumor suppressor is often inactivated in different types of cancers by mutation of the Rb gene itself, by loss of Rb expression, or by its functional inactivation. The Rb pathway is highly conserved in Drosophila. We have carried out a genetic screen in Drosophila to identify genes that can modulate the apoptosis of Rb mutant cells. Our genetic screen has led to the identification of a gene that is required specifically for preventing the apoptosis of Rb mutant cells both in developing fly tissues and in cancer cells. These observations suggest that our generic screen have led to the identification of a gene that can potentially be used as a target to specifically kill cancer cells with inactivated Rb tumor suppressor. In this grant, we will further investigate this idea to determine the mechanisms involved and to investigate the subset of cancer cells that can potentially be targeted. Furthermore we will develop assays to screen for small molecule inhibitors that can be used to specifically kill cancer cells with inactivated Rb pathway.
The proposed study aims to develop novel approaches to specifically target cancers with inactivated Rb tumor suppressor. The success of this project will promote the development of new therapies for a significant fraction of human cancers.
|Tanaka-Matakatsu, Miho; Miller, John; Du, Wei (2015) The homeodomain of Eyeless regulates cell growth and antagonizes the paired domain-dependent retinal differentiation function. Protein Cell 6:68-78|
|Tanaka-Matakatsu, Miho; Miller, John; Borger, Daniel et al. (2014) Daughterless homodimer synergizes with Eyeless to induce Atonal expression and retinal neuron differentiation. Dev Biol 392:256-65|
|Jin, H R; Liao, Y; Li, X et al. (2014) Anticancer compound Oplopantriol A kills cancer cells through inducing ER stress and BH3 proteins Bim and Noxa. Cell Death Dis 5:e1190|
|Zhao, Jiong; Zhang, Zhenyu; Liao, Yang et al. (2014) Mutation of the retinoblastoma tumor suppressor gene sensitizes cancers to mitotic inhibitor induced cell death. Am J Cancer Res 4:42-52|
|Zhang, Tianyi; Liao, Yang; Hsu, Fu-Ning et al. (2014) Hyperactivated Wnt signaling induces synthetic lethal interaction with Rb inactivation by elevating TORC1 activities. PLoS Genet 10:e1004357|
|Wang, Chong-Zhi; Li, Binghui; Wen, Xiao-Dong et al. (2013) Paraptosis and NF-*B activation are associated with protopanaxadiol-induced cancer chemoprevention. BMC Complement Altern Med 13:2|
|Gordon, Gabriel M; Zhang, Tianyi; Zhao, Jiong et al. (2013) Deregulated G1-S control and energy stress contribute to the synthetic-lethal interactions between inactivation of RB and TSC1 or TSC2. J Cell Sci 126:2004-13|
|Danos, Arpad M; Liao, Yang; Li, Xuan et al. (2013) Functional inactivation of Rb sensitizes cancer cells to TSC2 inactivation induced cell death. Cancer Lett 328:36-43|
|Wang, Chong-Zhi; Zhang, Zhiyu; Huang, Wei-Hua et al. (2013) Identification of potential anticancer compounds from Oplopanax horridus. Phytomedicine 20:999-1006|
|Gordon, Gabriel M; Du, Wei (2011) Targeting Rb inactivation in cancers by synthetic lethality. Am J Cancer Res 1:773-86|
Showing the most recent 10 out of 12 publications