Dr. Fuyu Tamanoi's research focuses on signal transduction involving the Ras-superfamily G-proteins, anti-cancer drugs and nanoparticle-based delivery of anticancer drugs.
The Ras-superfamily G-proteins play critical roles in cell growth and differentiation. Tamanoi and his colleagues have investigated the function and cellular localization of Ras that is mutated in a wide range of human cancer. More recently, they have focused their attention on a novel family of the Ras-superfamily G-proteins called Rheb. Rheb is conserved in a variety of organisms and possesses a unique structural feature. Genetic studies using fission yeast and Drosophila established that Rheb plays critical roles in both cell growth and cell cycle progression at the G1/S boundary and that this function of Rheb is mediated by its ability to activate the TOR/S6K signaling pathway. In addition to TOR, other downstream effectors of Rheb are being defined. Rheb is downregulated by TSC1/TSC2 complex. Mutations of TSC2 are responsible for tuberous sclerosis, a genetic disorder associated with benign tumors and mental retardation.
Tamanoi's laboratory has developed anti-cancer drugs against Ras proteins aimed at inhibiting their posttranslational modification and membrane association. This involves both farnesylation (catalyzed by protein farnesyltransferase) and geranylgeranylation (catalyzed by protein geranylgeranyltransferase-I). Small molecular inhibitors of protein geranylgeranyltransferase-I were identified from a library of compounds generated by phosphine catalysis of allenoate compounds. These drugs, called GGTIs, inhibit proliferation of various human cancer cells and inhibit tumor growth in animal model systems. They can be combined with farnesyltransferase inhibitors to block the function of K-Ras proteins. Recently, GGTIs were encapsulated into liposomes to provide tumor targeting capability.
Another research interest of Tamanoi's lab is to utilize mesoporous silica nanoparticles (MSNs) for controllable drug delivery system for cancer therapy. These particles, prepared in the presence of surfactants, contain thousands of pores which function as a storage space for anticancer drugs. Tamanoi and his researchers were the first to show that these nanoparticles can deliver anticancer drugs and inhibit tumor growth in vitro and in vivo. Tamanoi's lab is also exploring ways to use nanovalves to accomplish controlled release. These nanovalves can be attached to the openings of the pores to provide open and close function. Ways to use external stimuli such as light exposure to release anticancer drugs are being explored. Targeting to cancer by attaching ligands specific to cancer cells is currently being investigated. MSNs are also shown to be effective in delivering siRNA to tumor in vivo.
Mekaru H, Lu J, Tamanoi F. Development of mesoporous silica-based nanoparticles with controlled release capability for cancer therapy. Adv Drug Deliv Rev. 2015 Dec 1;95:40-9. doi: 10.1016/j.addr.2015.09.009. Epub 2015 Oct 3.
Finlay J, Roberts CM, Dong J, Zink JI, Tamanoi F, Glackin CA. Mesoporous silica nanoparticle delivery of chemically modified siRNA against TWIST1 leads to reduced tumor burden. Nanomedicine. 2015 Oct;11(7):1657-66. doi: 10.1016/j.nano.2015.05.011. Epub 2015 Jun 24.
Chantaravisoot N, Wongkongkathep P, Loo JA, Mischel PS, Tamanoi F. Significance of filamin A in mTORC2 function in glioblastoma. Mol Cancer. 2015 Jul 2;14:127. doi: 10.1186/s12943-015-0396-z.
Lu J, Yoshimura K, Goto K, Lee C, Hamura K, Kwon O, Tamanoi F. Nanoformulation of Geranylgeranyltransferase-I Inhibitors for Cancer Therapy: Liposomal Encapsulation and pH-Dependent Delivery to Cancer Cells. PLoS One. 2015 Sep 9;10(9):e0137595. doi: 10.1371/journal.pone.0137595. eCollection 2015.
Heard JJ, Fong V, Bathaie SZ, Tamanoi F. Recent progress in the study of the Rheb family GTPases. Cell Signal. 2014 Sep;26(9):1950-7. doi: 10.1016/j.cellsig.2014.05.011. Epub 2014 May 24.