The goal of our preclinical studies for cancer treatment are currently focused on preclinical evaluation of combination therapy with two drugs, rapamycin (mTOR inhibitor) and MS-275 (HDAC, histone deactylase inhibitor) which interact with the two signal transduction pathways, RB and PI3K. These drugs have been evaluated in tissue culture cell lines for the following cancers: multiple myeloma, plasmacytoma or plasma cell tumors, and mantle cell lymphoma.Combined treatment with low concentrations of MS-275 and rapamycin resulted in a synergistic effect on growth inhibition in vitro and in vivo. Rapamycin decreased phosphorylation of S6, and MS-275 increased acetylation of histone H3 and H4. Both effects were further accentuated by the combination treatment. Both drugs caused cell cycle arrest, via different signaling events;MS-275 induced the expression of p21, p27 and p16, whereas rapamycin reduced the expression of cyclin D and p21. In contrast to rapamycin alone, the combination treatment did not lead to MAPK or AKT activation. MS-275 and rapamycin increased, and their combination further enhanced, the expression of pro-apoptotic proteins Foxo and Bim, and decreased expression of the pro-survival protein Survivin. The therapeutic potential of the combination was supported by in vivo studies of MM xenografts.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011065-04
Application #
8349310
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2011
Total Cost
$329,797
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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He, Yunlong; Zhu, Wentao; Shin, Min Hwa et al. (2017) cFOS-SOX9 Axis Reprograms Bone Marrow-Derived Mesenchymal Stem Cells into Chondroblastic Osteosarcoma. Stem Cell Reports 8:1630-1644
Felsenstein, Kenneth M; Saunders, Lindsey B; Simmons, John K et al. (2016) Small Molecule Microarrays Enable the Identification of a Selective, Quadruplex-Binding Inhibitor of MYC Expression. ACS Chem Biol 11:139-48
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Simmons, John K; Amlin-Van Schaick, Jessica C; Geiger, Thomas R et al. (2012) Mouse genetics 2011: meeting report. Mamm Genome 23:225-31
Smrz, Daniel; Kim, Mi-Sun; Zhang, Shuling et al. (2011) mTORC1 and mTORC2 differentially regulate homeostasis of neoplastic and non-neoplastic human mast cells. Blood 118:6803-13
Zhang, Shuling; Readinger, Julie A; DuBois, Wendy et al. (2011) Constitutive reductions in mTOR alter cell size, immune cell development, and antibody production. Blood 117:1228-38