Serine/threonine kinase mTOR (mammalian target of rapamycin) is a central regulator of cell growth and proliferation that modulates the transcription and translation of critical cell cycle regulatory molecules. Rapamycin and its analogues are in clinical trials, but have induced clinical responses in only a subgroup of patients. Therefore, there is a pressing need to identify biomarkers that can predict and monitor treatment response. We hypothesize that rapamycin modulates breast cancer biology by altering the expression of specific genes encoding for critical cell cycle and survival molecules. These gene products can be used to monitor response, and to determine which tumors will have significant growth inhibition.
In specific Aim 1, we will determine the effect of rapamycin on the transcriptional, translational, and proteomic profile, and identify changes that occur in rapamycin-sensitive but not in rapamycin-resistant cells. We will determine the role of rapamycin-regulated genes in growth inhibition mediated by rapamycin. Then we will determine the effect of rapamycin analogue CCI-779 on the protein levels of selected targets in breast and prostate cancer patients treated with preoperative CCI-779.
In Aim 2, we will evaluate cyclin D1 and BAG-1 as pharmacodynamic markers of response. We will determine the mechanism of rapamycin-mediated cyclin D1 and BAG-1 downregulation, and their role in growth-inhibition.
In Aim 3, we will determine rapamycin's effect on DNA synthesis, protein synthesis, and glucose uptake in vivo by positron emission tomography and determine whether these studies may be early predictors of response.
In Aim 4, we will determine whether mTOR activity predicts chemoresistance in breast cancer patients treated with preoperative chemotherapy. In addition, we will determine the mechanism of rapamycin-mediated enhancement of chemotherapy-induced cytotoxicity. With this study, we not only expect to identify pharmacodynamic markers of response for mTOR inhibitors but also to significantly enhance our understanding of mTOR inhibitors' mechanism of action. ? ?
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| Emerling, Brooke M; Akcakanat, Argun (2011) Targeting PI3K/mTOR signaling in cancer. Cancer Res 71:7351-9 |
| Singh, Gopal; Akcakanat, Argun; Sharma, Chandeshwar et al. (2011) The effect of leucine restriction on Akt/mTOR signaling in breast cancer cell lines in vitro and in vivo. Nutr Cancer 63:264-71 |
| Gonzalez-Angulo, Ana M; Meric-Bernstam, Funda (2010) Metformin: a therapeutic opportunity in breast cancer. Clin Cancer Res 16:1695-700 |
| Luyimbazi, David; Akcakanat, Argun; McAuliffe, Priscilla F et al. (2010) Rapamycin regulates stearoyl CoA desaturase 1 expression in breast cancer. Mol Cancer Ther 9:2770-84 |
| Dong, Jinjiang; Akcakanat, Argun; Stivers, David N et al. (2009) RNA-binding specificity of Y-box protein 1. RNA Biol 6:59-64 |
| Akcakanat, Argun; Zhang, Li; Tsavachidis, Spiridon et al. (2009) The rapamycin-regulated gene expression signature determines prognosis for breast cancer. Mol Cancer 8:75 |
| Meric-Bernstam, Funda; Gonzalez-Angulo, Ana Maria (2009) Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 27:2278-87 |
| Kim, Doyil; Akcakanat, Argun; Singh, Gopal et al. (2009) Regulation and localization of ribosomal protein S6 kinase 1 isoforms. Growth Factors 27:12-21 |
| Akcakanat, Argun; Sahin, Aysegul; Shaye, Alexandra N et al. (2008) Comparison of Akt/mTOR signaling in primary breast tumors and matched distant metastases. Cancer 112:2352-8 |
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