The potent, sequence-specific gene silencing by small interfering RNA (siRNA) has become a powerful tool in cancer research and holds significant potential as novel molecular therapy for cancer. However, delivering the siRNA-based therapeutics efficiently and specifically to prostate cancer and its metastases remains a great challenge. We have developed a tumor-specific, ligand-targeting, self-assembled DNA-nanovector system for prostate cancer gene delivery. The nanovectors show promising efficiency and specificity in targeted delivery of various genes and anti-sense oligonucleotides to human prostate cancer, with limited effect on normal tissues (US Patent No. 6,749,863). This nanovector system is now in Phase I clinical trial for non-viral p53 gene therapy. The objective of this pilot project proposal is to explore the feasibility of using our patented nanovector system for tumor-targeted delivery of siRNA-based therapeutics for human prostate cancer. In our preliminary studies, we have designed siRNAs for human Bcl-2 and Bcl-xL that can potently knock-down Bcl-2/Bcl-xL up to 95%, leading to extensive cancer cell death (US Patent pending). We propose to use Bcl-2/Bcl-xL siRNA to test two inter-related hypotheses: (1) the self-assembled nanovectors can selectively deliver siRNA to prostate cancer and efficiently silence the target Bcl-2/Bcl-xL; (2); Knock-down of the anti-apoptotic Bcl-2/Bcl-xL will induce apoptosis in human prostate cancer cells that depend on Bcl-2/Bcl-xL for survival, thus overcome resistance and restore sensitivity of prostate cancer cells to chemo/radiotherapy. Our long-term goal is to develop the tumor-targeting siRNA-nanovectors as novel molecular therapy for prostate cancer. To test our hypothesis, we propose to carry out two SPECIFIC AIMS:
AIM 1 : To prepare and optimize the nanovectors for efficient RNA interference for human prostate cancer in vitro and in vivo;
AIM 2 : To investigate anti-tumor activities and target validation of Bcl-2/Bcl-xL siRNA-nanovectors in nude mouse xenograft models of human prostate cancer with high levels of Bcl-2/Bcl-xL. Anti-apoptotic proteins Bcl-2 and Bcl-xL are overexpressed in most of prostate cancer and contribute to prostate tumor initiation, progression and resistance to therapy. Molecular modulation of Bcl-2/Bcl-xL represents a promising strategy for overcoming the resistance to apoptosis induced by current cancer therapy. Combining siRNA-based molecular therapy with conventional therapy would improve the efficacy and overcome the resistance to current cancer treatment, especially for tumor metastasis, in which Bcl-2/Bcl-xL protein is overexpressed and for which conventional therapy is not very effective. Successfully carried out, our study will provide proof-of-concept that siRNA can be delivered by the self-assembled nanovectors for tumor-targeted RNA interference of the genes critical for prostate cancer progression and resistance. Combining tumor-targeted RNA interference of Bcl-2/Bcl-xL with conventional therapy would improve the efficacy and overcome the drug resistance to current cancer treatment, especially for metastasis, in which Bcl- 2/Bcl-xL protein is overexpressed and for which conventional therapy is not very effective. Successfully carried out, our studies will provide proof-of-concept that siRNA can be delivered by the self-assembled nanovectors for tumor-targeted silencing of the genes critical for prostate tumor progression and resistance. The success of tumor-targeted RNA interference by nanovectors in vivo will have a major impact on the development of siRNA-based novel therapeutics for various molecular targets of human prostate cancer. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA128220-02
Application #
7475129
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fu, Yali
Project Start
2007-08-01
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$127,680
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Wu, Xiaoqing; Li, Mingdong; Tang, Wenhua et al. (2011) Design, synthesis, and in vitro antitumor activity evaluation of novel 4-pyrrylamino quinazoline derivatives. Chem Biol Drug Des 78:932-40
Pan, Xinghua; Thompson, Rachel; Meng, Xiaojie et al. (2011) Tumor-targeted RNA-interference: functional non-viral nanovectors. Am J Cancer Res 1:25-42
Wu, Xiaoqing; Li, Mingdong; Qu, Yang et al. (2010) Design and synthesis of novel Gefitinib analogues with improved anti-tumor activity. Bioorg Med Chem 18:3812-22
Lian, Jiqin; Karnak, David; Xu, Liang (2010) The Bcl-2-Beclin 1 interaction in (-)-gossypol-induced autophagy versus apoptosis in prostate cancer cells. Autophagy 6:1201-3
Karnak, David; Xu, Liang (2010) Chemosensitization of prostate cancer by modulating Bcl-2 family proteins. Curr Drug Targets 11:699-707
Dai, Yao; Desano, Jeffrey; Tang, Wenhua et al. (2010) Natural proteasome inhibitor celastrol suppresses androgen-independent prostate cancer progression by modulating apoptotic proteins and NF-kappaB. PLoS One 5:e14153
Dai, Yao; Liu, Meilan; Tang, Wenhua et al. (2009) A Smac-mimetic sensitizes prostate cancer cells to TRAIL-induced apoptosis via modulating both IAPs and NF-kappaB. BMC Cancer 9:392
Dai, Yao; Lawrence, Theodore S; Xu, Liang (2009) Overcoming cancer therapy resistance by targeting inhibitors of apoptosis proteins and nuclear factor-kappa B. Am J Transl Res 1:1-15
DeSano, Jeffrey T; Xu, Liang (2009) MicroRNA regulation of cancer stem cells and therapeutic implications. AAPS J 11:682-92

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