The objectives of this U19 proposal are to design and synthesize highly potent and specific small-molecule inhibitors of Bcl-2/Bcl-xL. We will test these inhibitors in vitro and in vivo to determine their therapeutic potential in prostate cancer animal models. Our central rationale/ hypothesis is that (1) hormone-refractory prostate cancer cells with high levels of Bcl-2/Bcl-xL proteins depend upon the protection of Bcl-2/xL for survival advantage and so become resistant to chemotherapeutic agents;(2) inhibition of the anti-apoptotic function of Bcl-2/xL using a potent, cell-permeable small-molecule inhibitor may overcome chemoresistance and improve the efficacy of current chemotherapy, representing a highly effective and novel strategy for the treatment of hormone-refractory prostate cancer by overcoming apoptosis-resistance. To test our hypothesis, we propose to carry out three interrelated Specific Aims:
Aim 1 : To evaluate the in vitro anti-tumor activity of the most potent and promising Bcl-2 small-molecule inhibitors and investigate their mechanism of action in apoptosis induction;
Aim 2 : To evaluate the in vivo anti-tumor activity of the most potent and promising Bcl-2/xL inhibitors;
Aim 3 : To evaluate the Bcl-2 family of proteins in a VCaP model during tumor progression/transition from androgen sensitive to insensitive prostate cancer and the therapeutic potential of Bcl-2/xL inhibitors in overcoming chemoresistance of the androgen independent VCaP. Successfully carried out, our in vitro and in vivo studies will provide the important proof-of-concept that a highly potent and specific small-molecule inhibitor of Bcl-2/xL may have a great therapeutic potential to be developed as a new and effective therapy for treating hormone-refractory prostate cancer, alone and in combination with chemotherapy by overcoming apoptosis-resistance. This will provide the critical impetus to bring the best Bcl-2/xL small-molecule inhibitor to advanced preclinical development and future clinical studies as an entirely new class of cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19CA113317-05
Application #
7804584
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
5
Fiscal Year
2009
Total Cost
$374,197
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Bai, Longchuan; Chen, Jianfang; McEachern, Donna et al. (2014) BM-1197: a novel and specific Bcl-2/Bcl-xL inhibitor inducing complete and long-lasting tumor regression in vivo. PLoS One 9:e99404
Aguilar, Angelo; Zhou, Haibin; Chen, Jianfang et al. (2013) A potent and highly efficacious Bcl-2/Bcl-xL inhibitor. J Med Chem 56:3048-3067
Chen, Jianfang; Zhou, Haibin; Aguilar, Angelo et al. (2012) Structure-based discovery of BM-957 as a potent small-molecule inhibitor of Bcl-2 and Bcl-xL capable of achieving complete tumor regression. J Med Chem 55:8502-14
Zhou, Haibin; Aguilar, Angelo; Chen, Jianfang et al. (2012) Structure-based design of potent Bcl-2/Bcl-xL inhibitors with strong in vivo antitumor activity. J Med Chem 55:6149-61
Imai, Atsushi; Zeitlin, Benjamin D; Visioli, Fernanda et al. (2012) Metronomic dosing of BH3 mimetic small molecule yields robust antiangiogenic and antitumor effects. Cancer Res 72:716-25
Zhou, Haibin; Chen, Jianfang; Meagher, Jennifer L et al. (2012) Correction to Design of Bcl-2 and Bcl-xL Inhibitors with Subnanomolar Binding Affinities Based upon a New Scaffold. J Med Chem 55:5987
Zhou, Haibin; Chen, Jianfang; Meagher, Jennifer L et al. (2012) Design of Bcl-2 and Bcl-xL inhibitors with subnanomolar binding affinities based upon a new scaffold. J Med Chem 55:4664-82
McGregor, Natalie; Patel, Lalit; Craig, Matthew et al. (2010) AT-101 (R-(-)-gossypol acetic acid) enhances the effectiveness of androgen deprivation therapy in the VCaP prostate cancer model. J Cell Biochem 110:1187-94
Zeitlin, Benjamin D; Spalding, Aaron C; Campos, Marcia S et al. (2010) Metronomic small molecule inhibitor of Bcl-2 (TW-37) is antiangiogenic and potentiates the antitumor effect of ionizing radiation. Int J Radiat Oncol Biol Phys 78:879-87
Azmi, Asfar S; Aboukameel, Amro; Banerjee, Sanjeev et al. (2010) MDM2 inhibitor MI-319 in combination with cisplatin is an effective treatment for pancreatic cancer independent of p53 function. Eur J Cancer 46:1122-31

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