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Cyclin Kinase Inhibitors as Molecular Targets for Cancer

细胞周期蛋白激酶抑制剂作为癌症分子靶标

基本信息

批准号：
6623163
负责人：
ROBERT H. WEISS
金额：
$ 14.85万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2004-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6623163
关键词：
angiogenesis inhibitors antisense nucleic acid apoptosis breast neoplasms cyclins doxorubicin enzyme inhibitors gene therapy laboratory mouse neoplasm /cancer chemotherapy neoplasm /cancer genetics neoplasm /cancer therapy nonhuman therapy evaluation oligonucleotides oncoprotein p21 protein kinase vascular smooth muscle

项目摘要

DESCRIPTION (provided by applicant): This is a resubmission of a application which focuses on the cyclin kinase inhibitors (CKIs) as novel potential targets for cancer therapy. While the paradigm, until quite recently, has been that these proteins act solely as inhibitors of cell growth, our recent published work showing that the CKI p21 Wafl/Cipl has, under some conditions and with some cell types, permissive effects on vascular smooth muscle (VSM) cell growth, has led us to propose this class of molecules as novel potential targets in cancer chemotherapy. Since the first submission of this application, we have obtained new data further validating this molecule as such a target. Furthermore, we have more new (and, we modestly believe, very exciting) data providing evidence that inhibition of p21 by our simple antisense oligodeoxynucleotide (oligo) transfection technique leads to marked inhibition of tumor angiogenesis, as well as tumor growth, in an in vivo animal model of mammary cancer. The excitement which we hope to generate in this research is, in part, due to the ease of administration, the lack of toxicity, the absence of phenotypic changes in p21 knockouts (suggesting redundancy in signaling of p21 as an effector of the tumor suppressor p53), and the possibility for whole animal application of this novel antisense oligo technique against a novel target molecule for treatment of a devastating human disease. This resubmission has been modified, in response to the critiques received from the last submission, by the removal of many of the mechanistic experiments and a narrowing of the focus of the work to a single CKI, p21, concerning which we have the most data. Significantly more preliminary data is provided in this resubmission supporting our hypothesis, and we now propose to examine in some detail the exciting possibility that we have discovered an antiangiogenic molecule that is acting upon the VSM cell scaffolding in tumor angiogenic vessels. The Specific Aims are (1) to determine optimal by which the antisense CKI oligos are growth inhibitory, apoptosis-promoting, or anti-angiogenic; (2) to determine the effect of p21 antisense oligos locally on tumor cell growth and systemically in a mouse injected with metastatic tumor cells; and (3) to begin to study the mechanism of the anti-angiogenic effect of antisense p21 oligos. We believe that completion of the experiments in this application will fully validate the use of antisense oligos to p21 in the field of mammalian cancer and will lead not only to adequate data to submit a fundable R01 application, but, more importantly, to further animal, and ultimately human, trials of p21 inhibition as a viable treatment adjunct in human cancer.

描述（由申请人提供）：

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Antisense attenuation of p21 sensitizes kidney cancer to apoptosis in response to conventional DNA damaging chemotherapy associated with enhancement of phospho-p53.

p21 反义减弱使肾癌对细胞凋亡敏感，这是对与磷酸化 p53 增强相关的传统 DNA 损伤化疗的反应。

DOI：
10.1016/j.juro.2008.02.038
发表时间：
2008
期刊：
The Journal of urology
影响因子：
0
作者：
Park,See-Hyoung;Park,Jin-Young;Weiss,RobertH
通讯作者：
Weiss,RobertH

Targeting the PI3K-Akt pathway in kidney cancer.

靶向肾癌中的 PI3K-Akt 通路。

DOI：
10.1586/14737140.7.6.863
发表时间：
2007
期刊：
Expert review of anticancer therapy
影响因子：
3.3
作者：
Park,Jin-Young;Lin,Pei-yin;Weiss,RobertH
通讯作者：
Weiss,RobertH

High throughput screening of a small molecule one-bead-one-compound combinatorial library to identify attenuators of p21 as chemotherapy sensitizers.

高通量筛选小分子一珠一化合物组合文库，以鉴定 p21 衰减剂作为化疗增敏剂。

DOI：
10.4161/cbt.7.12.7069
发表时间：
2008
期刊：
Cancer biology & therapy
影响因子：
3.6
作者：
Park,See-Hyoung;Wang,Xiaobing;Liu,Ruiwu;Lam,KitS;Weiss,RobertH
通讯作者：
Weiss,RobertH

p21 is decreased in polycystic kidney disease and leads to increased epithelial cell cycle progression: roscovitine augments p21 levels.

DOI：
10.1186/1471-2369-8-12
发表时间：
2007-08-22
期刊：
BMC NEPHROLOGY
影响因子：
2.3
作者：
Park, Jin-Young;Schutzer, William E;Lindsley, Jessie N;Bagby, Susan P;Oyama, Terry T;Anderson, Sharon;Weiss, Robert H
通讯作者：
Weiss, Robert H

An antisense oligodeoxynucleotide to p21(Waf1/Cip1) causes apoptosis in human breast cancer cells.