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

• 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
• 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

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）： 这是针对细胞周期蛋白激酶的应用程序的重新提交 抑制剂（CKI）是癌症治疗的新型潜在靶标。而 直到最近，范式一直是这些蛋白质仅起作用 细胞生长的抑制剂，我们最近发表的工作表明CKI P21 WAFL/CIPL在某些条件下具有允许的 对血管平滑肌（VSM）细胞生长的影响，使我们提出了 这类分子是癌症化学疗法的新型潜在靶标。 自本应用程序的第一次提交以来，我们获得了新数据 进一步验证该分子作为这样的目标。此外，我们还有更多 新的（我们谦虚地相信，非常令人兴奋），提供了证据 通过我们的简单反义寡脱氧核苷酸（Oligo）抑制P21 转染技术导致明显抑制肿瘤血管生成，为 以及肿瘤的生长，在体内动物模型的乳腺癌模型中。这 我们希望在这项研究中引起的兴奋部分是由于 易于给药，缺乏毒性，缺乏表型 p21敲除的变化（表明p21信号的冗余性 肿瘤抑制剂p53的效应子，以及全动物的可能性 这种新颖的反义寡核技术对新目标的应用 用于治疗毁灭性人类疾病的分子。 该重新提交已修改，以应对收到的批评 从上次提交中，通过删除许多机械 实验和工作重点的狭窄到单个CKI，P21， 关于我们拥有最多的数据。明显更多的初步数据是 在此重新提交中提供支持我们假设的假设，我们现在建议 详细检查我们发现了一个令人兴奋的可能性 作用于肿瘤中VSM细胞脚手架的抗血管生成分子 血管生成血管。具体目的是（1）确定最佳 反义的CKI寡素是生长抑制，促凋亡促进性或 抗血管生成； （2）确定局部p21反义寡素的效果 关于肿瘤细胞生长，并在注射转移性的小鼠中系统地 肿瘤细胞； （3）开始研究抗血管生成的机制 反义p21寡聚的作用。 我们认为，本应用程序中实验的完成将完全 在哺乳动物癌症领域验证对P21的反义寡聚的使用 并将不仅导致足够的数据提交资金R01申请， 但是，更重要的是，要进一步动物，最终是人类的p21试验 作为人类癌症中可行的治疗辅助治疗的抑制作用。

项目成果

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
• 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

Attenuation of PTEN increases p21 stability and cytosolic localization in kidney cancer cells: a potential mechanism of apoptosis resistance.

• DOI: 10.1186/1476-4598-6-16
• 发表时间: 2007-02-14
• 期刊: Molecular cancer
• 影响因子: 37.3
• 作者: Lin PY;Fosmire SP;Park SH;Park JY;Baksh S;Modiano JF;Weiss RH
• 通讯作者: Weiss RH

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