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: 6463655
• 负责人: ROBERT H. WEISS
• 金额: $ 14.84万
• 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/6463655
• 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)： 这是一个专注于细胞周期蛋白激酶的申请的重新提交。 抑制物(CKIs)作为癌症治疗的新的潜在靶点。而当 直到最近，研究范式一直认为，这些蛋白质仅作为 细胞生长抑制因子，我们最近发表的工作表明，CKI p21 WAFL/CIPL在某些条件下和某些细胞类型下允许 对血管平滑肌(VSM)细胞生长的影响，导致我们提出 这类分子作为癌症化疗的新的潜在靶点。 自从第一次提交这份申请以来，我们获得了新的数据 进一步证实该分子是这样的靶子。此外，我们还有更多 新的(我们谦虚地相信，非常令人兴奋的)数据提供了证据 我们的简单反义寡核苷酸对p21的抑制作用 转基因技术显著抑制肿瘤血管生成，AS 以及肿瘤的生长，在乳腺癌的活体动物模型中。这个 我们希望在这项研究中激动人心的部分原因是 易于给药，无毒性，无表型 P21基因敲除的变化(提示p21作为 肿瘤抑制基因P53的效应因子)，以及对整个动物的可能性 这一新的反义寡核苷酸技术在针对新靶点的应用 治疗一种毁灭性人类疾病的分子。 根据收到的批评意见，对重新提交的文件进行了修改 从上次提交的文件中，删除了许多机械性的 实验和将工作的重点缩小到一个单一的CKI，p21， 关于这一点，我们有最多的数据。更为初步的数据是 在此重新提交支持我们的假设，我们现在建议 仔细研究一下我们发现了一种令人兴奋的可能性 作用于肿瘤VSM细胞支架上的抗血管生成分子 血管新生血管。具体目标是：(1)确定最优的依据 反义CKI寡核苷酸具有抑制生长、促进细胞凋亡或 抗血管生成；(2)局部检测p21反义寡核苷酸的作用 对肿瘤细胞生长和全身注射转移瘤小鼠的影响 肿瘤细胞；(3)开始研究抗血管生成的机制 反义p21寡核苷酸的作用。 我们相信，完成本应用程序中的实验将完全 验证p21反义寡核苷酸在哺乳动物肿瘤领域的应用 并将不仅导致有足够的数据来提交可资助的R01申请， 但是，更重要的是，进一步的动物试验，最终是对p21的人体试验。 抑制作为一种可行的人类癌症治疗辅助手段。